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Moffitt, Laura, Nazanin Karimnia, Andrew Stephens, and Maree Bilandzic. "Therapeutic Targeting of Collective Invasion in Ovarian Cancer." International Journal of Molecular Sciences 20, no. 6 (March 22, 2019): 1466. http://dx.doi.org/10.3390/ijms20061466.
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Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. Each histotype differs in etiology, pathogenesis, molecular biology, risk factors, and prognosis. Furthermore, the origin of ovarian cancer remains unclear, with ovarian involvement secondary to the contribution of other gynaecological tissues. Despite these complexities, the disease is often treated as a single entity, resulting in minimal improvement to survival rates since the introduction of platinum-based chemotherapy over 30 years ago. Despite concerted research efforts, ovarian cancer remains one of the most difficult cancers to detect and treat, which is in part due to the unique mode of its dissemination. Ovarian cancers tend to invade locally to neighbouring tissues by direct extension from the primary tumour, and passively to pelvic and distal organs within the peritoneal fluid or ascites as multicellular spheroids. Once at their target tissue, ovarian cancers, like most epithelial cancers including colorectal, melanoma, and breast, tend to invade as a cohesive unit in a process termed collective invasion, driven by specialized cells termed “leader cells”. Emerging evidence implicates leader cells as essential drivers of collective invasion and metastasis, identifying collective invasion and leader cells as a viable target for the management of metastatic disease. However, the development of targeted therapies specifically against this process and this subset of cells is lacking. Here, we review our understanding of metastasis, collective invasion, and the role of leader cells in ovarian cancer. We will discuss emerging research into the development of novel therapies targeting collective invasion and the leader cell population.
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Jeong, Miran, Yi-Yue Wang, Ju-Yeon Choi, Myong Cheol Lim, and Jung-Hye Choi. "CC Chemokine Ligand 7 Derived from Cancer-Stimulated Macrophages Promotes Ovarian Cancer Cell Invasion." Cancers 13, no. 11 (June 1, 2021): 2745. http://dx.doi.org/10.3390/cancers13112745.
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In the tumor microenvironment, macrophages have been suggested to be stimulated by tumor cells, becoming tumor-associated macrophages that promote cancer development and progression. We examined the effect of these macrophages on human ovarian cancer cell invasion and found that conditioned medium of macrophages stimulated by ovarian cancer cells (OC-MQs) significantly increased cell invasion. CC chemokine ligand 7 (CCL7) expression and production were significantly higher in OC-MQs than in the control macrophages. Peritoneal macrophages from patients with ovarian cancer showed higher CCL7 expression levels than those from healthy controls. Inhibition of CCL7 using siRNA and neutralizing antibodies reduced the OC-MQ-CM-induced ovarian cancer cell invasion. CC chemokine receptor 3 (CCR3) was highly expressed in human ovarian cancer cells, and a specific inhibitor of this receptor reduced the OC-MQ-CM-induced invasion. Specific signaling and transcription factors were associated with enhanced CCL7 expression in OC-MQs. CCL7-induced invasion required the expression of matrix metalloproteinase 9 via activation of extracellular signal-related kinase signaling in human ovarian cancer cells. These data suggest that tumor-associated macrophages can affect human ovarian cancer metastasis via the CCL7/CCR3 axis.
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Sun, Ningxia, Qing Zhang, Chen Xu, Qian Zhao, Yan Ma, Xinmei Lu, Liang Wang, and Wen Li. "Molecular regulation of ovarian cancer cell invasion." Tumor Biology 35, no. 11 (August 15, 2014): 11359–66. http://dx.doi.org/10.1007/s13277-014-2434-7.
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Chan, Clara K., Yinghong Pan, Kendra Nyberg, Marco A. Marra, Emilia L. Lim, Steven J. M. Jones, Dianna Maar, et al. "Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour." Open Biology 6, no. 11 (November 2016): 160275. http://dx.doi.org/10.1098/rsob.160275.
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The activities of pathways that regulate malignant transformation can be influenced by microRNAs (miRs). Recently, we showed that increased expression of five tumour-suppressor miRs, miR-508-3p, miR-508-5p, miR-509-3p, miR-509-5p and miR-130b-3p, correlate with improved clinical outcomes in human ovarian cancer patients, and that miR-509-3p attenuates invasion of ovarian cancer cell lines. Here, we investigate the mechanism underlying this reduced invasive potential by assessing the impact of these five miRs on the physical properties of cells. Human ovarian cancer cells (HEYA8, OVCAR8) that are transfected with miR mimics representing these five miRs exhibit decreased invasion through collagen matrices, increased cell size and reduced deformability as measured by microfiltration and microfluidic assays. To understand the molecular basis of altered invasion and deformability induced by these miRs, we use predicted and validated mRNA targets that encode structural and signalling proteins that regulate cell mechanical properties. Combined with analysis of gene transcripts by real-time PCR and image analysis of F-actin in single cells, our results suggest that these tumour-suppressor miRs may alter cell physical properties by regulating the actin cytoskeleton. Our findings provide biophysical insights into how tumour-suppressor miRs can regulate the invasive behaviour of ovarian cancer cells, and identify potential therapeutic targets that may be implicated in ovarian cancer progression.
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Li, Chanjuan, Hongjuan Ding, Jing Tian, Lili Wu, Yun Wang, Yuan Xing, and Min Chen. "Forkhead Box Protein C2 Promotes Epithelial-Mesenchymal Transition, Migration and Invasion in Cisplatin-Resistant Human Ovarian Cancer Cell Line (SKOV3/CDDP)." Cellular Physiology and Biochemistry 39, no. 3 (2016): 1098–110. http://dx.doi.org/10.1159/000447818.
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Background/Aims: Forkhead Box Protein C2 (FOXC2) has been reported to be overexpressed in a variety of human cancers. However, it is unclear whether FOXC2 regulates epithelial-mesenchymal transition (EMT) in CDDP-resistant ovarian cancer cells. The aim of this study is to investigate the effects of FOXC2 on EMT and invasive characteristics of CDDP-resistant ovarian cancer cells and the underlying molecular mechanism. Methods: MTT, Western blot, scratch wound healing, matrigel transwell invasion, attachment and detachment assays were performed to detect half maximal inhibitory concentration (IC50) of CDDP, expression of EMT-related proteins and invasive characteristics in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) and its parental cell line (SKOV3). Small hairpin RNA (shRNA) was used to knockdown FOXC2 and analyze the effect of FOXC2 knockdown on EMT and invasive characteristics of SKOV3/CDDP cells. Also, the effect of FOXC2 upregulation on EMT and invasive characteristics of SKOV3 cells was analyzed. Furthermore, the molecular mechanism underlying FOXC2-regulating EMT in ovarian cancer cells was determined. Results: Compared with parental SKOV3 cell line, SKOV3/CDDP showed higher IC50 of CDDP (43.26μM) (P<0.01) and acquired EMT phenotype and invasive characteristics. Gain- and loss-of-function assays indicated that shRNA-mediated FOXC2 knockdown could reverse EMT and reduce the capacity of migration, invasion, attachment and detachment in SKOV3/CDDP cell line and upregulation of FOXC2 could induce the reverse effects in parental SKOV3 cell line. Furthermore, it was found that activation of ERK or AKT/GSK-3β signaling pathways was involved in FOXC2-promoting EMT in CDDP-resistant ovarian cancer cells. Conclusions: Taken together, these data demonstrate that FOXC2 may be a promoter of EMT phenotype in CDDP-resistant ovarian cancer cells and a potential therapeutic target for the treatment of advanced ovarian cancer.
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Jeong, Bo Young, Kyung Hwa Cho, Se-Hee Yoon, Chang Gyo Park, Hwan-Woo Park, and Hoi Young Lee. "Discoidin Domain Receptor 2 Mediates Lysophosphatidic Acid-Induced Ovarian Cancer Aggressiveness." International Journal of Molecular Sciences 22, no. 10 (May 20, 2021): 5374. http://dx.doi.org/10.3390/ijms22105374.
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Lysophosphatidic acid (LPA), a bioactive lipid produced extracellularly by autotaxin (ATX), has been known to induce various pathophysiological events, including cancer cell invasion and metastasis. Discoidin domain receptor 2 (DDR2) expression is upregulated in ovarian cancer tissues, and is closely associated with poor clinical outcomes in ovarian cancer patients. In the present study, we determined a critical role and signaling cascade for the expression of DDR2 in LPA-induced ovarian cancer cell invasion. We also found ectopic expression of ATX or stimulation of ovarian cancer cells with LPA-induced DDR2 expression. However, the silencing of DDR2 expression significantly inhibited ATX- and LPA-induced ovarian cancer cell invasion. In addition, treatment of the cells with pharmacological inhibitors of phosphoinositide 3-kinase (PI3K), Akt, and mTOR abrogated LPA-induced DDR2 expression. Moreover, we observed that HIF-1α, located downstream of the mTOR, is implicated in LPA-induced DDR2 expression and ovarian cancer cell invasion. Finally, we provide evidence that LPA-induced HIF-1α expression mediates Twist1 expression to upregulate DDR2 expression. Collectively, the present study demonstrates that ATX, and thereby LPA, induces DDR2 expression through the activation of the PI3K/Akt/mTOR/HIF-1α/Twist1 signaling axes, aggravating ovarian cancer cell invasion.
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Lokman, Noor A., Zoe K. Price, Emily K. Hawkins, Anne M. Macpherson, Martin K. Oehler, and Carmela Ricciardelli. "4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer." Cancers 11, no. 8 (August 15, 2019): 1187. http://dx.doi.org/10.3390/cancers11081187.
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We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.
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Zhou, Hong Y., Yuen L. Pon, and Alice S. T. Wong. "Synergistic Effects of Epidermal Growth Factor and Hepatocyte Growth Factor on Human Ovarian Cancer Cell Invasion and Migration: Role of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase." Endocrinology 148, no. 11 (November 1, 2007): 5195–208. http://dx.doi.org/10.1210/en.2007-0361.
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Ovarian cancer is the primary cause of death from gynecological malignancies with a poor prognosis characterized by widespread peritoneal dissemination. However, mechanisms of invasion and metastasis in ovarian cancer remain poorly understood. Epidermal growth factor (EGF) and hepatocyte growth factor (HGF) are often both overexpressed and contribute to the growth of ovarian cancer by activating autocrine pathways. In the present study, we investigated the mechanisms of invasive activity of EGF, HGF, and their synergistic effects in human ovarian cancer cells. Here our data suggest that EGF and HGF may use unique and overlapping signaling cascades leading to the invasive phenotype. We revealed that HGF-mediated cell migration and invasion required the coordinate activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2. Although EGF-dependent invasive phenotype appeared to have similar requirements for phosphatidylinositol 3-kinase, this growth factor used the alternative p38 MAPK pathway for cell invasion. A significant role of p38 MAPK was further supported by the observation that expression of dominant negative p38 MAPK likewise inhibited EGF-dependent invasiveness and cell motility. We also showed that EGF cooperated with HGF to promote a highly invasive phenotype via the increased secretion of matrix metalloproteinase (MMP)-9. The coincident induction of MMP-9 was functionally significant because inclusion of MMP-9 inhibitor or an anti-MMP-9 neutralizing antibody abolished EGF- and HGF-induced cellular invasion. These findings provide insights into the mechanism of the malignant progression of ovarian cancer.
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Qiu, Xin, Jung-Chien Cheng, Hsun-Ming Chang, and Peter C. K. Leung. "COX2 and PGE2 mediate EGF-induced E-cadherin-independent human ovarian cancer cell invasion." Endocrine-Related Cancer 21, no. 4 (August 2014): 533–43. http://dx.doi.org/10.1530/erc-13-0450.
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Elevated expression of cyclooxygenase 2 (COX2 (PTGS2)) has been reported to occur in human ovarian cancer and to be associated with poor prognosis. We have previously demonstrated that COX2-derived prostaglandin E2 (PGE2) promotes human ovarian cancer cell invasion. We had also demonstrated that epidermal growth factor (EGF) induces human ovarian cancer cell invasion by downregulating the expression of E-cadherin through various signaling pathways. However, it remains unclear whether COX2 and PGE2 are involved in the EGF-induced downregulation of E-cadherin expression and cell invasion in human ovarian cancer cells. In this study, we showed that EGF treatment induces COX2 expression and PGE2 production in SKOV3 and OVCAR5 human ovarian cancer cell lines. Interestingly, COX2 is not required for the EGF-induced downregulation of E-cadherin expression. In addition, EGF treatment activates the phosphatidylinositol-3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling pathways, while only the PI3K/Akt pathway is involved in EGF-induced COX2 expression. Moreover, we also showed that EGF-induced cell invasion is attenuated by treatment with a selective COX2 inhibitor, NS-398, as well as PGE2 siRNA. This study demonstrates an important role for COX2 and its derivative, PGE2, in the mediation of the effects of EGF on human ovarian cancer cell invasion.
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Huang, Lu, Shanshan Xu, Dongxiao Hu, Weiguo Lu, Xing Xie, and Xiaodong Cheng. "IQGAP1 Is Involved in Enhanced Aggressive Behavior of Epithelial Ovarian Cancer Stem Cell-Like Cells During Differentiation." International Journal of Gynecologic Cancer 25, no. 4 (May 2015): 559–65. http://dx.doi.org/10.1097/igc.0000000000000394.
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BackgroundWide metastasis is one of characteristics of ovarian cancer. Cancer stem cells, as a source in cancer invasion and metastasis, possess powerful potential of differentiation. Scaffolding IQ domain GTPase-activating protein 1 (IQGAP1) plays a key role in the invasion and metastasis of cancer cells, but IQGAP1’s role in cancer stem cells including ovarian cancer was unclear.MethodsSpheroid culture with serum-free medium was used for enriching ovarian cancer stem cell-like cells (CSC-LCs) from 3AO cell line, and a medium with 10% fetal bovine serum was used to induce the differentiation of CSC-LCs. Immunofluorescence was for detecting the stem markers OCT4 and SOX2. The quantitative real-time-polymerase chain reaction and Western blotting were performed to determine the messenger RNA and protein expression of IQGAP1, respectively. The capacity of cell invasion was evaluated by transwell chamber assay.ResultsOvarian CSC-LCs obtained through spheroid culture showed irregularly elongated appearance, CD24 negative, and OCT4 and SOX2 positive. IQGAP1 expression was decreased in ovarian CSC-LCs compared with parental 3AO cells, but increased de novo during the differentiation of CSC-LCs. Knockdown of IQGAP1 by specific small interfering RNA remarkably weakened invasion capacity of 2-day differentiated ovarian CSC-LCs.ConclusionsIncreased IQGAP1 expression during the differentiation of CSC-LCs is involved in an aggressive cell behavior, which may contribute to metastasis of ovarian cancer.
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Bilandzic, Maree, Adam Rainczuk, Emma Green, Nicole Fairweather, Thomas W. Jobling, Magdalena Plebanski, and Andrew N. Stephens. "Keratin-14 (KRT14) Positive Leader Cells Mediate Mesothelial Clearance and Invasion by Ovarian Cancer Cells." Cancers 11, no. 9 (August 22, 2019): 1228. http://dx.doi.org/10.3390/cancers11091228.
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Epithelial ovarian cancer metastasis is driven by spheroids, which are heterogeneous cancer cell aggregates released from the primary tumour mass that passively disseminate throughout the peritoneal cavity to promote tumour spread, disease recurrence, and acquired chemoresistance. Despite their clinical importance, the molecular events that control spheroid attachment and invasion into underlying healthy tissues remain poorly understood. We examined a novel in vitro invasion model using imaging mass spectrometry to establish a “snapshot” of the spheroid/mesothelial interface. Amongst numerous adhesion-related proteins, we identified a sub-population of highly motile, invasive cells that expressed the basal epithelial marker KRT14 as an absolute determinant of invasive potential. The loss of KRT14 completely abrogated the invasive capacity, but had no impact on cell viability or proliferation, suggesting an invasion-specific role. Our data demonstrate KRT14 cells as an ovarian cancer “leader cell” phenotype underlying tumor invasion, and suggest their importance as a clinically relevant target in directed anti-tumour therapies.
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Xing, Xuefeng, Ming An, and Tonghua Chen. "LncRNA SNHG20 promotes cell proliferation and invasion by suppressing miR-217 in ovarian cancer." Genes & Genomics 43, no. 9 (July 24, 2021): 1095–104. http://dx.doi.org/10.1007/s13258-021-01138-4.
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Abstract Background Ovarian cancer is the most common female gynecological malignancy. SNHG20, as a long non-coding RNA, has been proven to be an important regulator in the occurrence and development of various tumors. However, the potential mechanism of SNHG20 in ovarian cancer is unclear. Objective The present study was aimed to investigate the functions and mechanisms of SNHG20 in ovarian cancer. Methods The expression of SNHG20 and miR-217 in ovarian cancer tissues and cell lines was detected by qRT-PCR. CCK-8 assay was used to measure cell proliferation in transfected cells. The transwell assay was used to detect the relative invasion rate of transfected cells. The putative binding sites between SNHG20 and miR-217 were predicted by software LncBase v.2, and the interaction between SNHG20 and miR-217 was confirmed by dual-luciferase reporter assays and RIP assay. The rescue experiments were used to illustrate potential mechanisms. Results SNHG20 was upregulated in ovarian cancer tissues and cell lines. Overexpression of SNHG20 promoted ovarian cancer cell proliferation and invasion. MiR-217 was downregulated in ovarian cancer tissues and cells, and was negatively regulated by SNHG20. Moreover, miR-217 overexpression inhibited ovarian cancer cell proliferation and invasion. Furthermore, miR-217 mimic reversed the inhibitory effect of SNHG20 overexpression on the biological behavior of ovarian cancer cells. Conclusions SNHG20 promoted cell proliferation and invasion by sponging miR-217 in ovarian cancer. These results suggested that SNHG20 and miR-217 might provide new targets for therapeutic application in ovarian cancer.
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Siu, Michelle K. Y., Yu-Xin Jiang, Jing-Jing Wang, Thomas H. Y. Leung, Chae Young Han, Benjamin K. Tsang, Annie N. Y. Cheung, Hextan Y. S. Ngan, and Karen K. L. Chan. "Hexokinase 2 Regulates Ovarian Cancer Cell Migration, Invasion and Stemness via FAK/ERK1/2/MMP9/NANOG/SOX9 Signaling Cascades." Cancers 11, no. 6 (June 12, 2019): 813. http://dx.doi.org/10.3390/cancers11060813.
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Metabolic reprogramming is a common phenomenon in cancers. Thus, glycolytic enzymes could be exploited to selectively target cancer cells in cancer therapy. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in glucose metabolism. Here, we demonstrated that HK2 was overexpressed in ovarian cancer and displayed significantly higher expression in ascites and metastatic foci. HK2 expression was significantly associated with advanced stage and high-grade cancers, and was an independent prognostic factor. Functionally, knockdown of HK2 in ovarian cancer cell lines and ascites-derived tumor cells hindered lactate production, cell migration and invasion, and cell stemness properties, along with reduced FAK/ERK1/2 activation and metastasis- and stemness-related genes. 2-DG, a glycolysis inhibitor, retarded cell migration and invasion and reduced stemness properties. Inversely, overexpression of HK2 promoted cell migration and invasion through the FAK/ERK1/2/MMP9 pathway, and enhanced stemness properties via the FAK/ERK1/2/NANOG/SOX9 cascade. HK2 abrogation impeded in vivo tumor growth and dissemination. Notably, ovarian cancer-associated fibroblast-derived IL-6 contributed to its up-regulation. In conclusion, HK2, which is regulated by the tumor microenvironment, controls lactate production and contributes to ovarian cancer metastasis and stemness regulation via FAK/ERK1/2 signaling pathway-mediated MMP9/NANOG/SOX9 expression. HK2 could be a potential prognostic marker and therapeutic target for ovarian cancer.
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Wang, Xuan, Yan Wang, Guichan Wang, and Peishu Liu. "miR-29b regulates cell proliferation and invasion in human ovarian clear cell carcinoma by targeting Lysyl oxidase (LOX)." Archives of Biological Sciences 68, no. 1 (2016): 155–63. http://dx.doi.org/10.2298/abs150420020w.
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Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its chemoresistance and frequent late diagnosis, and suggesting that a more effective treatment approach is needed. Lysyl oxidase (LOX) is involved in important biological processes such as gene regulation, cell signaling and cell motility, its deregulation contributing to tumor formation and development. Although it is known that LOX is involved in proliferation, migration and invasion in several types of tumors, studies of LOX in ovarian cancers are scarce. To explore the molecular regulation mechanisms in ovarian cancer tumorigenesis, the expression change and the function of LOX was confirmed in ovarian tissues and cells, which suggested that LOX is a tumor suppressor gene. To further understand how LOX expression is regulated in ovarian cancer, microRNAs(miRNAs) were considered because of their role in post-transcriptional regulation of many genes. Recent work has described differential expression of mature miRNAs in human cancers. Bioinformatics prediction which was used to find the appropriate miRNA regulating LOX, revealed that miR-29b regulates LOX protein level via its binding site on the 3'UTR of LOX mRNAin ES-2 cells, a human ovarian clear cell carcinoma cell line. miR-29b knockdown inhibited proliferation and invasion in ES-2 cells. Taken together, these findings suggest that influencing LOX regulation bychanging the level of miR-29b expression could provide a novel potential approachfor treating human ovarian clear cell carcinoma.
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Gogoi, R., M. Kudla, O. Gill, K. Horwitz, and D. Fishman. "The activity of the synthetic progestin medroxyprogesterone acetate on the invasive phenotype of ovarian cancer cells." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 16003. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.16003.
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16003 Background: Androgens play an integral role in the physiologic and pathologic processes of the ovary. Yet it has been difficult to study the role of the androgen recptors (AR) separately from the other steroid receptors such as the progesterone receptor (PR) in ovarian cancer. This has been made more complicated because most synthetic progestins such as Medroxyprogesterone acetate (MPA) bind both PR and AR. The objectives of our study were: 1. To create an ovarian cancer cell line constitutively expressing only AR. 2. To compare the role of AR activated by the synthetic progestin MPA vs. the pure androgen dihydrotestosterone (DHT) on the invasiveness of human breast and ovarian cancer cells. 3. To investigate the role of matrix metalloproteases (MMP's) associated with invasion. Methods: ER- and PR- human breast (T47D-Y) and ovarian (OvCa 429) cancer cells were engineered to stably express AR. Immunocytochemistry and western blot analyses confirmed that these breast and ovarian cancer cell lines (called Y-AR and OvCa-AR respectively) are PR-, but AR+. Boyden chamber invasion assays were performed using Y-AR and OvCa-AR cells treated with either vehicle, MPA or DHT. The MMP's associated with invasion were further investigated using zymographic assays. Results: AR activation by either MPA or DHT increased the invasive potential of both breast (p<0.05) and ovarian cancer cells with MPA being significantly more effective than DHT at stimulating invasion. However, regardless of the ligand, activation of AR increases tumor cell invasion. To elucidate the MMP's associated with this activation in OvCa-AR cells, we used zymographic analysis. Interestingly, we found that MPA activation of AR decreases both the total level and activation of MMP-9 compared to DHT and vehicle control. Conclusions: Using our model system we are able to study the role of AR independent of PR on the biology of breast and ovarian cancer cells. Our studies suggest that the use of pharmacological doses of synthetic progestins may actually increase the invasive potential of ovarian cancer cells through AR. We hypothesize that blockade of downstream AR targets or the use of selective AR modulators (SARMS) may be of therapeutic value in the treatment of ovarian cancer. No significant financial relationships to disclose.
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Bao, Huijing, Qianyu Huo, Qin Yuan, and Chen Xu. "Fibronectin 1: A Potential Biomarker for Ovarian Cancer." Disease Markers 2021 (May 22, 2021): 1–11. http://dx.doi.org/10.1155/2021/5561651.
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Object. Ovarian cancer is one of the most common cancers among females with high mortality rate, due to most patients diagnosed at the advanced stage of the disease. Seeking new biomarkers for ovarian cancer detection and progress indication is really important for the patients. Methods. OVCAR3 and A2780 are the two common cell lines that are used for ovarian cancer studies. The different invasion and migration abilities were observed by scratch tests and transwell experiments in our preliminary study. Gene chip was used to screen the expression gene in these two different cell lines, and then, the differentially expressed genes (at least 2-fold difference, P value < 0.05) were analyzed using KEGG. Result. Fibronectin 1 (FN1) was found to be the most strongly correlated with the invasion and migration abilities of the OVCAR3 cells. Real-time PCR and FN1 knockout cell line was conducted and confirmed this finding. Based on the Oncomine database analysis, comparing with normal people, ovarian cancer patients exhibited high levels of FN1 expression. Additionally, higher FN1 expression was found in patients with higher FIGO stages of cancer. Conclusion. FN1 could be a new biomarker for ovarian cancer detection and progress indicator.
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Wang, Ying-Chun, Yi-Nan Wu, Su-Li Wang, Qing-Hua Lin, Ming-Fang He, Qiao-lin Liu, and Jin-Hua Wang. "Docosahexaenoic Acid Modulates Invasion and Metastasis of Human Ovarian Cancer via Multiple Molecular Pathways." International Journal of Gynecologic Cancer 26, no. 6 (July 2016): 994–1003. http://dx.doi.org/10.1097/igc.0000000000000746.
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ObjectiveWe investigated the effect of docosahexaenoic acid (DHA) on the invasion and metastasis of ovarian cancer cells (A2780, HO8910, and SKOV-3).MethodsCytotoxicity assay was performed to determine the optimal doses of DHA in this experiment. The effects of DHA on invasion ability were assessed by invasion assay. The expressions of messenger RNA and/or proteins associated with invasion or metastasis were detected by quantitative Real Time-Polymerase Chain Reaction or Western blot. The effect of DHA on cell metastasis was assessed in xenograft model of zebrafish.ResultsDocosahexaenoic acid and α-linolenic acid could reduce the cell vitalities in dose-dependent manner. However, DHA inhibited the invasion and metastasis of ovarian cancer cells, but α-linolenic acid did not (**P < 0.01). Docosahexaenoic acid could downregulate the expressions of WAVE3, vascular endothelial cell growth factor, and MMP-9, and upregulate KISS-1, TIMP-1, and PPAR-γ, which negatively correlated with cell invasion and metastasis (*P < 0.05). Docosahexaenoic acid restrained the development of subintestinal vessels and cancer cell metastasis in xenograft model of zebrafish (**P < 0.01).ConclusionsDocosahexaenoic acid inhibited the invasion and metastasis of ovarian cancer cells in vitro and in vivo through the modulation of NF-κB signaling pathway, suggesting that DHA is a promising candidate for ovarian cancer therapy.
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Basu, Moitri, Satinath Mukhopadhyay, Uttara Chatterjee, and Sib Sankar Roy. "FGF16 Promotes Invasive Behavior of SKOV-3 Ovarian Cancer Cells through Activation of Mitogen-activated Protein Kinase (MAPK) Signaling Pathway." Journal of Biological Chemistry 289, no. 3 (November 19, 2013): 1415–28. http://dx.doi.org/10.1074/jbc.m113.535427.
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Uncontrolled cell growth and tissue invasion define the characteristic features of cancer. Several growth factors regulate these processes by inducing specific signaling pathways. We show that FGF16, a novel factor, is expressed in human ovary, and its expression is markedly increased in ovarian tumors. This finding indicated possible involvement of FGF16 in ovarian cancer progression. We observed that FGF16 stimulates the proliferation of human ovarian adenocarcinoma cells, SKOV-3 and OAW-42. Furthermore, through the activation of FGF receptor-mediated intracellular MAPK pathway, FGF16 regulates the expression of MMP2, MMP9, SNAI1, and CDH1 and thus facilitates cellular invasion. Inhibition of FGFR as well as MAPK pathway reduces the proliferative and invasive behavior of ovarian cancer cells. Moreover, ovarian tumors with up-regulated PITX2 expression also showed activation of Wnt/β-catenin pathway that prompted us to investigate possible interaction among FGF16, PITX2, and Wnt pathway. We identified that PITX2 homeodomain transcription factor interacts with and regulates FGF16 expression. Furthermore, activation of the Wnt/β-catenin pathway induces FGF16 expression. Moreover, FGF16 promoter possesses the binding elements of PITX2 as well as T-cell factor (Wnt-responsive), in close proximity, where PITX2 and β-catenin binds to and synergistically activates the same. A detail study showed that both PITX2 and T-cell factor elements and the interaction with their binding partners are necessary for target gene expression. Taken together, our findings indicate that FGF16 in conjunction with Wnt pathway contributes to the cancer phenotype of ovarian cells and suggests that modulation of its expression in ovarian cells might be a promising therapeutic strategy for the treatment of invasive ovarian cancers.
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Shen, Yufei, Rong Shen, Lili Ge, Qiaoying Zhu, and Fengshan Li. "Fibrillar Type I Collagen Matrices Enhance Metastasis/Invasion of Ovarian Epithelial Cancer Via β1 Integrin and PTEN Signals." International Journal of Gynecologic Cancer 22, no. 8 (October 2012): 1316–24. http://dx.doi.org/10.1097/igc.0b013e318263ef34.
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ObjectiveThis study investigated the involvement of fibrillar collagen in remodeling extracellular matrices (ECM) and its significant impact on the metastasis/invasion of epithelial ovarian cancer cells via β1 integrin/phosphatase and tensin homolog (PTEN) signaling.Materials/MethodsNormal ovarian surface epithelium tissues (n = 13), ovarian cancer tissues (n = 28), ovarian cancer cell lines, and a 3-dimensional model of fibrillar type I collagen that mimicked pathological ECM in vivo were used in the study. We explored the specific mechanisms behind ECM remodeling and the cellular signals that affected the invasion of ovarian cancer cells.ResultsThe data showed that increased β1 integrin expression in ovarian cancer cells led to enhance migration/invasion of ovarian cancer cells via regulation of PTEN/protein kinase B (Akt) signal in response to fibrillar type I collagen matrices. Low PTEN activity corresponded to the following: (1) increased PTEN degradation and (2) phosphorylation of PTEN. Decreased protein phosphatase 2A activity was detected in ovarian cancer. Protein phosphatase 2A might play a role in enhancing the progression of ovarian cancer through regulating PTEN/Akt signal.ConclusionThese findings indicate that fibrillar type I collagen, by modulating integrin-PTEN/PI3K/Akt signaling pathway in remodeling ECM, is very important in affecting the invasion of aggressive ovarian cancer cells. Moreover, these data provide direct evidence for pathological ECM remodeling and cell signaling networks involved in the invasion of ovarian cancer cells.
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Li, Yi, Ming Xiao, and Fangchun Guo. "The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis." Tumor Biology 39, no. 5 (May 2017): 101042831770550. http://dx.doi.org/10.1177/1010428317705508.
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SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.
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Wang, Liye, Shuang Zhou, and Bin Guo. "Vitamin D Suppresses Ovarian Cancer Growth and Invasion by Targeting Long Non-Coding RNA CCAT2." International Journal of Molecular Sciences 21, no. 7 (March 27, 2020): 2334. http://dx.doi.org/10.3390/ijms21072334.
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Ovarian cancer is the most deadly gynecologic cancer among women worldwide. Poor response to current treatment makes it necessary to discover new diagnostic biomarkers to detect the cancer early and develop new and effective prevention strategies. Calcitriol, the active metabolite of vitamin D, protects against multiple cancers through unelucidated mechanisms. The oncogenic long non-coding RNA (lncRNA) CCAT2 (colon cancer associated transcript 2) is overexpressed in ovarian cancer. Here, we foundd that calcitriol inhibited CCAT2 expression in ovarian cancer cell lines. Treatment with calcitriol inhibited ovarian cancer cell proliferation, migration, and invasion. As a result of CCAT2 inhibition, calcitriol decreased the binding of transcription factor TCF7L2 (TCF4) to the MYC promoter, resulting in the repression of c-Myc protein expression. Our results suggest a novel anti-cancer mechanism of vitamin D by targeting CCAT2 in ovarian cancer. The findings may help develop vitamin D as a practical and inexpensive nutraceutical for ovarian cancer prevention.
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Cheng, Lei, Jie Jiang, Ran Gao, Shuangyan Wei, Fangfang Nan, Shaoru Li, and Beihua Kong. "B7-H4 Expression Promotes Tumorigenesis in Ovarian Cancer." International Journal of Gynecologic Cancer 19, no. 9 (November 2009): 1481–86. http://dx.doi.org/10.1111/igc.0b013e3181ad0fa2.
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Introduction:It has been previously shown that B7-H4, one of the B7 family members that serve as negative regulators of T cell function, has altered expression levels in a variety of cancers, overexpression of B7-H4 promotes cellular transformation. However, there is still lack of adequate evidence to establish a direct connection between B7-H4 expression and malignant transformation.Methods:Herein, we constructed pE-green fluorescent protein-N1/B7-H4 mammalian expression vector and transfected into B7-H4-negative human ovarian cancer cell line SKOV3. Cellular proliferation, apoptosis, adhesion, motility, and invasion were examined in vitro. Cells injected subcutaneously into severe combined immunodeficient mouse were analyzed for the possible functions of B7-H4 in ovarian tumorigenesis in vivo.Results:Fluorescence microscopy studies confirmed that the B7-H4-green fluorescent protein localizes in the cytoplasm of SKOV3/B7-H4 cells, whereas green fluorescent protein is uniformly distributed throughout the cell. B7-H4 promoted cellular proliferation rate and increased cell adhesion, migration, and invasion. In addition, SKOV3 cells expressing B7-H4 gained growth advantage in the xenograft model in vivo.Conclusions:These studies demonstrate that B7-H4 directly promotes malignant transformation of ovarian cancer cell line, and provides a potential therapeutic strategy for targeting B7-H4 to inhibit progression of human ovarian cancers.
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Fleszar, Andrew J., Alyssa Walker, Pamela K. Kreeger, and Jacob Notbohm. "Substrate curvature induces fallopian tube epithelial cell invasion via cell–cell tension in a model of ovarian cortical inclusion cysts." Integrative Biology 11, no. 8 (August 2019): 342–52. http://dx.doi.org/10.1093/intbio/zyz028.
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Abstract Throughout the body, epithelial tissues contain curved features (e.g. cysts, ducts and crypts) that influence cell behaviors. These structures have varied curvature, with flat structures having zero curvature and structures such as crypts having large curvature. In the ovary, cortical inclusion cysts (CICs) of varying curvatures are found, and fallopian tube epithelial (FTE) cells have been found trapped within these cysts. FTE are the precursor for ovarian cancer, and the CIC niche has been proposed to play a role in ovarian cancer progression. We hypothesized that variations in ovarian CIC curvature that occur during cyst resolution impact the ability of trapped FTE cells to invade into the surrounding stroma. Using a lumen model in collagen gels, we determined that increased curvature resulted in more invasions of mouse FTE cells. To isolate curvature as a system parameter, we developed a novel technique to pattern concave curvatures into collagen gels. When FTE cells were seeded to confluency on curved substrates, increases in curvature increased the number of invading FTE cells and the invasion distance. FTE invasion into collagen substrates with higher curvature depended on matrix metalloproteinases (MMPs), but expression of collagen I degrading Mmps was not different on curved and flat regions. A finite-element model predicted that contractility and cell–cell connections were essential for increased invasion on substrates with higher curvature, while cell–substrate interactions had minimal effect. Experiments supported these predictions, with invasion decreased by blebbistatin, ethylene glycol-bis(β-aminoethyl ether)-N,N,N’,N’-tetraacetic acid (EGTA) or N-cadherin-blocking antibody, but with no effect from a focal adhesion kinase inhibitor. Finally, experimental evidence supports that cell invasion on curved substrates occurs in two phases—a cell–cell-dependent initiation phase where individual cells break away from the monolayer and an MMP-dependent phase as cells migrate further into the collagen matrix.
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ZHANG, DAN, SHUANG QIU, QI WANG, and JIANHUA ZHENG. "TMPRSS3 modulates ovarian cancer cell proliferation, invasion and metastasis." Oncology Reports 35, no. 1 (October 29, 2015): 81–88. http://dx.doi.org/10.3892/or.2015.4356.
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Zhu, Wei Pei, Ai Hua Gao, Xin Chen, Feng Li, Nan Jiang, and Hong Zhang. "Expression of KiSS-1 in Epithelial Ovarian Cancer and its Role in Metastasis." Applied Mechanics and Materials 140 (November 2011): 142–51. http://dx.doi.org/10.4028/www.scientific.net/amm.140.142.
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Objectives To study expression of KiSS-1 and its role in migration and invasion of ovarian cancer (OC). Methods Expression of KiSS-1 was detected in tissue of 46 cases of OC and 17 cases of benign ovarian neoplasm by immunohistochemistry examination. Human OC cell line HO8910 was transfected by pcDNA3-KiSS-1 vector. The cell proliferation and invasion properties were detected by RT-RCR, MTT, clone formation rate and Boyden Chamber invasion assay. Results (1) Immunostaining showed that expression of KiSS-1protein was significantly higher in OC than that in benign ovarian tumor (P<0.05). (2) KiSS-1 expression was significantly higher in cases of advanced stage and with lymphatic metastasis (P<0.05). KiSS-1 expression was significantly lower in clear cell cancer compared with other histologic types (P<0.05). (3)KiSS-1 gene was successfully integrated into the genomic DNA of ovarian cancer cell line HO8910. Boyden Chamber invasion assay revealed that the number of cells invading through the Matrigel filter was significantly decreased in the transfected group compared with the non-transfected. No differences were observed in cell proliferation between the two groups. Conclusion There was over expression of KiSS-1 in OC compared with that in benign ovarian tumor. The KiSS-1 gene could suppress HO8910 invasion in vitro. To elucidate the contradiction effects of metastasis suppressor genes KiSS-1in vivoandin vitroneeds deeper research.
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Dehghanipour, Somayeh, Sara Saadatmand, Nasim Hayati Roodbari, and Mehdi Mahdavi. "Assessment of Antitumor Activity of Vinca herbacea on Human Ovarian Cancer Cell Line." Immunoregulation 3, no. 2 (January 1, 2021): 115–26. http://dx.doi.org/10.32598/immunoregulation.3.2.6.
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Background: It seems that Vinca. herbacea has an anti-tumor effect. Here, the immunotherapeutic effect of this compound is assessed against human ovarian cancer (SKOV3) cells because of the high incidence of this tumor in women. Materials and Methods: The cytotoxic activity of V. herbacea extract against human ovarian cancer (SKOV3) cells was determined by MTT assay. The apoptosis-inducing potential of V. herbacea extract was investigated using the FITC-V Annexin kit. The Matrigel invasion assay was used to investigate the ability of V. herbacea extract in reducing ovarian cancer cells invasion. Real-time PCR using specific primers was performed to investigate the expression of angiogenesis (VEGFR1, VEGFR2, and VEGF-A), apoptosis (Bcl-2 and Bax), and metastasis (MMP2 and MMP9) genes. Results: V. herbacea caused a significant cytotoxic effect against human ovarian cancer cells in a dose-dependent manner. V. herbacea induced apoptosis in SKOV3 cells through caspase-3 activation and an increase in the expression ratio of Bax/Bcl-2. V. herbacea inhibited cancer cells’ angiogenesis, which was evident by the significant reduction in the expression of angiogenesis-related genes, including VEGF, VEGFR-1, and VEGFR-2. Besides, V. herbacea inhibited cancer cell adhesion and invasion. Conclusion: V. herbacea extract elicits a robust cytostatic effect in SKOV3 cells by modulating the activity and or the expression of proteins regulating the process of cellular apoptosis, adhesion invasion, and angiogenesis.
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Zhang, Xiao, Keqin Yan, Lin Deng, Jing Liang, Haiyan Liang, Dingqing Feng, and Bin Ling. "Cyclooxygenase 2 Promotes Proliferation and Invasion in Ovarian Cancer Cells via the PGE2/NF-κB Pathway." Cell Transplantation 28, no. 1_suppl (December 2019): 1S—13S. http://dx.doi.org/10.1177/0963689719890597.
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Ovarian cancer is the leading cause of death among gynecological malignancies. Cyclooxygenase 2 is widely expressed in various cancer cells and participates in the occurrence and development of tumors by regulating a variety of downstream signaling pathways. However, the function and molecular mechanisms of cyclooxygenase 2 remain unclear in ovarian cancer. Here, we demonstrated that cyclooxygenase 2 was highly expressed in ovarian cancer and the expression level was highly correlated with ovarian tumor grades. Further, ovarian cancer cells with high expression of cyclooxygenase 2 exhibit enhanced proliferation and invasion abilities. Specifically, cyclooxygenase 2 promoted the release of prostaglandin E2 upregulated the phosphorylation levels of phospho-nuclear factor-kappa B p65. Celecoxib, AH6809, and BAY11-7082 all can inhibit the promoting effect of cyclooxygenase 2 on SKOV3 and OVCAR3 cell proliferation and invasion. Besides, celecoxib inhibited SKOV3 cell growth in the xenograft tumor model. These data suggest that high expression of cyclooxygenase 2 promotes the proliferation and invasion of ovarian cancer cells through the prostaglandin E2/nuclear factor-kappa B signaling pathway. Cyclooxygenase 2 may be a potential therapeutic target for the treatment of ovarian cancer.
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Poon, Song Ling, Gareth T. Hammond, and Peter C. K. Leung. "Epidermal Growth Factor-Induced GnRH-II Synthesis Contributes to Ovarian Cancer Cell Invasion." Journal of Clinical Endocrinology & Metabolism 94, no. 9 (September 1, 2009): 3618. http://dx.doi.org/10.1210/jcem.94.9.9996.
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GnRH-II modulates ovarian cancer cells invasion and is expressed in normal ovary and ovarian epithelial cancer cells; however, the upstream regulator(s) of GnRH-II expression in these cells remains unclear. We now demonstrate that epidermal growth factor (EGF) increases GnRH-II mRNA levels in several human ovarian carcinoma cell lines and up-regulates GnRH-II promoter activity in OVCAR-3 cells in a dose-dependent manner, whereas an EGF receptor inhibitor (AG148) abolishes EGF-induced increases in GnRH-II promoter activity and GnRH-II mRNA levels. EGF increases the phosphorylation of cAMP-responsive element-binding protein (p-CREB) and its association with the coregulator, CCAAT/enhancer binding protein β, whereas blocking the EGF-induced ERK1/2 phosphorylation with MAPK inhibitors (PD98059/U0126) markedly reduced these effects. Moreover, depletion of CREB using small interfering RNA attenuated EGF-induced GnRH-II promoter activity. Chromatin immunoprecipitation assays demonstrated that EGF induces p-CREB binding to a cAMP responsive-element within the GnRH-II promoter, likely in association with CCAAT/enhancer binding protein β, and mutagenesis of this cAMP responsive-element prevented EGF-induced GnRH-II promoter activity in OVCAR-3 cells. Importantly, GnRH-II acts additively with EGF to promote invasion of OVCAR-3 and CaOV-3 cells, but not SKOV-3 cells that express low levels of GnRH receptor (GnRHR). Treatment with GnRHR small interfering RNA also partially inhibited the EGF-induced invasion of OVCAR-3 and CaOV-3 cells. Furthermore, EGF treatment transiently increases GnRHR levels in OVCAR-3 and CaOV-3, which likely accentuates the effects of increase GnRH-II production on cell invasion. These results provide evidence that EGF is an upstream regulator of the autocrine actions of GnRH-II on the invasive properties of ovarian cancer cells.
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Li, Diyou, Yinglin Pan, Yating Huang, Ping Zhang, and Xuhong Fang. "PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer." Analytical Cellular Pathology 2018 (September 2, 2018): 1–9. http://dx.doi.org/10.1155/2018/8073124.
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Ovarian cancer is the most lethal gynecologic cancer and currently ranks fifth in causing cancer-related deaths among women. P21cdc42/rac1-activated kinase 5 (PAK5) is a newly identified protein that has been indicated to have oncogenic potential. The present study investigated the expression level of PAK5 in clinical ovarian cancer and the functional roles of PAK5 in ovarian cancer progression. It was initially found that PAK5 was highly expressed in ovarian cancer tissues, particularly in patients with distant metastasis. Higher expression of PAK5 predicted poor survival fates in patients with ovarian cancer (p=0.008). Knockdown of PAK5 in SKOV3 cells caused epithelial cell phenotypes, whereas overexpression of PAK5 led to remarkable mesenchymal cell phenotypes in A2780 cells. When PAK5 was depleted from SKOV3 cells, cells exhibited impaired wound recovery abilities. Cell migration and invasion abilities were also significantly inhibited. On the contrary, when PAK5 was overexpressed in A2780 cells, the wound recovery ability was enhanced by 68%. Cell migration and invasion abilities were consistently increased to approximately 2-fold. After knockdown of PAK5, the phosphorylation levels of PI3K p85 at Tyr458 and its downstream AKT at Ser473 were both decreased. The total protein of PI3K and AKT as well as the phosphorylation level of AKT at Thr308 remained unaffected. These data suggested that PI3K induced epithelial-to-mesenchymal transition and promoted cell migration and invasion by activating the PI3K/AKT pathway in ovarian cancer. The oncogenic potential of PAK5 in ovarian cancer might suggest that any therapeutic strategies targeting PAK5 had the promising value for ovarian cancer treatment.
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Ahn, Ji-Hye, Dae Sik Jang, and Jung-Hye Choi. "Lancemaside A Isolated from the Root of Codonopsis lanceolata Inhibits Ovarian Cancer Cell Invasion via the Reactive Oxygen Species (ROS)-Mediated p38 Pathway." American Journal of Chinese Medicine 48, no. 04 (January 2020): 1021–34. http://dx.doi.org/10.1142/s0192415x20500494.
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Codonopsis lanceolata roots have been widely used in Korean cuisine and traditional medicine. This study aimed to investigate the antimetastatic effects of lancemaside A, a major triterpenoid saponin, isolated from the roots of C. lanceolata, in human ovarian cancer cells. Lancemaside A significantly suppressed the migration and invasion and the expression of matrix metalloproteinases (MMPs)-2 and -9 in ovarian cancer A2780 and SKOV3 cells. Treatment with lancemaside A generated reactive oxygen species (ROS) in ovarian cancer cells. However, treatment with anti-oxidant N-acetyl-L-cysteine (NAC) significantly negated the anti-invasive activity of lancemaside A. Additionally, lancemaside A activated p38 MAP kinase, which is mediated by ROS generation. This is the first study, to our knowledge, to reveal that lancemaside A isolated from the roots of C. lanceolata exerts antimetastatic activity through inhibition of MMP expression and cancer cell invasion via activation of the ROS-mediated p38 pathway.
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Eoh, Kyung Jin, Hee Jung Kim, Jong Woo Lee, Lee Kyung Kim, Sun-Ae Park, Hyun-Soo Kim, Young Tae Kim, and Peter J. Koo. "E2F8 Induces Cell Proliferation and Invasion through the Epithelial–Mesenchymal Transition and Notch Signaling Pathways in Ovarian Cancer." International Journal of Molecular Sciences 21, no. 16 (August 13, 2020): 5813. http://dx.doi.org/10.3390/ijms21165813.
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Background: Despite the recent research implicating E2F8 (E2F Transcription Factor 8) in cancer, the role of E2F8 in the progression of ovarian cancer has remained unclear. Hence, we explored the bio-functional effects of E2F8 knockdown on ovarian cancer cell lines in vitro and in vivo. Methods: The expression of E2F8 was compared between ovarian cancer and noncancer tissues, and its association with the progression-free survival of ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, we employed RNA interference to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8 knockdown was investigated in a xenograft mouse model of ovarian cancer. Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression compared to that of normal ovarian tissue. Clinical data showed that E2F8 was a significant predictor of progression-free survival. Moreover, the prognosis of the ovarian cancer patients with high E2F8 expression was poorer than that of the patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines demonstrated that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial–mesenchymal transition and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, signifying that E2F8 knockdown was significantly correlated with reduced tumor size and weight. Conclusions: Our findings indicate that E2F8 is highly correlated with ovarian cancer progression. Hence, E2F8 can be utilized as a prognostic marker and therapeutic target against ovarian malignancy.
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Wang, Ning, Qin-Xue Cao, Jun Tian, Lu Ren, Hai-Ling Cheng, and Shao-Qin Yang. "Circular RNA MTO1 Inhibits the Proliferation and Invasion of Ovarian Cancer Cells Through the miR-182-5p/KLF15 Axis." Cell Transplantation 29 (January 1, 2020): 096368972094361. http://dx.doi.org/10.1177/0963689720943613.
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Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs and have been shown to play important roles in a variety of physiological processes. Recently, dysregulation of circRNAs has been identified in many types of cancers. In this study, we analyzed the expression profile and biological functions of circMTO1 in ovarian cancer. We demonstrated that circMTO1 was downregulated in ovarian cancer tissues and cell lines. Upregulation of circMTO1 inhibited proliferation and invasion of ovarian cancer cells while downregulation of circMTO1 promoted these processes. Mechanistically, we showed that circMTO1 sponged miR-182-5p to support KLF15 expression, eventually leading to inhibition of ovarian cancer progression. In conclusion, our study suggested circMTO1 as a novel biomarker and therapeutic target for ovarian cancer treatment.
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Lu, Xiaoqin, Fuying Wang, Meizhou Fu, Yuankun Li, and Lijun Wang. "Long Noncoding RNA KCNQ1OT1 Accelerates the Progression of Ovarian Cancer via MicroRNA-212-3/LCN2 Axis." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, no. 2 (March 27, 2020): 135–46. http://dx.doi.org/10.3727/096504019x15719983040135.
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Long noncoding RNA KCNQ1OT1 (KCNQ1OT1) has been identified to be deregulated in several kinds of cancers. However, its expression pattern and functions in ovarian cancer remain unknown. Bioinformatics analysis showed that miR-212-3p, an identified suppressor in ovarian cancer, was a direct target of KCNQ1OT1, suggesting that KCNQ1OT1 may play a role in ovarian cancer progression via targeting miR-212-3p. Here we aimed to explore the effect of KCNQ1OT1 on the carcinogenesis of ovarian cancer, as well as to investigate miR-212-3p roles in this process. The expression of KCNQ1OT1 and miR-212-3p in ovarian cancer tissues and cells was detected by qPCR. MTT, flow cytometry, wound healing, Transwell chambers, and in vivo tumor formation assays were carried out to assess cell proliferation, apoptosis, migration, invasion, and tumorigenesis, respectively. RNA pulldown and luciferase gene reporter assays were used to evaluate the RNA‐RNA interaction. The results showed that KCNQ1OT1 was overexpressed in ovarian cancer tissues and cells, which closely associated with the advanced clinic process and poor prognosis in ovarian cancer patients. Upregulation of KCNQ1OT1 significantly enhanced cell growth, migration, and invasion and inhibited cell apoptosis via miR-212-3p. In addition, we identified that lipocalin2 (LCN2) was a direct target of miR-212-3p and functioned as an oncogene to promote cell growth and to inhibit cell apoptosis. Furthermore, we observed that KCNQ1OT1 overexpression significantly enhanced the tumorigenesis of SKOV3 cells, whereas this effect was significantly impaired when LCN2 expression was downregulated. Overall, the present study reveals that KCNQ1OT1 functions as an oncogene in ovarian cancer via targeting miR-212-3p/LCN2 axis, which might provide new markers and targets for ovarian cancer diagnosis and treatment.
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Zhang, Li-qian, Su-qing Yang, Ying Wang, Qiao Fang, Xian-jun Chen, Hong-sheng Lu, and Ling-ping Zhao. "Long Noncoding RNA MIR4697HG Promotes Cell Growth and Metastasis in Human Ovarian Cancer." Analytical Cellular Pathology 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/8267863.
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Ovarian cancer is one of the three most common gynecological malignant tumors worldwide. The prognosis of patients suffering from this malignancy remains poor because of limited therapeutic strategies. Herein, we investigated the role of a long noncoding RNA named MIR4697 host gene (MIR4697HG) in the cell growth and metastasis of ovarian cancer. Results showed that the transcriptional level of MIR4697HG in cancerous tissues increased twofold compared with that in adjacent noncancerous tissues. MIR4697HG was differentially expressed in ovarian cancer cell lines, with the highest levels in OVCAR3 and SKOV3 cells. MIR4697HG knockdown by specific shRNA significantly inhibited cell proliferation and colony formation in both OVCAR3 and SKOC3 cells. Consistently, in a xenograft model of ovarian cancer, MIR4697HG depletion also significantly restricted tumor volumes and weights. Furthermore, MIR4697HG knockdown inhibited cell migration and invasion capacities. Invasion ability was inhibited by 58% in SKOV3 cells and 40% in OVCAR3 cells, and migration ability was inhibited by 73% in SKOV3 cells and 62% in OVCAR3 cells after MIR4697HG knockdown. MIR4697HG knockdown also caused a decrease in matrix metalloprotease-9, phosphorylated ERK, and phosphorylated AKT. These data suggested that MIR4697HG promoted ovarian cancer growth and metastasis. The aggressive role of MIR4697HG in ovarian cancer may be related to the ERK and AKT signaling pathways.
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You, Yang, Qi Fan, Jianyun Huang, Yaoqiu Wu, Haiyan Lin, and Qingxue Zhang. "Ferroptosis-Related Gene Signature Promotes Ovarian Cancer by Influencing Immune Infiltration and Invasion." Journal of Oncology 2021 (May 26, 2021): 1–16. http://dx.doi.org/10.1155/2021/9915312.
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Ovarian cancer is a kind of gynecological malignancy with high mortality. Ferroptosis is a new type of iron-dependent cell death characterized by the formation of lipid peroxides and excessive accumulation of reactive oxygen species. Studies have shown that ferroptosis modulates tumor genesis, progression, and invasion, including ovarian cancer. Based on the mRNA expression data from TCGA, we construct a scoring system using consensus clustering analysis, univariate Cox regression analysis, and least absolute selection operator. Then, we systematically evaluate the relationship between score and clinical characteristics of ovarian cancer. The result from the prediction of biofunction pathways shows that score serves as an independent prognostic marker for ovarian cancer and affects tumor progression by modulating tumor metastasis. Moreover, immunocytes such as activated CD4 T cell, activated CD8 T cell, regulatory T cells, macrophage, and stromal cells, including adipocytes, epithelial cells, and fibroblast infiltrate more in the tumor microenvironment in a high-score group, indicating ferroptosis can also affect tumor immune landscape. Critically, four potentially sensitive drugs, including staurosporine, epothilone B, DMOG, and HG6-64-1 based on the scores, are predicted, and DMOG is recognized as a novel targeted drug for ovarian cancer. In general, we construct the scoring system based on ferroptosis-related genes that can predict the prognosis of ovarian cancer patients and propose that ferroptosis may affect ovarian cancer progression by mediating tumor metastasis and immune landscape. Novel drugs to target ovarian cancer are also predicted.
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Tan, Hongwei, Jin Qi, Guanghua Chu, and Zhaoyang Liu. "Tripartite Motif 16 Inhibits the Migration and Invasion in Ovarian Cancer Cells." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 25, no. 4 (April 14, 2017): 551–58. http://dx.doi.org/10.3727/096504016x14758370595285.
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Tripartite motif 16 (TRIM16), a member of the RING B-box coiled-coil (RBCC)/tripartite motif (TRIM) protein family, has been shown to play a role in tumor development and progression. However, the role of TRIM16 in ovarian cancer has never been revealed. Thus, in this study, we investigated the roles and mechanisms of TRIM16 in ovarian cancer. Our results demonstrated that TRIM16 expression was low in ovarian cancer cell lines. In addition, overexpression of TRIM16 significantly inhibited the migration and invasion in vitro, as well as suppressed the epithelial‐mesenchymal transition (EMT) phenotype in ovarian cancer cells. Furthermore, overexpression of TRIM16 greatly inhibited the protein expression levels of Shh, Smo, Ptc, Gli-1, MMP2, and MMP9 in ovarian cancer cells. Taken together, these results strongly suggest that TRIM16 inhibits the migration and invasion via suppressing the Sonic hedgehog signaling pathway in ovarian cancer cells. Thus, TRIM16 may be a novel potential therapeutic target for ovarian cancer.
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Huang, Qin, Ting Du, and Qiu-Xia Qu. "Tea polyphenol decreased growth and invasion in human ovarian cancer cells." European Journal of Inflammation 14, no. 3 (October 17, 2016): 206–11. http://dx.doi.org/10.1177/1721727x16674480.
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Tea polyphenols (TP) are functional substances present in tea, which is one of the most promising preventive agents for cancer. This study was carried out to analyze the effects of TP on the ovarian cancer cells and possible mechanisms involved. TP led to inhibition of cell growth in a time- and dose-dependent manner, and promoted entry into the apoptosis-phase of the cell cycle. TP also decreased the invasion of ovarian cancer cells in vitro. In addition, TP treatment upregulated the mRNA expressions rate of Bax/Bcl-2 and downregulated Cyclin D and MMP2 mRNA expressions. Taken together, our data highlight that TP could be a potential therapeutic strategy for ovarian cancer. These findings also suggested that oncogens are involved in the anti-cancer effects of TP.
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Fu, Chunhong, Ming Yuan, Jie Sun, Gang Liu, Xiaojuan Zhao, Wei Chang, and Zhongling Ma. "RNA-Binding Motif Protein 11 (RBM11) Serves as a Prognostic Biomarker and Promotes Ovarian Cancer Progression." Disease Markers 2021 (August 14, 2021): 1–7. http://dx.doi.org/10.1155/2021/3037337.
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Ovarian cancer is one of the most lethal gynecologic malignancies for women. Due to the lack of efficient target therapy, the overall survival rate for patients with advanced ovarian cancer is still low. Illustrating the molecular mechanisms dictating ovarian cancer progression is critically important to develop novel therapeutic agents. Here, we found that RNA-binding motif protein 11 (RBM11) was highly elevated in ovarian cancer tissues compared with normal ovary, while RBM11 depletion in ovarian cancer cells resulted in impaired cell growth and invasion. Moreover, knockdown of RBM11 also retarded tumor growth in the A2780 ovarian cancer xenograft model. Mechanically, we found that RBM11 positively regulated Akt/mTOR signaling pathway activation in ovarian cancer cells. Thus, these results identify RBM11 is a novel oncogenic protein and prognostic biomarker for ovarian cancers.
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Song, Ning, Hao Liu, Xiaoxin Ma, and Shulan Zhang. "Placental Growth Factor Promotes Ovarian Cancer Cell Invasion via ZEB2." Cellular Physiology and Biochemistry 38, no. 1 (2016): 351–58. http://dx.doi.org/10.1159/000438635.
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Background/Aims: The aggressive manner of ovarian cancer (OVC) cells accounts for the majority of its lethality. Recently, we have shown that placental growth factor (PLGF) promotes metastases of OVC cells through miR-543-regulated MMP7. In the current study, we analyzed the effects of PLGF on another cell invasion associated protein, ZEB2, in OVC cells. Methods: The PLGF and ZEB2 levels in OVC tissues were compared to the paired adjacent non-tumor ovary tissue. We modified ZEB2 levels in OVC cells, and examined its effects on PLGF mRNA and protein levels by RT-qPCR and by Western blot, respectively. We also modified PLGF levels in OVC cells, and examined its effects on ZEB2 mRNA and protein levels by RT-qPCR and by Western blot, respectively. Then, we examined the cell invasiveness in PLGF-modified OVC cells in a transwell cell invasion assay. Finally, we used specific signal pathway inhibitors to treat PLGF-modified OVC cells and examined the effects on ZEB2 activation. Results: PLGF and ZEB2 levels were both significantly increased in OVC tissues, compared to the paired adjacent non-tumor ovary tissue. The PLGF and ZEB2 levels were strongly correlated. ZEB2 modification did not alter PLGF levels. Overexpression of PLGF in OVC cells significantly increased ZEB2 levels and cell invasiveness, while PLGF depletion in OVC cells significantly decreased ZEB2 levels and cell invasiveness. Application of a specific MAPK-p38 inhibitor, but not application of specific inhibitors for MAPK-p42/p44, PI3k/Akt, or JNK signaling pathways, to PLGF-overexpressing OVC cells substantially abolished the PLGF-induced ZEB2 activation. Conclusion: PLGF enhances OVC cell invasion through MAPK-p38-dependent activation of ZEB2.
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Prasad, Parash, and Sib Sankar Roy. "Glutamine regulates ovarian cancer cell migration and invasion through ETS1." Heliyon 7, no. 5 (May 2021): e07064. http://dx.doi.org/10.1016/j.heliyon.2021.e07064.
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Novak, Caymen M., Eric N. Horst, Emily Lin, and Geeta Mehta. "Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor." Cancers 12, no. 6 (June 10, 2020): 1521. http://dx.doi.org/10.3390/cancers12061521.
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This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic load from hydrostatic pressure, displacement of surrounding cells, and growth induced stress. External dynamic stimuli have been correlated with an increase in metastasis, cancer stem cell marker expression, chemoresistance, and proliferation in a variety of cancers. However, how these compressive stimuli contribute to ovarian cancer progression is not fully understood. In this report, high grade serous ovarian cancer cell lines were encapsulated within an ECM mimicking hydrogel comprising of agarose and collagen type I, and stimulated with confined cyclic or static compressive stresses for 24 and 72 h. Compression stimulation resulted in a significant increase in proliferation, invasive morphology, and chemoresistance. Additionally, CDC42 was upregulated in compression stimulated conditions, and was necessary to drive increased proliferation and chemoresistance. Inhibition of CDC42 lead to significant decrease in proliferation, survival, and increased chemosensitivity. In summary, the dynamic in vitro 3D platform developed in this report, is ideal for understanding the influence of compressive stimuli, and can be widely applicable to any epithelial cancers. This work reinforces the critical need to consider compressive stimulation in basic cancer biology and therapeutic developments.
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Guan, Xue, Shuo Chen, Yao Liu, Li-li Wang, Yang Zhao, and Zhi-Hong Zong. "PUM1 promotes ovarian cancer proliferation, migration and invasion." Biochemical and Biophysical Research Communications 497, no. 1 (February 2018): 313–18. http://dx.doi.org/10.1016/j.bbrc.2018.02.078.
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Chen, Shenglan, Ai Jiang, Yan Wang, and Yina Wang. "Long Non-Coding RNA X Inactive Specific Transcript Suppressed the Proliferation and Invasion of Ovarian Cancer Cells by Restricting the Expression of Staphylococcal Nuclease Domain Containing 1." Journal of Biomaterials and Tissue Engineering 10, no. 12 (December 1, 2020): 1793–99. http://dx.doi.org/10.1166/jbt.2020.2490.
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Ovarian cancer is one kind of a deadly gynecological malignancy. Recent study has shown that SND1 was associated with the development of ovarian cancer. Furthermore, the expression of lncRNA XIST in ovarian cancer was down-regulated. However, it is unclear whether lncRNA XIST could affect the occurrence and development of ovarian cancer by targeting SND1. In this study, we used the lentivirus to establish the overexpression and knockdown SND1 ovarian cancer cells. And we next detected the proliferation and invasion of these cells in diverse groups. Then, the luciferase assays were performed to detect the targeted effect of lncRNA XIST on SND1 and determined the expression of SND1 in the overexpressed lncRNA XIST ovarian cancer cells. We found that SND1 promoted the proliferation and invasion of ovarian cancer cells. And the lncRNA XIST targeted and suppressed the expression of SND1. Overexpression of lncRNA XIST inhibited the proliferation and invasion of ovarian cancer cells. However, the overexpression of SND1 alleviated the inhibitory efficacy of lncRNA XIST on the proliferation and invasion of ovarian cancer cells. LncRNA XIST inhibited the proliferation and invasion of ovarian cancer by suppressing the expression of SND1.
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Suri, A., K. Schuler, C. Zhou, K. Malloy, H. Dickens, T. Steplowski, G. Huh, P. Gehrig, and V. Bae-Jump. "Metformin Potently Inhibits Cell Proliferation, Adhesion and Invasion in Ovarian Cancer Cells." Gynecologic Oncology 125, no. 2 (May 2012): S189—S190. http://dx.doi.org/10.1016/j.ygyno.2012.01.018.
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Lv, Yinfeng, Rongxia He, Jia Lu, Aihong Wei, and Ruijuan Chen. "FOXQ1 promotes proliferation and metastasis of epithelial ovarian cancer via activation of SIRT1/NRF2 signaling pathway." Tropical Journal of Pharmaceutical Research 18, no. 7 (May 28, 2021): 1397–404. http://dx.doi.org/10.4314/tjpr.v18i7.5.
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Purpose: To investigate the role of FOXQ1 in the progression of epithelial ovarian cancer and the underlying mechanism.
Methods: Forkhead Box Q1 overexpression was evaluated by quantitative reverse-transcription (qRTPCR) in clinical epithelial ovarian cancer samples and cell lines. Proliferation, migration, and invasion of cancer cells were determined using CCK8, wound healing and transwell assay.
Results: FOXQ1 depletion inhibited the proliferation, migration, and invasion of `epithelial ovarian cancer cells. Moreover, FOXQ1 overexpression increased the amount of cells in S phase of the cell cycle, and FOXQ1 knockdown arrested cells inG1 phase. Results from ChIP and luciferase reporter assays showed that FOXQ1 was able to bind SIRT1 promoters. In addition, it was involved in sustaining the stability of nuclear factor erythroid derived 2-like 2 (NRF2) by decreasing its acetylation (p < 0.01), which was mediated by SIRT1. The data also demonstrated that NRF2 promotes proliferation, migration, and invasion of cancer cells upon FOXQ1 overexpression.
Conclusion: Forkhead Box Q1 contributes to the progression of epithelial ovarian cancer partly via SIRT1/NRF2 signaling pathway, this highlighting a novel strategy for treating epithelial ovarian cancer.
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Chang, Rui-Xia, Ai-Ling Cui, Lu Dong, Su-Ping Guan, Ling-Yan Jiang, and Cong-Xiu Miao. "Overexpression of RASAL1 indicates poor prognosis and promotes invasion of ovarian cancer." Open Life Sciences 14, no. 1 (May 21, 2019): 133–40. http://dx.doi.org/10.1515/biol-2019-0015.
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AbstractRAS protein activator like-1 (RASAL1) exists in numerous human tissues and has been commonly demonstrated to act as a tumor suppressor in several cancers. This study aimed to identify the functional characteristics of RASAL1 in ovarian adenocarcinoma and a potential mechanism of action. We analyzed RASAL1 gene expression in ovarian adenocarcinoma samples and normal samples gained from the GEO and Oncomine databases respectively. Then the relationship between RASAL1 expression and overall survival (OS) was assessed using the Kaplan-Meier method. Furthermore, the biological effect of RASAL1 in ovarian adenocarcinoma cell lines was assessed by Quantitative real time-PCR (qRT-PCR), Cell Counting Kit-8 (CCK-8), western blot, wound healing and transwell assay. The statistical analysis showed patients with higher RASAL1 expression correlated with worse OS. The in vitro assays suggested knockdown of RASAL1 could inhibit cell proliferation, cell invasion and migration of ovarian adenocarcinoma. Moreover, the key proteins in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway were also decreased in ovarian adenocarcinoma cells with RASAL1 silencing. These findings provide promising evidence that RASAL1 may be not only a powerful biomarker but also an effective therapeutic target of ovarian adenocarcinoma.
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Hossein, Ghamartaj, Somayeh Arabzadeh, Zahra Salehi-Dulabi, Zeinab Dehghani-Ghobadi, Yassaman Heidarian, and Maryam Talebi-Juybari. "Wnt5A regulates the expression of ROR2 tyrosine kinase receptor in ovarian cancer cells." Biochemistry and Cell Biology 95, no. 6 (December 2017): 609–15. http://dx.doi.org/10.1139/bcb-2016-0216.
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Wnt5A and receptor tyrosine kinase-like orphan receptor 2 (ROR2) proteins both regulate developmental processes, cell movement, and cell polarity. The purpose of this study was to evaluate a possible regulatory role of Wnt5A on ROR2 expression in human ovarian cancer cell lines. Moreover, the expression of Wnt5A and ROR2 mRNA and protein levels were assessed in human epithelial serous ovarian cancer (HSOC) specimens. ROR2 was strongly decreased in cells treated with siRNA against Wnt5A compared with scramble-treated or lipofectamine-treated cells (P < 0.001). There was 34% decreased cell invasion (P < 0.01) in Wnt5A knock-down cells compared with lipofectamine-treated and scramble-treated cells; however, cell invasion remained unchanged upon addition of anti-ROR2 antibody to the culture media of these cells. In contrast, addition of anti-ROR2 antibody to the culture media for lipofectamine-treated and scramble-treated cells led to 32% decreased cell invasion (P < 0.01). Normal ovarian specimens were negative, and variable immunostaining was observed in HSOC for Wnt5A and ROR2 immunostaining. Furthermore, there was a positive correlation between Wnt5A and ROR2 expression in high-grade SOC samples at the mRNA level (P < 0.05; r = 0.38). This is the first report to show the regulatory role of Wnt5A on ROR2 expression in ovarian cancer.
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Cui, Yajie, Li Qin, Defu Tian, Ting Wang, Lijing Fan, Peilian Zhang, and Zhongqi Wang. "ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2." Chemotherapy 63, no. 5 (2018): 262–71. http://dx.doi.org/10.1159/000493864.
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Ovarian cancer is one of the deadliest gynecological malignancies in women. Chemoresistance has been a major obstacle for ovarian cancer treatment. Zinc finger E-box-binding homeobox 1 (ZEB1) is an important regulator of tumor development in various types of cancer. Abnormal expression of SLC3A2 (CD98hc), a type 2 transmembrane cell surface molecule, has been described in several cancers. This study was designed to investigate the role of ZEB1 and SLC3A2 in the chemoresistance to cisplatin in ovarian cancer cells. We found that ZEB1 was increased in cisplatin-resistant SKOV3/DPP cells. Downregulation of ZEB1 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. In addition, downregulation of ZEB1 decreased the volume and weight of implanted tumors. SLC3A2 was decreased in cisplatin-resistant SKOV3/DPP cells. Upregulation of SLC3A2 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. Moreover, upregulation of SLC3A2 decreased the volume and weight of implanted tumors. Downregulation of ZEB1 resulted in a significant increase of SLC3A2 expression. Moreover, downregulation of SLC3A2 significantly inhibited ZEB1 knockdown-mediated inhibition of cisplatin-resistance. ZEB1-mediated regulation of SLC3A2 was involved in the chemoresistance to cisplatin in ovarian cancer cells. Overall, we provide new insights into the mechanism of chemoresistance to cisplatin in ovarian cancer cells. ZEB1/SLC3A2 may be promising therapeutic targets for enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy.
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Hsu, Erin L., Natalie Chen, Aya Westbrook, Feng Wang, Ruixue Zhang, Robert T. Taylor, and Oliver Hankinson. "Modulation of CXCR4, CXCL12, and Tumor Cell Invasion Potential In Vitro by Phytochemicals." Journal of Oncology 2009 (2009): 1–9. http://dx.doi.org/10.1155/2009/491985.
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CXCR4 is a chemokine receptor frequently overexpressed on primary tumor cells. Organs to which these cancers metastasize secrete CXCL12, the unique ligand for CXCR4, which stimulates invasion and metastasis to these sites. Similar to our previous work with the chemoprotective phytochemical, 3,3′-diindolylmethane (DIM), we show here that genistein also downregulates CXCR4 and CXCL12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells. Moreover, genistein and DIM elicit a significantly greater cumulative effect in lowering CXCR4 and CXCL12 levels than either compound alone. Our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination, these compounds may prove even more efficacious.
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Ogata, Seiji, Ken-Ichirou Morishige, Kenjiro Sawada, Kae Hashimoto, Seiji Mabuchi, Chiaki Kawase, Chifumi Ooyagi, Masahiro Sakata, and Tadashi Kimura. "Fasudil Inhibits Lysophosphatidic Acid-Induced Invasiveness of Human Ovarian Cancer Cells." International Journal of Gynecologic Cancer 19, no. 9 (November 2009): 1473–80. http://dx.doi.org/10.1111/igc.0b013e3181c03909.
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Ovarian cancer is known to be highly invasive. The poor prognosis of advanced ovarian cancer comes from increased invasiveness of human ovarian cancer cells. The lysophosphatidic acid (LPA)/Rho/Rho-associated kinase (ROCK) pathway is intimately involved in the course of ovarian cancer progression, and the inhibition of this pathway attenuates ovarian cancer invasiveness. Fasudil (1-[5-isoquinolinesulfonyl]-homopiperazine; HA-1077) is a drug that has been in clinical use in Japan for the prevention of vasospasm after subarachnoid hemorrhage and is known to be a potent ROCK-specific inhibitor. In this study, we examined the effect of fasudil on LPA-induced invasiveness of human ovarian cancer cells to explore the potential of fasudil as an anticancer agent against ovarian cancer. Fasudil induced changes in cell morphology but not in cell viability. Fasudil significantly inhibited LPA-induced invasion and motility of human ovarian cancer cells in a dose-dependent manner. Furthermore, fasudil caused the loss of intracellular cytoskeletal rearrangement, which is necessary for cell motility, such as stress fiber formation and focal adhesion assembly. Fasudil suppressed LPA-induced tyrosine phosphorylation of paxillin, a representative focal adhesion protein, and serine phosphorylation of myosin light chain, which are essential for the process for cell migration. These findings showed that fasudil attenuated the invasiveness of human ovarian cancer cells via inhibition of the LPA/Rho/ROCK pathway. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with fasudil significantly reduced tumor burden and ascites formation. Our findings suggest that fasudil might be useful to prevent the progression of ovarian cancer in clinical settings.