Статті в журналах: "Erythropoietin-producing hepatocellular B4 receptor"

1

Li, Chaohao, Nadia A. Lanman, Yifan Kong, Daheng He, Fengyi Mao, Elia Farah, Yanquan Zhang, et al. "Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance." Journal of Biological Chemistry 295, no. 16 (March 17, 2020): 5470–83. http://dx.doi.org/10.1074/jbc.ra119.011385.

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Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

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2

Du, Jing, Wei Zhao, Yusheng Wang, and Yan Cai. "Lentivirus Vector-Mediated Knockdown of Erythropoietin-Producing Hepatocellular Carcinoma Receptors B4 Inhibits Laser-Induced Choroidal Neovascularization." Journal of Ocular Pharmacology and Therapeutics 29, no. 1 (February 2013): 14–22. http://dx.doi.org/10.1089/jop.2012.0077.

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Lafleur, Karine, Danzhi Huang, Ting Zhou, Amedeo Caflisch, and Cristina Nevado. "Structure-Based Optimization of Potent and Selective Inhibitors of the Tyrosine Kinase Erythropoietin Producing Human Hepatocellular Carcinoma Receptor B4 (EphB4)." Journal of Medicinal Chemistry 52, no. 20 (October 22, 2009): 6433–46. http://dx.doi.org/10.1021/jm9009444.

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4

Dong, Ling-Dan, Xiang-Lin Cheng, Long Zhou, Qing Huang, Jun-Chuan Li, and Cun-Jian Yi. "Overexpression of erythropoietin-producing hepatocyte receptor B4 and ephrin-B2 is associated with estrogen receptor expression in endometrial adenocarcinoma." Oncology Letters 13, no. 4 (February 8, 2017): 2109–14. http://dx.doi.org/10.3892/ol.2017.5698.

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5

Singh, Deo R., QingQing Cao, Christopher King, Matt Salotto, Fozia Ahmed, Xiang Yang Zhou, Elena B. Pasquale, and Kalina Hristova. "Unliganded EphA3 dimerization promoted by the SAM domain." Biochemical Journal 471, no. 1 (September 21, 2015): 101–9. http://dx.doi.org/10.1042/bj20150433.

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Erythropoietin-producing hepatocellular carcinoma A3 (EphA3) can form dimers in the absence of ligand binding, which are stabilized by the sterile α-motif (SAM) domain. This challenges the current understanding of EphA3 activation events and establishes a new role for the EphA3 SAM domain in receptor-receptor interactions.

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6

Rudzitis‐Auth, Jeannette, Sophia A. Fuß, Vivien Becker, Michael D. Menger, and Matthias W. Laschke. "Inhibition of erythropoietin‐producing hepatoma receptor B4 (EphB4) signalling suppresses the vascularisation and growth of endometriotic lesions." British Journal of Pharmacology 177, no. 14 (April 12, 2020): 3225–39. http://dx.doi.org/10.1111/bph.15044.

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7

Furukawa, Takenori, Hiroyuki Kimura, Hanae Torimoto, Yusuke Yagi, Hidekazu Kawashima, Kenji Arimitsu, and Hiroyuki Yasui. "A Putative Single-Photon Emission CT Imaging Tracer for Erythropoietin-Producing Hepatocellular A2 Receptor." ACS Medicinal Chemistry Letters 12, no. 8 (July 14, 2021): 1238–44. http://dx.doi.org/10.1021/acsmedchemlett.1c00030.

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8

Butler, Noah S., and Nathan W. Schmidt. "Erythropoietin-producing hepatocellular receptor B2 receptor tyrosine kinase: A novel regulator of infection- and inflammation-induced liver fibrosis." Hepatology 62, no. 3 (May 26, 2015): 680–83. http://dx.doi.org/10.1002/hep.27868.

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9

Sun, Chen-Li, Cheng-Wen Li, Nong He, Yuan-Zhang Tang, Xiu-Liang Li, Fu-Shan Xue, and Jia-Xiang Ni. "Blockade of Erythropoietin-Producing Human Hepatocellular Carcinoma Receptor B1 in Spinal Dorsal Horn Alleviates Visceral Pain in Rats." Pain Research and Management 2021 (April 7, 2021): 1–9. http://dx.doi.org/10.1155/2021/7582494.

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Objective. This experiment was designed to determine whether erythropoietin-producing human hepatocellular carcinoma (Eph) receptors were involved in the development of visceral pain. Methods. Adult male Sprague-Dawley rats were randomly divided into three groups receiving different treatments (n = 16 per group): intracolonic vehicle (control group), intracolonic 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) (TNBS group), and intracolonic TNBS and intrathecal EphB1 receptor blocking reagent (TNBS + EphB2-Fc group). Visceral hyperalgesia was evaluated with quantification of visceral pain threshold induced by colorectal distention. The spinal expressions of EphB1 and ephrinB2 and levels of their phosphorylated forms (p-EphB1 and p-ephrinB2) were assessed by Western blotting and immunohistochemistry. Results. The TNBS-treated rats developed significant visceral hyperalgesia. The spinal expressions of EphB1, p-EphB1, ephrinB2, and p-ephrinB2 were significantly increased in the TNBS group compared with the control group, but visceral hyperalgesia and elevation of spinal EphB1 and p-EphB1 expressions were evidently alleviated by intrathecal administration of EphB2-Fc in the TNBS + EphB2-Fc group. The number of EphB1- and p-EphB1-immunopositive cells, the average optical (AO) value of EphB1, and its phosphorylated form in the spinal dorsal horn were significantly increased in the TNBS group than in the control group, but they were obviously reduced by intrathecal administration of EphB2-Fc. There were no significant differences in the number of ephrinB2- and p-ephrinB2-immunopositive cells and the AO value of ephrinB2 and its phosphorylated form between the TNBS and TNBS + EphB2-Fc groups. Conclusion. EphB1 receptors in the spinal dorsal horn play a pivotal role in the development of visceral pain and may be considered as a potential target for the treatment of visceral pain.

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10

Aasheim, Hans-Christian, Else Munthe, Steinar Funderud, Erlend B. Smeland, Klaus Beiske, and Ton Logtenberg. "A splice variant of human ephrin-A4 encodes a soluble molecule that is secreted by activated human B lymphocytes." Blood 95, no. 1 (January 1, 2000): 221–30. http://dx.doi.org/10.1182/blood.v95.1.221.001k01_221_230.

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Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)

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11

Kim, Kyoung-Yeon, Seung-Ku Lee, Min-Ho Kim, Jae-Youn Cheong, Sung-Won Cho, Kap-Seok Yang, and Kyu-Bum Kwack. "Erythropoietin-producing Human Hepatocellular Carcinoma Receptor B1 Polymorphisms are Associated with HBV-infected Chronic Liver Disease and Hepatocellular Carcinoma in a Korean Population." Genomics & Informatics 6, no. 4 (December 31, 2008): 192–201. http://dx.doi.org/10.5808/gi.2008.6.4.192.

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12

Aasheim, Hans-Christian, Else Munthe, Steinar Funderud, Erlend B. Smeland, Klaus Beiske, and Ton Logtenberg. "A splice variant of human ephrin-A4 encodes a soluble molecule that is secreted by activated human B lymphocytes." Blood 95, no. 1 (January 1, 2000): 221–30. http://dx.doi.org/10.1182/blood.v95.1.221.

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Abstract Ephrin-A4 is a ligand for the erythropoietin-producing hepatocellular (Eph) receptor family of tyrosine kinases. We have identified a secreted form of ephrin-A4, denoted ephrin-A4 (s), which is encoded by an alternatively spliced mRNA and is produced by in vivo activated B cells in tonsils. Blood B cells secrete ephrin-A4 (s) upon stimulation via the B-cell antigen receptor. A subpopulation of tonsil cells in the crypts with a dendritic cell phenotype was shown to express EphA2, an Eph receptor tyrosine kinase that was found to be capable of binding an ephrin-A4 immunoglobulin chimeric protein. We conclude that ephrin-A4 (s) may play a role in the interaction between activated B lymphocytes and dendritic cells in human tonsils. (Blood. 2000;95:221-230)

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13

Psilopatis, Iason, Eleni Souferi-Chronopoulou, Kleio Vrettou, Constantinos Troungos, and Stamatios Theocharis. "EPH/Ephrin-Targeting Treatment in Breast Cancer: A New Chapter in Breast Cancer Therapy." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15275. http://dx.doi.org/10.3390/ijms232315275.

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Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC.

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14

Li, Shang, Junyu Zhai, Bing Xu, Jiansheng Liu, Weiwei Chu, Dongshuang Wang, Xueying Geng, Zi-Jiang Chen, and Yanzhi Du. "Erythropoietin-producing hepatocellular receptor A7 restrains estrogen negative feedback of luteinizing hormone via ephrin A5 in the hypothalamus of female rats." American Journal of Physiology-Endocrinology and Metabolism 319, no. 1 (July 1, 2020): E81—E90. http://dx.doi.org/10.1152/ajpendo.00046.2020.

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We have previously shown that systemic injection of erythropoietin-producing hepatocellular receptor A7 (EPHA7)-Fc raises serum luteinizing hormone (LH) levels before ovulation in female rats, indicating the induction of EPHA7 in ovulation. In this study, we aimed to identify the mechanism and hypothalamus-pituitary-ovary (HPO) axis level underlying the promotion of LH secretion by EPHA7. Using an ovariectomized (OVX) rat model, in conjunction with low-dose 17β-estradiol (E2) treatment, we investigated the association between EPHA7-ephrin (EFN)A5 signaling and E2 negative feedback. Various rat models (OVX, E2-treated OVX, and abarelix treated) were injected with the recombinant EPHA7-Fc protein through the caudal vein to investigate the molecular mechanism underlying the promotion of LH secretion by EPHA7. Efna5 was observed strongly expressed in the arcuate nucleus of the female rat by using RNAscope in situ hybridization. Our results indicated that E2, combined with estrogen receptor (ER)α, but not ERβ, inhibited Efna5 and gonadotropin-releasing hormone 1 ( Gnrh1) expressions in the hypothalamus. In addition, the systemic administration of EPHA7-Fc restrained the inhibition of Efna5 and Gnrh1 by E2, resulting in increased Efna5 and Gnrh1 expressions in the hypothalamus as well as increased serum LH levels. Collectively, our findings demonstrated the involvement of EPHA7-EFNA5 signaling in the regulation of LH and the E2 negative feedback pathway in the hypothalamus, highlighting the functional role of EPHA7 in female reproduction.

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15

Yang, Xiao-Yi, Wei-Jie Zhu, and Huan Jiang. "Activation of erythropoietin-producing hepatocellular receptor A2 attenuates cell adhesion of human fallopian tube epithelial cells via focal adhesion kinase dephosphorylation." Molecular and Cellular Biochemistry 361, no. 1-2 (October 19, 2011): 259–65. http://dx.doi.org/10.1007/s11010-011-1111-z.

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16

Pergaris, Alexandros, Eugene Danas, Dimitrios Goutas, Alexandros G. Sykaras, Angelos Soranidis, and Stamatios Theocharis. "The Clinical Impact of the EPH/Ephrin System in Cancer: Unwinding the Thread." International Journal of Molecular Sciences 22, no. 16 (August 5, 2021): 8412. http://dx.doi.org/10.3390/ijms22168412.

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Erythropoietin-producing human hepatocellular receptors (EPHs) compose the largest known subfamily of receptor tyrosine kinases (RTKs). They bind and interact with the EPH family receptor interacting proteins (ephrins). EPHs/ephrins are implicated in a variety of physiological processes, as well as in cancer pathogenesis. With neoplastic disease remaining a leading cause of death world-wide, the development of novel biomarkers aiding in the field of diagnosis, prognosis, and disease monitoring is of utmost importance. A multitude of studies have proven the association between the expression of members of the EPH/ephrin system and various clinicopathological parameters, including disease stage, tumor histologic grade, and patients’ overall survival. Besides their utilization in timely disease detection and assessment of outcome, EPHs/ephrins could also represent possible novel therapeutic targets. The aim of the current review of the literature was to present the existing data regarding the association between EPH/ephrin system expression and the clinical characteristics of malignant tumors.

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17

Holen, Halvor L., Lillian Zernichow, Kristine E. Fjelland, Ida M. Evenroed, Kristian Prydz, Heidi Tveit, and Hans-Christian Aasheim. "Ephrin-B3 binds to a sulfated cell-surface receptor." Biochemical Journal 433, no. 1 (December 15, 2010): 215–23. http://dx.doi.org/10.1042/bj20100865.

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The ephrins are a family of proteins known to bind the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinase family. In the present paper, we provide data showing that ephrin-B3 binds a sulfated cell-surface protein on HEK-293T (human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40) and HeLa cells, a binding that is nearly completely blocked by treatment of these cell lines with chlorate or heparinase, or by addition of the heavily sulfated glycosaminoglycan heparin. This indicates that heparan sulfate on these cells is essential for cell-surface binding of ephrin-B3. Heparin did not affect ephrin-B3 binding to EphB receptors expressed on transfected HEK-293T cells, indicating further that ephrin-B3 binds an alternative receptor which is a heparan sulfate proteoglycan. Site-directed mutagenesis analysis revealed that Arg178 and Lys179 are important for heparin binding of ephrin-B3 and also for ephrin-B3 binding to cells. These amino acids, when introduced in the non-heparin-binding ephrin-B1, conferred the heparin-binding property. Functional studies reveal that ephrin-B3 binding to cells induces cellular signalling and influences cell rounding and cell spreading. In conclusion, our data provide evidence for an unknown ephrin-B3-binding cell-surface proteoglycan involved in cellular signalling.

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Shi, Wei, Bei Ye, Marion Rame, Yujia Wang, Dominique Cioca, Sophie Reibel, Junzheng Peng, et al. "The receptor tyrosine kinase EPHB6 regulates catecholamine exocytosis in adrenal gland chromaffin cells." Journal of Biological Chemistry 295, no. 22 (April 22, 2020): 7653–68. http://dx.doi.org/10.1074/jbc.ra120.013251.

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The erythropoietin-producing human hepatocellular receptor EPH receptor B6 (EPHB6) is a receptor tyrosine kinase that has been shown previously to control catecholamine synthesis in the adrenal gland chromaffin cells (AGCCs) in a testosterone-dependent fashion. EPHB6 also has a role in regulating blood pressure, but several facets of this regulation remain unclear. Using amperometry recordings, we now found that catecholamine secretion by AGCCs is compromised in the absence of EPHB6. AGCCs from male knockout (KO) mice displayed reduced cortical F-actin disassembly, accompanied by decreased catecholamine secretion through exocytosis. This phenotype was not observed in AGCCs from female KO mice, suggesting that testosterone, but not estrogen, contributes to this phenotype. Of note, reverse signaling from EPHB6 to ephrin B1 (EFNB1) and a 7-amino acid-long segment in the EFNB1 intracellular tail were essential for the regulation of catecholamine secretion. Further downstream, the Ras homolog family member A (RHOA) and FYN proto-oncogene Src family tyrosine kinase (FYN)–proto-oncogene c-ABL–microtubule-associated monooxygenase calponin and LIM domain containing 1 (MICAL-1) pathways mediated the signaling from EFNB1 to the defective F-actin disassembly. We discuss the implications of EPHB6's effect on catecholamine exocytosis and secretion for blood pressure regulation.

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19

Huang, Zhimin, Simeng Liu, Anna Tang, Laith Al-Rabadi, Mark Henkemeyer, Patrice N. Mimche, and Yufeng Huang. "Key role for EphB2 receptor in kidney fibrosis." Clinical Science 135, no. 17 (September 2021): 2127–42. http://dx.doi.org/10.1042/cs20210644.

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Abstract Erythropoietin producing hepatocellular (Eph)–Eph receptor interacting (Ephrin) receptor–ligand signaling has been implicated in the development of tissue fibrosis, though it has not been well defined in the kidney. We detected substantial up-regulation of expression and phosphorylation of the EphB2 receptor tyrosine kinase in fibrotic kidney tissue obtained both from mice subjected to the unilateral renal ischemia–reperfusion (IR) model at 14 days and in patients suffering from chronic kidney disease (CKD). Knockout (KO) mice lacking EphB2 expression exhibited a normal renal structure and function, indicating no major role for this receptor in kidney development or action. Although IR injury is well-known to cause tissue damage, fibrosis, and renal dysfunction, we found that kidneys from EphB2KO mice showed much less renal tubular injury and retained a more preserved renal function. IR-injured kidneys from EphB2 KOs exhibited greatly reduced fibrosis and inflammation compared with injured wildtype (WT) littermates, and this correlated with a significant reduction in renal expression of profibrotic molecules, inflammatory cytokines, NADPH oxidases, and markers for cell proliferation, tubular epithelial-to-mesenchymal transition (EMT), myofibroblast activation, and apoptosis. A panel of 760 fibrosis-associated genes were further assessed, revealing that 506 genes in WT mouse kidney following IR injury changed their expression. However, 70.9% of those genes were back to or close to normal in expression when EphB2 was deleted. These data indicate that endogenous EphB2 expression and signaling are abnormally activated after kidney injury and subsequently contribute to the development of renal fibrosis via regulation of multiple profibrotic pathways.

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Nasreen, Najmunnisa, Nazli Khodayari, Peruvemba S. Sriram, Jawaharlal Patel, and Kamal A. Mohammed. "Tobacco smoke induces epithelial barrier dysfunction via receptor EphA2 signaling." American Journal of Physiology-Cell Physiology 306, no. 12 (June 15, 2014): C1154—C1166. http://dx.doi.org/10.1152/ajpcell.00415.2012.

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Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors are the largest family of receptor tyrosine kinases (RTKs) that mediate various cellular and developmental processes. The degrees of expression of these key molecules control the cell-cell interactions. Although the role of Eph receptors and their ligand Ephrins is well studied in developmental processes, their function in tobacco smoke (TS)-induced epithelial barrier dysfunction is unknown. We hypothesized that TS may induce permeability in bronchial airway epithelial cell (BAEpC) monolayer by modulating receptor EphA2 expression, actin cytoskeleton, adherens junction, and focal adhesion proteins. Here we report that in BAEpCs, acute TS exposure significantly upregulated EphA2 and EphrinA1 expression, disrupted the actin filaments, decreased E-cadherin expression, and increased protein permeability, whereas the focal adhesion protein paxillin was unaffected. Silencing the receptor EphA2 expression with silencing interference RNA (siRNA) significantly attenuated TS-induced hyperpermeability in BAEpCs. In addition, when BAEpC monolayer was transfected with EphA2-expressing plasmid and treated with recombinant EphrinA1, the transepithelial electrical resistance decreased significantly. Furthermore, TS downregulated E-cadherin expression and induced hyperpermeability across BAEpC monolayer in a Erk1/Erk2, p38, and JNK MAPK-dependent manner. TS induced hyperpermeability in BAEpC monolayer by targeting cell-cell adhesions, and interestingly cell-matrix adhesions were unaffected. The present data suggest that TS causes significant damage to the BAEpCs via induction of EphA2 and downregulation of E-cadherin. Induction of EphA2 in the BAEpCs exposed to TS may be an important signaling event in the pathogenesis of TS-induced epithelial injury.

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Li, Huiting, Peng Zhang, Cencen Liu, Yiwei Wang, Yan Deng, Wei Dong, and Yang Yu. "The Structure, Function and Regulation of Protein Tyrosine Phosphatase Receptor Type J and its Role in Diseases." Cells 12, no. 1 (December 20, 2022): 8. http://dx.doi.org/10.3390/cells12010008.

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Protein tyrosine phosphatase receptor type J (PTPRJ), also known as DEP-1, HPTPη, or CD148, belongs to the R3 subfamily of receptor protein tyrosine phosphatases (RPTPs). It was first identified as an antioncogene due to its protein level being significantly downregulated in most epithelial tumors and cancer cell lines (e.g., colon, lung, thyroid, breast, and pancreas). PTPRJ regulates mouse optic nerve projection by inhibiting the phosphorylation of the erythropoietin-producing hepatocellular carcinoma (Eph) receptor and abelson murine leukemia viral oncogene homolog 1 (c-Abl). PTPRJ is crucial for metabolism. Recent studies have demonstrated that PTPRJ dephosphorylates JAK2 at positions Y813 and Y868 to inhibit leptin signaling. Akt is more phosphorylated at the Ser473 and Thr308 sites in Ptprj−/− mice, suggesting that PTPRJ may be a novel negative regulator of insulin signaling. PTPRJ also plays an important role in balancing the pro- and anti-osteoclastogenic activity of the M-CSF receptor (M-CSFR), and in maintaining NFATc1 expression during the late stages of osteoclastogenesis to promote bone-resorbing osteoclast (OCL) maturation. Furthermore, multiple receptor tyrosine kinases (RTKs) as substrates of PTPRJ are probably a potential therapeutic target for many types of diseases, such as cancer, neurodegenerative diseases, and metabolic diseases, by inhibiting their phosphorylation activity. In light of the important roles that PTPRJ plays in many diseases, this review summarizes the structural features of the protein, its expression pattern, and the physiological and pathological functions of PTPRJ, to provide new ideas for treating PTPRJ as a potential therapeutic target for related metabolic diseases and cancer.

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22

Ding, Linlin, Yaodong Shen, Jing Ni, Yiqing Ou, Yangyu Ou, and Hong Liu. "EphA4 promotes cell proliferation and cell adhesion–mediated drug resistance via the AKT pathway in multiple myeloma." Tumor Biology 39, no. 3 (March 2017): 101042831769429. http://dx.doi.org/10.1177/1010428317694298.

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Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion–mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion–mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion–mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.

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23

Ge, Yu-Wei, Kai Feng, Xiao-Liang Liu, Hong-Fang Chen, Zhen-Yu Sun, Cai-Feng Wang, Zhi-Qing Liu, et al. "The Recombinant Protein EphB4-Fc Changes the Ti Particle-Mediated Imbalance of OPG/RANKL via EphrinB2/EphB4 Signaling Pathway and Inhibits the Release of Proinflammatory Factors In Vivo." Oxidative Medicine and Cellular Longevity 2020 (June 6, 2020): 1–15. http://dx.doi.org/10.1155/2020/1404915.

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Aseptic loosening caused by wear particles is one of the common complications after total hip arthroplasty. We investigated the effect of the recombinant protein ephB4-Fc (erythropoietin-producing human hepatocellular receptor 4) on wear particle-mediated inflammatory response. In vitro, ephrinB2 expression was analyzed using siRNA-NFATc1 (nuclear factor of activated T-cells 1) and siRNA-c-Fos. Additionally, we used Tartrate-resistant acid phosphatase (TRAP) staining, bone pit resorption, Enzyme-linked immunosorbent assay (ELISA), as well as ephrinB2 overexpression and knockdown experiments to verify the effect of ephB4-Fc on osteoclast differentiation and function. In vivo, a mouse skull model was constructed to test whether the ephB4-Fc inhibits osteolysis and inhibits inflammation by micro-CT, H&E staining, immunohistochemistry, and immunofluorescence. The gene expression of ephrinB2 was regulated by c-Fos/NFATc1. Titanium wear particles activated this signaling pathway to the promoted expression of the ephrinB2 gene. However, ephrinB2 protein can be activated by osteoblast membrane receptor ephB4 to inhibit osteoclast differentiation. In in vivo experiments, we found that ephB4 could regulate Ti particle-mediated imbalance of OPG/RANKL, and the most important finding was that ephB4 relieved the release of proinflammatory factors. The ephB4-Fc inhibits wear particle-mediated osteolysis and inflammatory response through the ephrinB2/EphB4 bidirectional signaling pathway, and ephrinB2 ligand is expected to become a new clinical drug therapeutic target.

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Psilopatis, Iason, Ioannis Karniadakis, Konstantinos Stylianos Danos, Kleio Vrettou, Kleita Michaelidou, Konstantinos Mavridis, Sofia Agelaki, and Stamatios Theocharis. "May EPH/Ephrin Targeting Revolutionize Lung Cancer Treatment?" International Journal of Molecular Sciences 24, no. 1 (December 21, 2022): 93. http://dx.doi.org/10.3390/ijms24010093.

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Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting.

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Kaminskyy, Vitaliy O., Petra Hååg, Metka Novak, Ákos Végvári, Vasiliki Arapi, Rolf Lewensohn, and Kristina Viktorsson. "EPHA2 Interacts with DNA-PKcs in Cell Nucleus and Controls Ionizing Radiation Responses in Non-Small Cell Lung Cancer Cells." Cancers 13, no. 5 (February 28, 2021): 1010. http://dx.doi.org/10.3390/cancers13051010.

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Ephrin (EFN)/Erythropoietin-producing human hepatocellular receptors (Eph) signaling has earlier been reported to regulate non-small cell lung cancer (NSCLC) cell survival and cell death as well as invasion and migration. Here, the role of Ephrin type-A receptor 2 (EphA2) on the DNA damage response (DDR) signaling and ionizing radiation (IR) cellular effect was studied in NSCLC cells. Silencing of EphA2 resulted in IR sensitization, with increased activation of caspase-3, PARP-1 cleavage and reduced clonogenic survival. Profiling of EphA2 expression in a NSCLC cell line panel showed a correlation to an IR refractory phenotype. EphA2 was found to be transiently and rapidly phosphorylated at Ser897 in response to IR, which was paralleled with the activation of ribosomal protein S6 kinase (RSK). Using cell fractionation, a transient increase in both total and pSer897 EphA2 in the nuclear fraction in response to IR was revealed. By immunoprecipitation and LC-MS/MS analysis of EphA2 complexes, nuclear localized EphA2 was found in a complex with DNA-PKcs. Such complex formation rapidly increased after IR but returned back to basal level within an hour. Targeting EphA2 with siRNA or by treatment with EFNA1 ligand partly reduced phosphorylation of DNA-PKcs at S2056 at early time points after IR. Thus, we report that EphA2 interacts with DNA-PKcs in the cell nucleus suggesting a novel mechanism involving the EphA2 receptor in DDR signaling and IR responsiveness.

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Ruan, Hailong, Sen Li, Lin Bao, and Xiaoping Zhang. "Enhanced YB1/EphA2 axis signaling promotes acquired resistance to sunitinib and metastatic potential in renal cell carcinoma." Oncogene 39, no. 38 (August 19, 2020): 6113–28. http://dx.doi.org/10.1038/s41388-020-01409-6.

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Abstract VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression, and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain unclear. In our study, we found that increased expression of Y-box binding protein 1 (YB1, a multidrug resistance associated protein) and EphA2 (a member of the erythropoietin-producing hepatocellular (Eph) receptor family, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stability of EphA2 through inhibition of the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.

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Psilopatis, Iason, Alexandros Pergaris, Kleio Vrettou, Gerasimos Tsourouflis, and Stamatios Theocharis. "The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management." International Journal of Molecular Sciences 23, no. 6 (March 17, 2022): 3249. http://dx.doi.org/10.3390/ijms23063249.

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Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact.

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Colapietro, Alessandro, Giovanni Luca Gravina, Francesco Petragnano, Irene Fasciani, Bianca Maria Scicchitano, Filip Beirinckx, Philippe Pujuguet, et al. "Antitumorigenic Effects of Inhibiting Ephrin Receptor Kinase Signaling by GLPG1790 against Colorectal Cancer Cell Lines In Vitro and In Vivo." Journal of Oncology 2020 (February 27, 2020): 1–16. http://dx.doi.org/10.1155/2020/9342732.

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Erythropoietin-producing hepatocellular receptors (Eph) promote the onset and sustain the progression of cancers such as colorectal cancer (CRC), in which the A2 subtype of Eph receptor expression has been shown to correlate with a poor prognosis and has been identified as a promising therapeutic target. Herein, we investigated, in vitro and in vivo, the effects of treatment with GLPG1790, a potent pan-Eph inhibitor. The small molecule has selective activity against the EphA2 isoform in human HCT116 and HCT15 CRC cell lines expressing a constitutively active form of RAS concurrently with a wild-type or mutant form of p53, respectively. GLPG1790 reduced EPHA2 phosphorylation/activation and induced G1/S cell-cycle growth arrest by downregulating the expression of cyclin E and PCNA, while upregulating p21Waf1/Cip1 and p27Cip/Kip. The inhibition of ephrin signaling induced quiescence in HCT15 and senescence in HCT116 cells. While investigating the role of CRC-related, pro-oncogenic p53 and RAS pathways, we found that GLPG1790 upregulated p53 expression and that silencing p53 or inhibiting RAS (human rat sarcoma)/ERKs (extracellular signal-regulated kinase) signaling restrained the ability of GLPG1790 to induce senescence in HCT116 cells. On the other hand, HCT15 silencing of p53 predisposed cells to GLPG1790-induced senescence, whilst no effects of ERK inhibition were observed. Finally, GLPG1790 hindered the epithelial-mesenchymal transition, reduced the migratory capacities of CRC, and affected tumor formation in xenograft models in vivo more efficiently using HCT116 than HCT15 for xenografts. Taken together, our data suggest the therapeutic potential of GLPG1790 as a signal transduction-based therapeutic strategy in to treat CRC.

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Goutas, Dimitrios, Alexandros Pergaris, Nikolaos Goutas, and Stamatios Theocharis. "Utilizing Exosomal-EPHs/Ephrins as Biomarkers and as a Potential Platform for Targeted Delivery of Therapeutic Exosomes." International Journal of Molecular Sciences 23, no. 7 (March 24, 2022): 3551. http://dx.doi.org/10.3390/ijms23073551.

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Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients’ management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed.

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Miura, Koichi, Jin-Min Nam, Chie Kojima, Naoki Mochizuki, and Hisataka Sabe. "EphA2 Engages Git1 to Suppress Arf6 Activity Modulating Epithelial Cell–Cell Contacts." Molecular Biology of the Cell 20, no. 7 (April 2009): 1949–59. http://dx.doi.org/10.1091/mbc.e08-06-0549.

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ADP-ribosylation factor (Arf) 6 activity is crucially involved in the regulation of E-cadherin–based cell–cell adhesions. Erythropoietin-producing hepatocellular carcinoma (Eph)-family receptors recognize ligands, namely, ephrins, anchored to the membrane of apposing cells, and they mediate cell–cell contact-dependent events. Here, we found that Arf6 activity is down-regulated in Madin-Darby canine kidney cells, which is dependent on cell density and calcium ion concentration, and we provide evidence of a novel signaling pathway by which ligand-activated EphA2 suppresses Arf6 activity. This EphA2-mediated suppression of Arf6 activity was linked to the induction of cell compaction and polarization, but it was independent of the down-regulation of extracellular signal-regulated kinase 1/2 kinase activity. We show that G protein-coupled receptor kinase-interacting protein (Git) 1 and noncatalytic region of tyrosine kinase (Nck) 1 are involved in this pathway, in which ligand-activated EphA2, via its phosphorylated Tyr594, binds to the Src homology 2 domain of Nck1, and then via its Src homology 3 domain binds to the synaptic localizing domain of Git1 to suppress Arf6 activity. We propose a positive feedback loop in which E-cadherin–based cell–cell contacts enhance EphA-ephrinA signaling, which in turn down-regulates Arf6 activity to enhance E-cadherin–based cell–cell contacts as well as the apical-basal polarization of epithelial cells.

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Yeo, Changhwan, Deok-Soo Han, Hyo-Jeong Lee, and Eun-Ok Lee. "Epigallocatechin-3-Gallate Suppresses Vasculogenic Mimicry through Inhibiting the Twist/VE-Cadherin/AKT Pathway in Human Prostate Cancer PC-3 Cells." International Journal of Molecular Sciences 21, no. 2 (January 9, 2020): 439. http://dx.doi.org/10.3390/ijms21020439.

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Vasculogenic mimicry (VM) is the alternative process of forming vessel-like networks by aggressive tumor cells, and it has an important role in tumor survival, growth, and metastasis. Epigallocatechin-3-gallate (EGCG) is well known to have diverse bioactivities including anti-cancer effects. However, the efficacy of EGCG on VM is elusive. In this study, we explored whether and how EGCG affects VM in human prostate cancer (PCa) PC-3 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Invasive and VM formation abilities were assessed by an invasion assay and a three-dimensional (3D) culture VM tube formation assay, respectively. Western blots were carried out. An immunofluorescence assay was performed to detect nuclear twist expression. EGCG effectively inhibited the invasive ability, as well as tubular channel formation, without affecting cell viability. EGCG significantly downregulated the expression of vascular endothelial cadherin (VE-cadherin) and its transcription factor, twist, N-cadherin, vimentin, phosphor-AKT, and AKT, but not phospho-erythropoietin-producing hepatocellular receptor A2 (EphA2) and EphA2. In addition, EGCG diminished the nuclear localization of twist. Treatment with SC79, an AKT activator, effectively rescued EGCG-inhibited VM formation. These results demonstrated for the first time that EGCG causes marked suppression of VM through inhibiting the twist/VE-cadherin/AKT pathway in human PCa PC-3 cells.

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Trinidad, Eva M., Mónica Ballesteros, Jaime Zuloaga, Agustín Zapata, and Luis M. Alonso-Colmenar. "An impaired transendothelial migration potential of chronic lymphocytic leukemia (CLL) cells can be linked to ephrin-A4 expression." Blood 114, no. 24 (December 3, 2009): 5081–90. http://dx.doi.org/10.1182/blood-2009-03-210617.

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Abstract Chronic lymphocytic leukemia (CLL) cell migration into lymphoid tissues is an important aspect of the pathobiology of this disease. Here, we investigated the role of ephrin-A4 (EFNA4) in the transendothelial migration (TEM) capacity of CLL and normal B cells through interacting with endothelial EphA2 (erythropoietin-producing hepatocellular carcinoma). CLL cells showed a remarkable impairment in the adhesion to and transmigration through human umbilical vein endothelial cell (HUVEC) monolayers, correlating with their higher EFNA4 expression. In vitro, TEM was mediated by EFNA4 binding to endothelial EphA2 receptor, which is highly expressed in tumor necrosis factor-α–activated HUVECs as well as in the CD31+ endothelial cells of human lymph nodes. The pretreatment of CLL cells with EphA2 homodimers further impaired their adhesion to and transmigration through HUVEC monolayers, whereas pretreatment of HUVECs with EFNA4 homodimers improved those phenomena in both CLL and normal B cells, suggesting that EFNA4 signaling negatively contributed to TEM. In fact, EFNA4 signaling into CLL cells significantly reduced their adhesion to intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and several extracellular matrix molecules and impaired CCL-19–mediated TEM and chemotaxis. Our results suggest that EFNA4-EphA2 interactions are involved in CLL cell trafficking between blood and the tissues and therefore may become a therapeutic target in the future.

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Gravina, Giovanni, Andrea Mancini, Alessandro Colapietro, Simona Delle Monache, Roberta Sferra, Flora Vitale, Loredana Cristiano, et al. "The Small Molecule Ephrin Receptor Inhibitor, GLPG1790, Reduces Renewal Capabilities of Cancer Stem Cells, Showing Anti-Tumour Efficacy on Preclinical Glioblastoma Models." Cancers 11, no. 3 (March 13, 2019): 359. http://dx.doi.org/10.3390/cancers11030359.

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Therapies against glioblastoma (GBM) show a high percentage of failure associated with the survival of glioma stem cells (GSCs) that repopulate treated tumours. Forced differentiation of GSCs is a promising new approach in cancer treatment. Erythropoietin-producing hepatocellular (Eph) receptors drive tumourigenicity and stemness in GBM. We tested GLPG1790, a first small molecule with inhibition activity versus inhibitor of various Eph receptor kinases, in preclinical GBM models using in vitro and in vivo assays. GLPG1790 rapidly and persistently inhibited Ephrin-A1-mediated phosphorylation of Tyr588 and Ser897, completely blocking EphA2 receptor signalling. Similarly, this compound blocks the ephrin B2-mediated EphA3 and EphB4 tyrosine phosphorylation. This resulted in anti-glioma effects. GLPG1790 down-modulated the expression of mesenchymal markers CD44, Sox2, nestin, octamer-binding transcription factor 3/4 (Oct3/4), Nanog, CD90, and CD105, and up-regulated that of glial fibrillary acidic protein (GFAP) and pro-neural/neuronal markers, βIII tubulin, and neurofilaments. GLPG1790 reduced tumour growth in vivo. These effects were larger compared to radiation therapy (RT; U251 and T98G xenografts) and smaller than those of temozolomide (TMZ; U251 and U87MG cell models). By contrast, GLPG1790 showed effects that were higher than Radiotherapy (RT) and similar to Temozolomide (TMZ) in orthotopic U87MG and CSCs-5 models in terms of disease-free survival (DFS) and overall survival (OS). Further experiments were necessary to study possible interactions with radio- and chemotherapy. GLPG1790 demonstrated anti-tumor effects regulating both the differentiative status of Glioma Initiating Cells (GICs) and the quality of tumor microenvironment, translating into efficacy in aggressive GBM mouse models. Significant common molecular targets to radio and chemo therapy supported the combination use of GLPG1790 in ameliorative antiglioma therapy.

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Ngo, Kenneth, Elena V. Ivanova, Tyler J. Teceno, Carly Campbell, Johanna Lahdenranta, Stephen J. Blakemore, Gavin Bennett, Pasi A. Jänne, Cloud P. Paweletz, and Prafulla C. Gokhale. "Abstract 333: Activity of the erythropoietin-producing hepatocellular A2 receptor (EphA2) targeting Bicycle® Toxin Conjugate (BTC™) BCY6033 in EGFR inhibitor resistant non-small lung cancer (NSCLC) patient derived xenografts." Cancer Research 82, no. 12_Supplement (June 15, 2022): 333. http://dx.doi.org/10.1158/1538-7445.am2022-333.

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Abstract Introduction: EphA2 regulates cell migration, adhesion, proliferation and differentiation, and is overexpressed in human cancers which have been shown to correlate with tumor progression. BCY6033 contains a bicyclic peptide targeting EphA2, linked to the cytotoxin Monomethyl auristatin E via a molecular spacer and cleavable linker designed to target EphA2 expressing tumors. BCY6033 is analogous to BT5528, a BTC™ currently in phase I/II clinical trial in patients with advanced malignancies associated with EphA2 expression. Recent literature indicate that tumor EphA2 expression may be up regulated in EGFR mutant lung models following 1st, 2nd and possibly 3rd generation EGFR inhibitors. Here we report on EphA2 expression in well characterized and clinically annotated patient derived xenografts (PDX) of NSCLC including EGFR mutant NSCLC derived either from erlotinib or osimertinib resistant patients. In vivo activity of BCY6033 is presented in two EphA2 expressing PDX models. Experimental procedures: In vivo, an initial tolerability study was conducted with once weekly administration of BCY6033 by intravenous injection in NSG mice. The activity of BCY6033 was evaluated in EphA2 expressing EGFR mutant PDX models, DFCI-161 and DFCI-220 in NSG mice. A TMA was constructed containing FFPE derived from 69 PDX models (NSCLC n=61, SCLC-transformed n=5, de novo SCLC n=3). Of the 69 models, 35 were EGFR mutant. The TMA was subsequently stained via immunohistochemistry (IHC) using an α-EphA2 (R&D Systems) primary antibody. Tumor membranous H-score was assigned by a pathologist and a score of ≥50 was considered positive. Results: Of the 69 PDXs, 16 were determined to be EphA2 positive. No correlation with genotype or clinical history was observed with EphA2 expression. EphA2 IHC was repeated on at least 5 different tumors for 5 PDX models with fast and robust in vivo growth latency. Two models, DFCI-161 and DFCI-220 with the most reproducible EphA2 staining were selected. Treatment with BCY6033 showed that a dose of 3 mg/kg once weekly administered intravenously was well tolerated in female NSG mice. BCY6033 treatment led to significant tumor growth inhibition with >80% tumor regressions in both DFCI-161 and DFCI-220 PDX models. Re-challenge of tumor out-growth showed that they retain sensitivity to BCY6033 treatment. Conclusion: BCY6033 is a potentially promising drug effective against EphA2 expressing PDX models. Future studies and clinical trials will seek to determine the efficacy of BT5528 in EphA2 expressing tumors. Citation Format: Kenneth Ngo, Elena V. Ivanova, Tyler J. Teceno, Carly Campbell, Johanna Lahdenranta, Stephen J. Blakemore, Gavin Bennett, Pasi A. Jänne, Cloud P. Paweletz, Prafulla C. Gokhale. Activity of the erythropoietin-producing hepatocellular A2 receptor (EphA2) targeting Bicycle® Toxin Conjugate (BTC™) BCY6033 in EGFR inhibitor resistant non-small lung cancer (NSCLC) patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 333.

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Niu, Xu, Haitao Sun, Feng Qiu, Jing Liu, Tianchi Yang, and Wei Han. "miR-10b-5p Suppresses the Proliferation and Invasion of Primary Hepatic Carcinoma Cells by Downregulating EphA2." BioMed Research International 2021 (December 29, 2021): 1–12. http://dx.doi.org/10.1155/2021/1382061.

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Objective. To analyze the function of miR-10b-5p in suppressing the invasion and proliferation of primary hepatic carcinoma cells by downregulating erythropoietin-producing hepatocellular receptor A2 (EphA2). Material and Methods. Eighty-six hepatic carcinoma (HCC) tissue specimens and 86 corresponding adjacent tissue specimens were collected, and the mRNA expression of miR-10b-5p and Ephrin type-A receptor 2 (EphA2) in the specimens was determined using a reverse transcription-polymerase chain reaction (RT-PCR) assay. Western blot was employed to quantify EphA2, B-cell chronic lymphocytic leukemia/lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and Caspase-3 in the cells, and CCK8, Transwell assay, and flow cytometry were applied to evaluate the proliferation, invasion, and apoptosis of cells, respectively. Moreover, the dual luciferase reporter assay was utilized for correlation analysis between miR-10b-5p and EphA2. Results. miR-10b-5p was lowly expressed in HCC, while EphA2 was highly expressed. Cell experiments revealed that miR-10b-5p overexpression or EphA2 knockdown could reduce cell proliferation, accelerate apoptosis, strongly upregulate Bax and Caspase-3, and downregulate Bcl-2. In contrast, miR-10b-5p knockdown or EphA2 overexpression gave rise to reverse biological phenotypes. Furthermore, dual luciferase reporter assay verified that miR-10b-5p was a target of EphA2, and the rescue experiment implied that transfection of pCMV-EphA2 or Si-EphA2 could reverse EphA2 expression and cell biological functions caused by miR-10b-5p overexpression or knockdown. Conclusions. miR-10b-5p reduced HCC cell proliferation but accelerate apoptosis by regulating EphA2, suggesting it has the potential to be a clinical target for HCC.

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Arnone, Claudia Manuela, Vinicia Assunta Polito, Angela Mastronuzzi, Andrea Carai, Francesca Camassei Diomedi, Laura Antonucci, Lucia Lisa Petrilli, et al. "Oncolytic adenovirus and gene therapy with EphA2-BiTE for the treatment of pediatric high-grade gliomas." Journal for ImmunoTherapy of Cancer 9, no. 5 (May 2021): e001930. http://dx.doi.org/10.1136/jitc-2020-001930.

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BackgroundPediatric high-grade gliomas (pHGGs) are among the most common and incurable malignant neoplasms of childhood. Despite aggressive, multimodal treatment, the outcome of children with high-grade gliomas has not significantly improved over the past decades, prompting the development of innovative approaches.MethodsTo develop an effective treatment, we aimed at improving the suboptimal antitumor efficacy of oncolytic adenoviruses (OAs) by testing the combination with a gene-therapy approach using a bispecific T-cell engager (BiTE) directed towards the erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2), conveyed by a replication-incompetent adenoviral vector (EphA2 adenovirus (EAd)). The combinatorial approach was tested in vitro, in vivo and thoroughly characterized at a molecular level.ResultsAfter confirming the relevance of EphA2 as target in pHGGs, documenting a significant correlation with worse clinical outcome of the patients, we showed that the proposed strategy provides significant EphA2-BiTE amplification and enhanced tumor cell apoptosis, on coculture with T cells. Moreover, T-cell activation through an agonistic anti-CD28 antibody further increased the activation/proliferation profiles and functional response against infected tumor cells, inducing eradication of highly resistant, primary pHGG cells. The gene-expression analysis of tumor cells and T cells, after coculture, revealed the importance of both EphA2-BiTE and costimulation in the proposed system. These in vitro observations translated into significant tumor control in vivo, in both subcutaneous and a more challenging orthotopic model.ConclusionsThe combination of OA and EphA2-BiTE gene therapy strongly enhances the antitumor activity of OA, inducing the eradication of highly resistant tumor cells, thus supporting the clinical translation of the approach.

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Ivanov, Andrei I., Alexandre A. Steiner, Adrienne C. Scheck, and Andrej A. Romanovsky. "Expression of Eph receptors and their ligands, ephrins, during lipopolysaccharide fever in rats." Physiological Genomics 21, no. 2 (April 14, 2005): 152–60. http://dx.doi.org/10.1152/physiolgenomics.00043.2004.

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Erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinases and their ligands, ephrins, are involved in embryogenesis and oncogenesis by mediating cell adhesion and migration. Although ephrins can be induced by bacterial LPS in vitro, whether they are involved in inflammation in vivo is unknown. Using differential mRNA display, we found that a febrigenic dose of LPS (50 μg/kg iv) induces a strong transcriptional upregulation of ephrin-A1 in rat liver. We confirmed this finding by real-time RT-PCR. We then quantified the mRNA expression of different ephrins and Eph receptors at phases 1–3 of LPS fever in different organs. Febrile phases 2 (90 min post-LPS) and 3 (300 min) were characterized by robust upregulation (up to 16-fold) and downregulation (up to 21-fold) of several ephrins and Eph receptors. With the exception of EphA2, which showed upregulation in the brain at phase 2, expressional changes of Eph receptors and ephrins were limited to the LPS-processing organs: liver and lung. Characteristic, counter-directed changes in expressional regulation of Eph receptors and their corresponding ligands were found: upregulation of EphA2, downregulation of ephrin-A1 in the liver and lung at phase 2; downregulation of EphB3, upregulation of ephrin-B2 in the liver at phase 2; downregulation of EphA1 and EphA3, upregulation of ephrins-A1 and -A3 in liver at phase 3. In the liver, transcriptional changes of EphA2 and EphB3 at phase 2 were confirmed at protein level. These coordinated, phase-specific responses suggest that different sets of ephrins and Eph receptors may be involved in cellular events (such as disruption of tissue barriers and leukocyte transmigration) underlying different stages of systemic inflammatory response to LPS.

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Satoh, Taroh, Kohei Shitara, Satoru Iwasa, Kensei Yamaguchi, Kei Muro, Yoshito Komatsu, Tomohiro Nishina, et al. "Dose escalation and expansion cohort study for DS-8895a in patients with advanced solid tumors." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 99. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.99.

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99 Background: Erythropoietin-producing hepatocellular receptor A2 (EPHA2) is overexpressed on the cell surface of many tumors and is associated with poor prognosis, suggesting EPHA2 as a target for cancer therapy. DS-8895a is an afucosylated, humanized anti-EPHA2 IgG1 monoclonal antibody with potent cytotoxicity. We report results from a phase I clinical trial to determine safety, tolerability, and pharmacokinetics (PK) of DS-8895a in Japanese patients with advanced solid tumors (NCT02004717). Methods: Step 1 (dose escalation cohort) had patients with advanced solid tumors and comprised of six dose levels (0.1–20 mg/mL, intravenous infusion, every 2 weeks [Q2W]) with a 28-day dose limiting toxicity (DLT) evaluation period. Step 2 (expansion cohort) patients had gastric or esophageal cancer confirmed to be EPHA2 positive by immunohistochemistry. Dose level in Step 2 was determined based on results obtained in Step 1. We evaluated safety, PK, potential biomarkers including circulating NK cells and cytokines, and tumor response. Results: Maximum tolerated dose was not reached in Step 1 (n = 22). DS-8895a was administered at 20 mg/kg Q2W in Step 2 (n = 15). Among 37 patients in the safety analysis set, adverse events (AEs) were reported in 97.3% (64.9% drug-related); 35.1% presented grade ≥ 3 AEs (8.1% drug-related). Dose delay and study discontinuation due to AEs (treatment related: grade 4 platelet decrease, hypoesthesia, hypotension, peripheral coldness, nausea, and vomiting) were observed in one and four patients (20 mg/kg), respectively. Infusion-related reactions occurred in 51.4% of patients resulting in 10 dose interruptions with one discontinuation. Serum inflammatory cytokines were transiently increased 4 h from the end of infusion drug administration. Serum DS-8895a maximum and trough concentrations increased dose-dependently. Biomarkers had no apparent relationship to best overall response. Seven patients in Step 1 achieved stable disease; in Step 2, six patients achieved stable disease and one patient achieved partial response. Conclusions: DS-8895a was safe and well tolerated up to 20 mg/kg. The PK of DS-8895a was dose-dependent as expected. Clinical trial information: NCT02004717.

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Gupta, Kuldeep, Ajay Kumar Sharma, Akhilesh Mishra, Sophia Y. Chen, Gabi Lofland, Todd M. Armstrong, Lei Zhang, Elizabeth M. Jaffee, and Sridhar Nimmagadda. "Abstract 2481: Imaging pancreatic ductal adenocarcinoma using an EphA2 receptor tyrosine kinase binding 68Ga-labeled peptide radiotracer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2481. http://dx.doi.org/10.1158/1538-7445.am2022-2481.

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Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose and has dismal survival rates. Molecular imaging techniques such as positron emission tomography (PET) could fulfill an unmet need and enable an early diagnosis of PDAC to potentially improve survival. EphA2, a member of Erythropoietin-producing hepatocellular (Eph) receptors, plays a pivotal role in the tumorigenesis and development of an immune suppressive microenvironment in PDAC. We therefore developed a peptide-based PET imaging agent for EphA2, [68Ga]AJ201, and evaluated its pharmacokinetics and potential to non-invasively quantify variable EphA2 expression in PDAC. Methods: A Gallium-68 labeled EphA2 binding peptide, [68Ga]AJ201, was synthesized in high radiochemical yields and purity. Surface plasmon resonance (SPR) analysis was carried out to measure binding affinity. EphA2 expression was assessed in PDAC cell lines and tissues in CCLE and TCGA. EphA2 expression in seven PDAC cell lines (Panc1, AsPC1 BxPC3, CFPAC1, Hs766T, Panc1005, and SU8686) was validated by RT-qPCR and flow cytometry. Those cell lines were then used for in vitro binding assays and the corresponding xenografts in NSG mice for PET imaging and ex vivo biodistribution studies (n=4-5/tumor). Specificity of [68Ga]AJ201 was confirmed by co-injection of a blocking dose of non-radioactive AJ201 (1 mg/kg). Results: SPR analysis showed that AJ201 binds EphA2 with a high affinity (KD) of 0.2 nM. TCGA analysis revealed higher expression of EphA2 in PDAC vs healthy tissues. Flow cytometry analysis revealed high and variable EphA2 expression in all the PDAC cell lines tested with Panc1 exhibiting the highest levels. In vitro binding assays showed high and variable [68Ga]AJ201 uptake in all the PDAC cell lines and low uptake in the presence of 1µM non-radioactive AJ201 and in EphA2 negative Jurkat cells. Pharmacokinetics of [68Ga]AJ201 in mice with Panc1 tumors showed high contrast images of EphA2 expression at 60 minutes with a tumor/muscle ratio of 25.9±6.7. That high tumor uptake was significantly reduced in mice receiving blocking dose confirming the specificity of the radiotracer. Also, [68Ga]AJ201 PET quantified variable EphA2 expression in all the seven PDAC xenografts tested, with highest uptake observed in Panc1 tumor, followed by SU8686, and lowest in CFPAC1. Ex vivo biodistribution studies corroborated PET imaging findings. Conclusion: [68Ga]AJ201 is a EphA2 specific high affinity peptide-based PET imaging agent that provides high contrast PET images of PDAC by 60 minutes. [68Ga]AJ201 PET has the potential to non-invasively detect PDAC in patients. Citation Format: Kuldeep Gupta, Ajay Kumar Sharma, Akhilesh Mishra, Sophia Y. Chen, Gabi Lofland, Todd M. Armstrong, Lei Zhang, Elizabeth M. Jaffee, Sridhar Nimmagadda. Imaging pancreatic ductal adenocarcinoma using an EphA2 receptor tyrosine kinase binding 68Ga-labeled peptide radiotracer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2481.

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Iliklerden, Ümit Haluk, and Tolga Kalayci. "New Diagnostic Biomarker-Soluble Erythropoietin-producing hepatocellular receptor A2 (EphA2) for colon cancer." Indian Journal of Surgery, April 19, 2022. http://dx.doi.org/10.1007/s12262-022-03360-0.

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Xu, Huihui, Li Tao, Jinfeng Cao, Peng Zhang, Hui Zeng, and Hongyan Zhao. "Yi Shen Juan Bi Pill alleviates bone destruction in inflammatory arthritis under postmenopausal conditions by regulating ephrinB2 signaling." Frontiers in Pharmacology 13 (September 30, 2022). http://dx.doi.org/10.3389/fphar.2022.1010640.

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Yi Shen Juan Bi Pill (YSJB) is a traditional Chinese medicine (TCM) formulation that has a therapeutic effect upon rheumatoid arthritis (RA), but how YSJB affects bone destruction in arthritis under postmenopausal conditions is not known. We evaluated the therapeutic role of YSJB in bone destruction in postmenopausal arthritis, We used collagen-induced arthritis (CIA) rats who had been ovariectomized (OVX) as models and explored the possible mechanism from the synovium and bone marrow (BM). Arthritis was generated after ovariectomy or sham surgery for 12 weeks. After 14 days of primary immunization, rats were administered YSJB or estradiol valerate (EV) for 28 days. YSJB could prevent bone destruction in the inflamed joints of rats in the OVX + CIA group. CIA promoted osteoclast differentiation significantly in the synovial membrane according to tartrate resistant acid phosphatase (TRACP) staining, and OVX tended to aggravate the inflammatory reaction of CIA rats according to hematoxylin-and-eosin staining. Immunohistochemistry revealed that the synovium did not have significant changes in erythropoietin-producing hepatocellular interactor (ephrin)B2 or erythropoietin-producing hepatocellular (eph) B4 expression after YSJB treatment, but YSJB treatment reduced nuclear factor of activated T cells (NFATc)1 expression. The BM of rats in the OVX + CIA exhibited remarkable increases in the number of osteoclasts and NFATc1 expression, as well as significantly reduced expression of ephrinB2 and ephB4 compared with the CIA group and sham group. YSJB treatment reduced NFATc1 expression significantly but also increased ephrinB2 expression in the BM markedly. These data suggest that YSJB exhibit a bone-protective effect, it may be a promising therapeutic strategy for alleviating bone destruction in arthritis under postmenopausal conditions, and one of the mechanisms is associated with the modulation of ephrinB2 signaling.

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Liu, Xiaoxue, Jianrui Li, Xiang Liao, Zhongqiang Luo, Qiang Xu, Hao Pan, Qing Zhou, et al. "Radiomics-based MRI for predicting Erythropoietin-producing hepatocellular receptor A2 expression and tumor grade in brain diffuse gliomas." Neuroradiology, August 9, 2021. http://dx.doi.org/10.1007/s00234-021-02780-1.

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Liu, Wei, Chengpeng Yu, Jianfeng Li, and Jiwei Fang. "The Roles of EphB2 in Cancer." Frontiers in Cell and Developmental Biology 10 (February 10, 2022). http://dx.doi.org/10.3389/fcell.2022.788587.

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The erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their Eph receptor-interacting (ephrin) ligands together constitute a vital cell communication system with diverse roles. Experimental evidence revealed Eph receptor bidirectional signaling with both tumor-promoting and tumor-suppressing activities in different cancer types and surrounding environment. Eph receptor B2 (EphB2), an important member of the Eph receptor family, has been proved to be aberrantly expressed in many cancer types, such as colorectal cancer, gastric cancer and hepatocellular carcinoma, resulting in tumor occurrence and progression. However, there are no reviews focusing on the dual roles of EphB2 in cancer. Thus, in this paper we systematically summarize and discuss the roles of EphB2 in cancer. Firstly, we review the main biological features and the related signaling regulatory mechanisms of EphB2, and then we summarize the roles of EphB2 in cancer through current studies. Finally, we put forward our viewpoint on the future prospects of cancer research focusing on EphB2, especially with regard to the effects of EphB2 on tumor immunity.

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Song, Leixin, Fan Yang, Zhengtao Wang, Li Yang та Yue Zhou. "Ginsenoside Rg5 inhibits cancer cell migration by inhibiting the nuclear factor‑κB and erythropoietin‑producing hepatocellular receptor A2 signaling pathways". Oncology Letters 21, № 6 (8 квітня 2021). http://dx.doi.org/10.3892/ol.2021.12713.

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Jiang, Huan, Xiao-Yi Yang, and Wei-Jie Zhu. "Dysregulated erythropoietin-producing hepatocellular receptor A2 (EphA2) is involved in tubal pregnancy via regulating cell adhesion of the Fallopian tube epithelial cells." Reproductive Biology and Endocrinology 16, no. 1 (September 3, 2018). http://dx.doi.org/10.1186/s12958-018-0403-5.

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46

Crnkovic, Slaven, Sonja Rittchen, Katharina Jandl, Jürgen Gindlhuber, Diana Zabini, Ayse Ceren Mutgan, Francesco Valzano, et al. "Divergent Roles of Ephrin-B2/EphB4 Guidance System in Pulmonary Hypertension." Hypertension, December 15, 2022. http://dx.doi.org/10.1161/hypertensionaha.122.19479.

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BACKGROUND: Smooth muscle cell (SMC) expansion is one key morphological hallmark of pathologically altered vasculature and a characteristic feature of pulmonary vascular remodeling in pulmonary hypertension. Normal embryonal vessel maturation requires successful coverage of endothelial tubes with SMC, which is dependent on ephrin-B2 and EphB4 ligand-receptor guidance system. In this study, we investigated the potential role of ephrin-B2 and EphB4 on neomuscularization in adult pulmonary vascular disease. METHODS AND RESULTS: Ephrin-B2 and EphB4 expression is preserved in smooth muscle and endothelial cells of remodeled pulmonary arteries. Chronic hypoxia-induced pulmonary hypertension was not ameliorated in mice with SMC-specific conditional ephrin-B2 knockout. In mice with global inducible ephrin-B2 knockout, pulmonary vascular remodeling and right ventricular hypertrophy upon chronic hypoxia exposure were significantly diminished compared to hypoxic controls, while right ventricular systolic pressure was unaffected. In contrast, EphB4 receptor kinase activity inhibition reduced right ventricular systolic pressure in hypoxia-induced pulmonary hypertension without affecting pulmonary vascular remodeling. Genetic deletion of ephrin-B2 in murine pulmonary artery SMC, and pharmacological inhibition of EphB4 in human pulmonary artery smooth muscle cells, blunted mitogen-induced cell proliferation. Loss of EphB4 signaling additionally reduced RhoA expression and weakened the interaction between human pulmonary artery smooth muscle cells and endothelial cells in a three-dimensional coculture model. CONCLUSIONS: In sum, pulmonary vascular remodeling was dependent on ephrin-B2-induced Eph receptor (erythropoietin-producing hepatocellular carcinoma receptor) forward signaling in SMC, while EphB4 receptor activity was necessary for RhoA expression in SMC, interaction with endothelial cells and vasoconstrictive components of pulmonary hypertension.

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Liu, Beibei, Wei Sun, Wuyue Gao, Liqiang Li, Zhenxue Cao, Xiaohuai Yang, Jianmin Liu, and Yuanyuan Guo. "microRNA-451a promoter methylation regulated by DNMT3B expedites bladder cancer development via the EPHA2/PI3K/AKT axis." BMC Cancer 20, no. 1 (October 21, 2020). http://dx.doi.org/10.1186/s12885-020-07523-8.

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Abstract Background The downregulation of microRNA (miR)-451a has been reported in bladder cancer (BCa) tissues. Herein, we elucidated the role of miR-451a in BCa with the involvement of DNA methyltransferase 3B (DNMT3B). Methods We first screened the differentially expressed miRNAs from the serum of 12 BCa patients and 10 healthy controls in the BCa database GSE113486. Subsequently, we detected miR-451a expression and CpG island methylation of the promoter in BCa cells T24 and 5637 with DNMT3B knockdown. The downstream mRNAs of miR-451a were predicted by bioinformatics and KEGG enrichment analysis. Afterwards, the expression patterns of DNMT3B, miR-451a and erythropoietin-producing hepatocellular receptor tyrosine kinase class A2 (EPHA2) were altered in BCa cells to test the ability of cell proliferation, apoptosis, migration as well as invasion. Finally, the effect of miR-451a and DNMT3B was evaluated in vivo. Results miR-451a was significantly reduced in serum of BCa patients and cell lines. Moreover, the expression of DNMT3B in BCa cells was significantly increased, thus promoting methylation of the miR-451a promoter, resulting in miR-451a inhibition. Additionally, we found that miR-451a targeted and negatively regulated EPHA2, while EPHA2 could activate the PI3K/AKT signaling, driving BCa cell growth and metastasis. Conclusions Our study proposed and demonstrated that miR-451a downregulation mediated by DNMT3B is critical for proliferation, migration, and invasion of BCa, which may be beneficial for developing more effective therapies against BCa.

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Antonucci, Laura, Gabriele Canciani, Angela Mastronuzzi, Andrea Carai, Giada Del Baldo, and Francesca Del Bufalo. "CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies." Frontiers in Immunology 13 (May 4, 2022). http://dx.doi.org/10.3389/fimmu.2022.867154.

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High-Grade Gliomas (HGG) are among the deadliest malignant tumors of central nervous system (CNS) in pediatrics. Despite aggressive multimodal treatment - including surgical resection, radiotherapy and chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches. Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric proteins, known as chimeric antigen receptors (CARs), targeting selected tumor-associated antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the antigens common to adult glioblastoma – such as interleukin-13 receptor alpha 2 (IL-13α2), human epidermal growth factor receptor 2 (HER-2) and erythropoietin-producing human hepatocellular carcinoma A2 receptor (EphA2). CAR-T therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target antigen expression and the difficulty of accessing the tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells – like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T therapies overcoming these hurdles.

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Luan, Wenkang, Yuting Ding, Haolan Xi, Hongru Ruan, Feng Lu, Shaojun Ma, and Jinlong Wang. "Exosomal miR-106b-5p derived from melanoma cell promotes primary melanocytes epithelial-mesenchymal transition through targeting EphA4." Journal of Experimental & Clinical Cancer Research 40, no. 1 (March 19, 2021). http://dx.doi.org/10.1186/s13046-021-01906-w.

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Abstract Background Cancer-secreted exosomal miRNAs regulates the biological processes of many tumours. The serum level of exosomal miR-106b-5p is significantly increased in melanoma patients. However, the role and molecular mechanisms of exosomal miR-106b-5p in melanoma remains unclear. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-106b-5p and EphA4 in melanoma tissues. Transmission electron microscopy (TEM) and western blotting were used to identify exosome. QRT-qPCR and Cy3-labelled miR-106b-5p were used to demonstrated the transmission of melanoma cell-secreted exosomal miR-106b-5p. Western blotting, Immunofluorescence, adhesion, transwell and scratch wound assay were used to explore the role of exosomal miR-106b-5p in melanocytes. Luciferase reporter assays and RNA-Chromatin Immunoprecipitation (ChIP) assay were used to confirm whether erythropoietin-producing hepatocellular carcinoma receptor A4 (EphA4) was a direct target of miR-106b-5p. Results We found that miR-106b-5p levels were increased in melanoma tissue, and high miR-106b-5p expression is an independent risk factor for the overall survival of patients with melanoma. miR-106b-5p is enriched in melanoma cell-secreted exosomes and transferred to melanocytes. Exosomal miR-106b-5p promotes the epithelial-to-mesenchymal transition (EMT), migration, invasion and adhesion of melanocytes. Exosomal miR-106b-5p exerted its role by targeting EphA4 to activate the ERK pathway. We demonstrated that exosomal miR-106b-5p promoted melanoma metastasis in vivo through pulmonary metastasis assay. Conclusions Thus, melanoma cell-secreted exosomal miR-106b-5p may serve as a diagnostic indicator and potential therapeutic target in melanoma patients.

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