Academic literature on the topic 'IGF1R overexpression'
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Journal articles on the topic "IGF1R overexpression"
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Kim, Jenny J., Nilda Gonzalez-Roibon, Alcides Chaux, et al. "Overexpression of IGF1R to predict outcome in invasive urothelial carcinoma of urinary bladder." Journal of Clinical Oncology 31, no. 6_suppl (2013): 280. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.280.
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280 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed (OE) in several tumors including bladder cancer and is currently under investigation as a target of Rx. Here we explore IGF1R expression in urothelial carcinoma (UC), its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered OE in cases with score 1. Endpoints of the study included overall survival and cancer-specific survival. Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R was OE in 62% of UC. No differences were noted between normal urothelium and malignant counterparts (74% vs. 60%; P=0.14). IGFR1 was more frequently OE in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). pT4 tumors OE IGF1R more frequently than pT1-pT3 tumors (71% vs. 29%, P=0.005). No association was found with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis). Overall survival (OS) and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients whose tumors OE IGF1R had a lower OS and DSS compared to those whose tumors did not OE IGF1R (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R overexpression remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: Overexpression of IGF1R was found in 62% of UC. High stage tumors OE IGF1R more frequently than low stage tumors. More importantly, IGF1R overexpression was a significant independent predictor of OS and DSS.
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Walser, Marion, Maria Teresa Samà, Ruth Wickelgren, et al. "Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus." Journal of Endocrinology 215, no. 2 (2012): 257–68. http://dx.doi.org/10.1530/joe-12-0077.
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GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2′-deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increasedIgf1andGfapmRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a(Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2(Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs(Glul)). However, IGF1R was correlated with the expression ofDor,Nr2a,Sapap2,GsandGfap. In summary, although localbGHexpression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose–response curve and cell-specific expression ofbGH.
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Gonzalez-Ribbon, Nilda, Jenny J. Kim, Alcides Chaux, et al. "Association of IGF1R overexpression (OE) with outcome in invasive urothelial carcinoma (UC) of urinary bladder." Journal of Clinical Oncology 31, no. 15_suppl (2013): 4523. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4523.
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4523 Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed in several tumors including UC and is currently under investigation as a target of Rx. We here explore IGF1R expression in UC, its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered overexpressed in cases with score 1. Endpoints of the study included overall survival (OS) and disease-specific survival (DSS). Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R OE was found in 62% of UC. No differences were noted between normal urothelium and UC regarding IGF1R OE (74% vs. 60%; P=0.14). IGFR1 OE was more frequent in tumors from African-American patients compared to Caucasians (100% vs. 59%, P=0.04). Tumors at stage pT4 overexpressed IGF1R more frequently than tumors at stages pT1-pT3 (71% vs. 29%, P=0.005). No association with other analyzed clinicopathologic parameters such as patient's age or gender, muscularis propria invasion, or lymph node metastasis) was found. OS and disease-specific survival (DSS) rates were 58% and 69%, respectively. Patients with tumors overexpressing IGF1R had a lower OS and DSS compared to those without IGF1R OE (Mantel-Cox P=0.0007 and P=0.006, respectively). Using Cox proportional hazards regression, IGF1R OE remained a significant predictor of OS (HR=3.49, P=0.001) and DSS (HR=3.54, P=0.007) after adjusting for pathologic stage. Conclusions: OE of IGF1R was found in 62% of UC. High stage tumors overexpressed IGF1R more frequently than low stage tumors. Further, IGF1R OE was a significant independent predictor of OS and DSS in invasive UC.
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McMullen, Julie R., Tetsuo Shioi, Li Zhang, et al. "Deletion of Ribosomal S6 Kinases Does Not Attenuate Pathological, Physiological, or Insulin-Like Growth Factor 1 Receptor-Phosphoinositide 3-Kinase-Induced Cardiac Hypertrophy." Molecular and Cellular Biology 24, no. 14 (2004): 6231–40. http://dx.doi.org/10.1128/mcb.24.14.6231-6240.2004.
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ABSTRACT Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1−/−, S6K2−/−, and S6K1−/− S6K2−/− mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.
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Kavurma, Mary M., Nichola Figg, Martin R. Bennett, John Mercer, Levon M. Khachigian, and Trevor D. Littlewood. "Oxidative stress regulates IGF1R expression in vascular smooth-muscle cells via p53 and HDAC recruitment." Biochemical Journal 407, no. 1 (2007): 79–87. http://dx.doi.org/10.1042/bj20070380.
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Apoptosis of VSMCs (vascular smooth-muscle cells) leads to features of atherosclerotic plaque instability. We have demonstrated previously that plaque-derived VSMCs have reduced IGF1 (insulin-like growth factor 1) signalling, resulting from a decrease in the expression of IGF1R (IGF1 receptor) compared with normal aortic VSMCs [Patel, Zhang, Siddle, Soos, Goddard, Weissberg and Bennett (2001) Circ. Res. 88, 895–902]. In the present study, we show that apoptosis induced by oxidative stress is inhibited by ectopic expression of IGF1R. Oxidative stress repressed IGF1R expression at multiple levels, and this was also blocked by mutant p53. Oxidative stress also induced p53 phosphorylation and apoptosis in VSMCs. p53 negatively regulated IGF1R promoter activity and expression and, consistent with this, p53−/− VSMCs demonstrated increased IGF1R expression, both in vitro and in advanced atherosclerotic plaques in vivo. Oxidative-stress-induced interaction of endogenous p53 with TBP (TATA-box-binding protein) was dependent on p53 phosphorylation. Oxidative stress also increased the association of p53 with HDAC1 (histone deacetylase 1). Trichostatin A, a specific HDAC inhibitor, or p300 overexpression relieved the repression of IGF1R following oxidative stress. Furthermore, acetylated histone-4 association with the IGF1R promoter was reduced in cells subjected to oxidative stress. These results suggest that oxidative-stress-induced repression of IGF1R is mediated by the association of phosphorylated p53 with the IGF1R promoter via TBP, and by the subsequent recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF1R promoter–TBP–p53 complex.
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Bareja, Akshay, Conrad P. Hodgkinson, Alan J. Payne, Richard E. Pratt, and Victor J. Dzau. "HASF (C3orf58) is a novel ligand of the insulin-like growth factor 1 receptor." Biochemical Journal 474, no. 5 (2017): 771–80. http://dx.doi.org/10.1042/bcj20160976.
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We have recently shown that hypoxia and Akt-induced stem cell factor (HASF) protects the heart from ischemia-induced damage and promotes cardiomyocyte proliferation. While we have identified certain signaling pathways responsible for these protective effects, the receptor mediating these effects was unknown. Here, we undertook studies to identify the HASF receptor. A yeast two-hybrid screen identified a partial fragment of insulin-like growth factor 1 receptor (IGF1R) as a binding partner of HASF. Subsequent co-immunoprecipitation experiments showed that HASF bound to full-length IGF1R. Binding assays revealed a high affinity of HASF for IGF1R. The treatment of neonatal ventricular cardiomyocytes with HASF resulted in the phosphorylation of IGF1R and other proteins known to be involved in IGF1R-mediated signaling pathways. HASF-mediated ERK activation was abrogated by IGF1R pharmacological inhibitors and siRNAs that targeted IGF1R. However, siRNA-mediated knockdown of either IGF2R or the insulin receptor had no effect on HASF-induced cell signaling. Additionally, pharmacologic inhibition of IGF1R impeded HASF's ability to induce cardiomyocyte proliferation. Finally, we documented that in vivo deletion of the IGF1R completely abolished the ability of HASF to promote cardiomyocyte proliferation in an overexpression mouse model providing further evidence in vivo that the IGF1R is the functional receptor for HASF.
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Panebianco, Federica, Lindsey M. Kelly, Pengyuan Liu, et al. "THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer." Proceedings of the National Academy of Sciences 114, no. 9 (2017): 2307–12. http://dx.doi.org/10.1073/pnas.1614265114.
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Thyroid cancer development is driven by known point mutations or gene fusions found in ∼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in ∼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit.
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Jen, Hsin-Wei, De-Leung Gu, Yaw-Dong Lang, and Yuh-Shan Jou. "PSPC1 Potentiates IGF1R Expression to Augment Cell Adhesion and Motility." Cells 9, no. 6 (2020): 1490. http://dx.doi.org/10.3390/cells9061490.
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Paraspeckle protein 1 (PSPC1) overexpression in cancers is known to be the pro-metastatic switch of tumor progression associated with poor prognosis of cancer patients. However, the detail molecular mechanisms to facilitate cancer cell migration remain elusive. Here, we conducted integrated analysis of human phospho-kinase antibody array, transcriptome analysis with RNA-seq, and proteomic analysis of protein pulldown to study the molecular detail of PSPC1-potentiated phenotypical transformation, adhesion, and motility in human hepatocellular carcinoma (HCC) cells. We found that PSPC1 overexpression re-assembles and augments stress fiber formations to promote recruitment of focal adhesion contacts at the protruding edge to facilitate cell migration. PSPC1 activated focal adhesion-associated kinases especially FAK/Src signaling to enhance cell adhesion and motility toward extracellular matrix (ECM). Integrated transcriptome and gene set enrichment analysis indicated that PSPC1 modulated receptor tyrosine kinase IGF1R involved in the focal adhesion pathway and induction of diverse integrins expression. Knockdown IGF1R expression and treatment of IGF1R inhibitor suppressed PSPC1-induced cell motility. Interestingly, knockdown PSPC1-interacted paraspeckle components including NONO, FUS, and the lncRNA Neat1 abolished PSPC1-activated IGF1R expression. Together, PSPC1 overexpression induced focal adhesion formation and facilitated cell motility via activation of IGF1R signaling. PSPC1 overexpression in tumors could be a potential biomarker of target therapy with IGF1R inhibitor for improvement of HCC therapy.
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Corless, C. L., C. Beadling, E. Justusson, and M. C. Heinrich. "Evaluation of the presence of IGF1R overexpression in wild-type and kinase mutant GI stromal tumors." Journal of Clinical Oncology 27, no. 15_suppl (2009): 10506. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10506.
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10506 Background: Most adult GI stromal tumors have gain-of-function mutations in KIT (80%) or PDGFRA (5–7%). These pathogenetic mutations are the target for kinase inhibitor therapy. The pathogenesis of the 10–15% of GISTs lacking kinase mutations (WT GIST) is unknown; this includes most pediatric GISTs. Recently, Tarn et al. (PNAS 2008) identified IGF1R over-expression in all WT GIST in their series of cases, including one pediatric case. IGF1R may represent a novel therapeutic target for WT GISTs. Methods: We developed a quantitative RQ-PCR assay for IGF1R and GAPDH transcripts that is linear over 5 logs (R2 values of 0.99 and 0.98, respectively). We prepared cDNA from RNA isolated from 79 archival, formalin-fixed, paraffin-embedded GIST specimens and quantified IGF1R expression as the % ratio of IGF1R/GAPDH transcripts. We had previously genotyped the tumors to identify any kinase mutations. Results: Adult WT GIST had a 10–15 fold higher expression of IGF1R transcript than kinase mutant GISTs (WT GIST 13.7 ±18, n=35; KIT exon 11 mutant GIST 1.0 ± 1.1, n=26; PDGFRA mutant GIST 0.9 ± 1.0, n=8; KIT 9 or 13 mutation 0.8 ± 0.6, n=5). Interestingly, the WT GIST group could be further divided into tumors with low vs. high IGF1R expression. The low IGF1R expression group (mean 0.6, range 0.1–1.9, n=14), had similar IGF1R expression to kinase mutant GISTs. In contrast, the high expression group had more than 30-fold higher levels of IGF1R transcript (mean 22.5, range 7.3–76.5, n=21). We also examined IGF1R expression in 5 WT pediatric GISTs. The mean IGF1R expression in pediatric GISTs resembled that of the adult high expression group, with 4 of 5 cases showing IGF1R over-expression. Conclusions: WT GISTs are heterogeneous with regard to IGF1R expression and can be divided into two subgroups. One third of the WT GISTs overlap with kinase-mutant GISTs, while the remainder express IGF1R at more than 30-fold higher levels. These results have implications for evolving models of GIST pathogenesis and the clinical testing of IGF1R monoclonal antibodies for treatment of metastatic GIST. [Table: see text]
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Ferreira Mendes, Jéssica Mariane, Ludmila de Faro Valverde, Manuela Torres Andion Vidal, et al. "Effects of IGF-1 on Proliferation, Angiogenesis, Tumor Stem Cell Populations and Activation of AKT and Hedgehog Pathways in Oral Squamous Cell Carcinoma." International Journal of Molecular Sciences 21, no. 18 (2020): 6487. http://dx.doi.org/10.3390/ijms21186487.
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(1) Background: Activation of the PI3K-AKT pathway controls most hallmarks of cancer, and the hedgehog (HH) pathway has been associated with oral squamous cell carcinoma (OSCC) development and progression. We hypothesized that fibroblast-derived insulin-like growth factor-1 (IGF-1) acts in oral squamous cell carcinoma (OSCC) cells, leading to the non-canonical activation of the HH pathway, maintaining AKT activity and promoting tumor aggressiveness. (2) Methods: Primary fibroblasts (MF1) were genetically engineered for IGF-1 overexpression (MF1-IGF1) and CRISPR/Cas9-mediated IGF1R silencing was performed in SCC-4 cells. SCC-4 cells were co-cultured with fibroblasts or incubated with fibroblast conditioned medium (CM) or rIGF-1 for functional assays and the evaluation of AKT and HH pathways. (3) Results: Gene expression analysis confirmed IGF-1 overexpression in MF1-IGF1 and the absence of IGF-1 expression in SCC-4, while elevated IGF1R expression was detected. IGF1R silencing was associated with decreased survival of SCC-4 cells. Ihh was expressed in both MF1 and MF1-IGF1, and increased levels of GLI1 mRNA were observed in SCC-4 after stimulation with CM-MF1. Activation of both PI3K-AKT and the HH pathway (GLI1, Ihh and SMO) were identified in SCC-4 cells cultured in the presence of MF1-IGF1-CM. rIGF-1 promoted tumor cell proliferation, migration, invasion and tumorsphere formation, whereas CM-MF1 significantly stimulated angiogenesis. (4) Conclusions: IGF-1 exerts pro-tumorigenic effects by stimulating SCC-4 cell proliferation, migration, invasion and stemness. AKT and HH pathways were activated by IGF-1 in SCC-4, reinforcing its influence on the regulation of these signaling pathways.
Dissertations / Theses on the topic "IGF1R overexpression"
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Oberthür, Rabea. "Analysis of the function of the IGF1R during the development and therapy of colorectal cancer." Doctoral thesis, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7CC8-1.
Full textBook chapters on the topic "IGF1R overexpression"
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Yang, Xu, Wei Li, Hangyuan He, et al. "H3K9 Acetylation Level of 11β-HSD2 in Human Wharton’s Jelly-Derived Mesenchymal Stem Cells: A Potential Biomarker for Evaluating Susceptibility to Multiple Chronic Diseases in Adulthood." In Stem Cells and Regenerative Medicine. IOS Press, 2021. http://dx.doi.org/10.3233/bhr210009.
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Objective: A large number of studies have suggested that low birth weight fetuses were susceptible to fetal-originated diseases in adulthood. The purpose of this study was to investigate whether the histone 3 Lysine 9 (H3K9) acetylation level of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) was an early warning marker for the susceptibility of multiple chronic diseases in adulthood. Methods: The epigenetic and expressional abnormality of 11β-HSD2 in human WJ-MSCs induced by a variety of prenatal adverse xenobiotic factors were analyzed by real-time quantitative PCR (RT-qPCR), chromatin immunoprecipitation (ChIP) and western blotting (WB). The expression of insulin-like growth factor 1 (IGF1) in human WJ-MSCs after overexpression or knockdown of 11β-HSD2 gene was analyzed by RT-qPCR. Finally, immunofluorescence and ChIP-PCR were used to analyze the H3K9 acetylation level and expression of 11β-HSD2 in the human umbilical cord with intrauterine growth retardation (IUGR). Results: The mRNA and protein expression of 11β-HSD2 in WJ-MSCs were decreased after treatment with caffeine, nicotine, and ethanol. The histone acetylation level in 11β-HSD2 promoter region (H3K9) was significantly reduced simultaneously. In the proliferation model of WJ-MSCs, 300 nM of cortisol promoted the gene expression of the IGF1 pathway, while 1200 nM inhibited the gene expression of the IGF1 pathway. The expression of IGF1 treated with cortisol at 300 nM was decreased after overexpression of 11β-HSD2, while the expression of IGF1 was increased after treatment with 1200 nM cortisol. After knockdown of 11β-HSD2, the expression of IGF1 was decreased after treatment with 300 nM cortisol, and IGF1 gene expression decreased further after treatment with 1200 nM cortisol. Besides, the expression and H3K9 acetylation level of 11β-HSD2 in the IUGR-derived human umbilical cord was also reduced. Conclusion: The decreased expression and H3K9 acetylation level of 11β-HSD2 in WJ-MSCs induced by multiple xenobiotics exposures may mediate the decreased expression of IGF1. The H3K9 acetylation level of 11β-HSD2 in the human umbilical cord might be an early warning biomarker for evaluating susceptibility to multiple chronic diseases in adulthood.
Conference papers on the topic "IGF1R overexpression"
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Zhu, Shoumin, Mohammed Soutto, Zheng Chen, and Wael El-Rifai. "Abstract 5447: Overexpression of DARPP-32 promotes activation of STAT3 through IGF1R-SRC axis in gastric cancer." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5447.
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