Research IndicatorsGraph generated 11 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (3)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IRS2 (cancer-related)
Therapies targeting the type I insulin-like growth factor receptor (IGF-1R) have not been developed with predictive biomarkers to identify tumors with receptor activation. We have previously shown that the insulin receptor substrate (IRS) adaptor proteins are necessary for linking IGF1R to downstream signaling pathways and the malignant phenotype in breast cancer cells. The purpose of this study was to identify gene expression profiles downstream of IGF1R and its two adaptor proteins. IRS-null breast cancer cells (T47D-YA) were engineered to express IRS-1 or IRS-2 alone and their ability to mediate IGF ligand-induced proliferation, motility, and gene expression determined. Global gene expression signatures reflecting IRS adaptor specific and primary vs. secondary ligand response were derived (Early IRS-1, Late IRS-1, Early IRS-2 and Late IRS-2) and functional pathway analysis examined. IRS isoforms mediated distinct gene expression profiles, functional pathways, and breast cancer subtype association. For example, IRS-1/2-induced TGFb2 expression and blockade of TGFb2 abrogated IGF-induced cell migration. In addition, the prognostic value of IRS proteins was significant in the luminal B breast tumor subtype. Univariate and multivariate analyses confirmed that IRS adaptor signatures correlated with poor outcome as measured by recurrence-free and overall survival. Thus, IRS adaptor protein expression is required for IGF ligand responses in breast cancer cells. IRS-specific gene signatures represent accurate surrogates of IGF activity and could predict response to anti-IGF therapy in breast cancer.
Amplification of genes at 13q34 has been reported to be associated with tumor proliferation and progression in diverse types of cancers. However, its role in intrahepatic cholangiocarcinoma (iCCA) has yet to be explored. We examined two iCCA cell lines and 86 cases of intrahepatic cholangiocarcinoma to analyze copy number of three target genes, including cullin 4A (CUL4A), insulin receptor substrate 2 (IRS2), and transcription factor Dp-1 (TFDP1) at 13q34 by quantitative real-time polymerase chain reaction. The cell lines and all tumor samples were used to test the relationship between copy number (CN) alterations and protein expression by western blotting and immunohistochemical assays, respectively. IRS2 was introduced, and each target gene was silenced in cell lines. The mobility potential of cells was compared in the basal condition and after manipulation using cell migration and invasion assays. CN alterations correlated with protein expression levels. The SNU1079 cell line containing deletions of the target genes demonstrated decreased protein expression levels and significantly lower numbers of migratory and invasive cells, as opposed to the RBE cell line, which does not contain CN alterations. Overexpression of IRS2 by introducing IRS2 in SUN1079 cells increased the mobility potential. In contrast, silencing each target gene showed a trend or statistical significance toward inhibition of migratory and invasive capacities in RBE cells. In tumor samples, the amplification of each of these genes was associated with poor disease-free survival. Twelve cases (13.9%) demonstrated copy numbers > 4 for all three genes tested (CUL4A, IRS2, and TFDP1), and showed a significant difference in disease-free survival by both univariate and multivariate survival analyses (hazard ratio, 2.69; 95% confidence interval, 1.23 to 5.88; P = 0.013). Our data demonstrate that amplification of genes at 13q34 plays an oncogenic role in iCCA featuring adverse disease-free survival, which may provide new directions for targeted therapy.
Liu H, Ren G, Zhu L, et al.The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2.
Tumour Biol. 2016; 37(4):4641-7 [PubMed
] Related Publications
In recent years, microRNAs, also called as miRNAs, play an important role in carcinogenesis, and the dysregulation of miRNAs is closely associated with cancer progression. Till now, little has been known about the role of miRNA-146a in the esophageal squamous cell carcinomas (ESCC). In the present study, we used in vitro assays to investigate the mechanisms of miRNA-146a in ESCC cell lines and 60 ESCC tissues. Here, we found that miRNA-146a expression is downregulated in both ESCC cell lines and tissues and obviously associated with pathological indicators, such as metastasis and stage of ESCC. In addition, the overexpression of miRNA-146a suppressed EC109 and TE8 cell proliferation and invasion. Meanwhile, miRNA-146a overexpression extremely inhibited the protein expression of insulin receptor substrate 2 (IRS2). Notably, the enforced expression of IRS2 in EC109 cells with miRNA-146a overexpression attenuated the inhibitory effects of miRNA-146a. In conclusion, our findings suggest that miRNA-146a may function as a useful clinical tool in the treatment and diagnosis of ESCC, and its overexpression suppressed cell growth through inhibition of IRS2. Thus, miRNA-146a pathway may be recommended as potential makers for drug design.
Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.
Anjali G, Kaur S, Lakra R, et al.FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients.
Cell Signal. 2015; 27(12):2452-66 [PubMed
] Related Publications
Follicle stimulating hormone (FSH) plays a central role in growth and differentiation of ovarian follicles. A plethora of information exists on molecular aspects of FSH responses but little is known about the mechanisms involved in its cross-talk with insulin/IGF-1 pathways implicated in the coordination of energy homeostasis in preovulatory granulosa cells (GCs). In this study, we hypothesized that FSH may regulate IRS-2 expression and thereby maintain the energy balance in GCs. We demonstrate here that FSH specifically increases IRS-2 expression in human and rat GCs. FSH-stimulated IRS-2 expression was inhibited by actinomycin D or cycloheximide. Furthermore, FSH decreases IRS-2 mRNA degradation indicating post-transcriptional stabilization. Herein, we demonstrate a role of cAMP pathway in the activation of IRS-2 expression by FSH. Scan and activity analysis of IRS-2 promoter demonstrated that FSH regulates IRS-2 expression through SP1 binding sites. FSH stimulates SP1 translocation into nucleus and its binding to IRS-2 promoter. These results are corroborated by the fact that siRNA mediated knockdown of IRS-2 decreased the FSH-stimulated PI3K activity, p-Akt levels, GLUT4 translocation and glucose uptake. However, FSH was not able to increase IRS-2 expression in GCs from PCOS women undergoing IVF. Interestingly, IRS-2 mRNA expression was downregulated in GCs from the PCOS rat model. Taken together, our findings establish that FSH induces IRS-2 expression and thereby activates PI3K, Akt and glucose uptake. Crucially, our data confirms a molecular defect in FSH action in PCOS GCs which may cause deceleration of metabolism and follicular growth leading to infertility. These results lend support for a therapeutic potential of IRS-2 in the management of PCOS.
Park DH, Jeon HS, Lee SY, et al.MicroRNA-146a inhibits epithelial mesenchymal transition in non-small cell lung cancer by targeting insulin receptor substrate 2.
Int J Oncol. 2015; 47(4):1545-53 [PubMed
] Related Publications
During cancer progression, some tumor cells show changes in their plasticity by morphological and phenotypical conversions, as an expression of mesenchymal markers and loss of epithelial markers, collectively referred to as epithelial-mesenchymal transition (EMT). EMT has been increasingly recognized as a critical phenomenon in lung cancer progression. The goal of this study was to identify microRNAs involved in lung cancer progression. A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in mesenchymal-like lung cancer cells. The role of miR‑146a in lung cancer progression was measured by invasion and migration assays in vitro. Bioinformatics and luciferase report assays were used to identify the target of miR‑146a. The expression of miR‑146a was reduced in mesenchymal-like lung cancer cell lines. The overexpression of miR‑146a induced a marked reduction of the mesenchymal marker and increase the epithelial marker in lung cancer cell lines. Moreover, the overexpression of miR‑146a suppressed lung cancer cell migration and invasion. Co-treatment with miR‑146a and gefitinib treatment showed a significant reduction of invasion in the resistant lung cancer cells induced by EMT. The expression of miR‑146a was downregulated in advanced lung cancer tissues. Insulin receptor substrate 2 (IRS2), an adaptor protein that modulates normal growth, metabolism, survival, and differentiation, was identified as a target of miR‑146a. miR‑146a regulated the expression of IRS2 at the mRNA and protein levels. These data demonstrate for the first time that miR‑146a suppresses lung cancer progression by repressing IRS2 expression. This provides new insight into the post-transcriptional regulation of lung cancer progression by miRNAs, a potential approach for the treatment of lung cancer.
Xin C, Jing D, Jie T, et al.The expression difference of insulin-like growth factor 1 receptor in breast cancers with or without diabetes.
J Cancer Res Ther. 2015 Apr-Jun; 11(2):295-9 [PubMed
] Related Publications
CONTEXT: The insulin-like growth factor (IGF) and insulin receptors' (IR) axes play important roles in both breast cancer and diabetes mellitus.
AIM: We tend to explore the expression characteristics of proteins in IGF/IR axis in breast cancer with type 2 diabetes mellitus (T2DM).
SETTINGS AND DESIGN: We conducted a case-control investigation of T2DM and non-diabetes (n = 40, 1:1) in breast cancer patients.
MATERIALS AND METHODS: Some important molecules of IGF/IR axis were detected in breast cancer tissues by immunohistochemical staining. The multivariable analyses of the relationship of clinicopathological characters with the significant molecules were also detected.
STATISTICAL ANALYSIS USED: The results were statistically evaluated by Statistical Package for the Social Sciences (SPSS version 17.0) software. Chi-square test and logistic regression are used.
RESULTS: Higher expression of IGF 1 receptor (IGF1R) was found in breast cancers of patients with T2DM, compared those without diabetes (P = 0.044). Negative expression of human epidermal growth factor receptor 2 (Her2) was found to be associated with higher expression of IGF1R in the breast cancers of patients with T2DM. There were no differences found in the expression of proteins of IGF-1, IGF-2, IGF-binding protein 3 (IGFBP3), IR, insulin receptor substrate (IRS)-1, IRS-2 and mammalian target of rapamycin (mTOR) between T2DM group and non-diabetes group.
CONCLUSION: Our study found that breast cancer with T2DM had a higher expression of IGF1R, and the higher IGF1R was associated with negative Her2 expression.
BACKGROUND: The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.
CASE PRESENTATIONS: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.
CONCLUSIONS: Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.
Ma Y, Zhang H, He X, et al.miR-106a* inhibits the proliferation of renal carcinoma cells by targeting IRS-2.
Tumour Biol. 2015; 36(11):8389-98 [PubMed
] Related Publications
MicroRNAs play critical roles in the development and progression of human cancers. Although it has been reported that miR-106a* is downregulated in follicular lymphoma, its role in renal cell carcinoma (RCC) remains unknown. This study investigated the expression and role of miR-106a* in human RCC. Our results showed that the miR-106a* expression decreased dramatically in clinical RCC tissues and cell lines. In vitro, overexpression of miR-106a* suppressed RCC cell proliferation and S/G2 transition, whereas inhibition of miR-106a* promoted cell proliferation and S/G2 transition. It was also found that miR-106a* expression was inversely correlated with the expression of insulin receptor substrate 2 (IRS-2). IRS-2 was determined to be a direct target of miR-106a* by a luciferase reporter assay. Importantly, silencing IRS-2 resulted in the same biologic effects as those of miR-106a* overexpression in RCC cells, including inhibition of RCC cell proliferation and triggering of S/G2 cell cycle arrest with inhibition of the PI3K/Akt signaling pathway. These results indicate that miR-106a* affects RCC progression by targeting IRS-2 with suppression of the PI3K/Akt signaling pathway in RCC cells. The findings suggest miR-106a* as a novel strategy for RCC treatment.
Zekri AR, Hassan ZK, Bahnassy AA, et al.Differentially expressed genes in metastatic advanced Egyptian bladder cancer.
Asian Pac J Cancer Prev. 2015; 16(8):3543-9 [PubMed
] Related Publications
BACKGROUND: Bladder cancer is one of the most common cancers worldwide. Gene expression profiling using microarray technologies improves the understanding of cancer biology. The aim of this study was to determine the gene expression profile in Egyptian bladder cancer patients.
MATERIALS AND METHODS: Samples from 29 human bladder cancers and adjacent non-neoplastic tissues were analyzed by cDNA microarray, with hierarchical clustering and multidimensional analysis.
RESULTS: Five hundred and sixteen genes were differentially expressed of which SOS1, HDAC2, PLXNC1, GTSE1, ULK2, IRS2, ABCA12, TOP3A, HES1, and SRP68 genes were involved in 33 different pathways. The most frequently detected genes were: SOS1 in 20 different pathways; HDAC2 in 5 different pathways; IRS2 in 3 different pathways. There were 388 down-regulated genes. PLCB2 was involved in 11 different pathways, MDM2 in 9 pathways, FZD4 in 5 pathways, p15 and FGF12 in 4 pathways, POLE2 in 3 pathways, and MCM4 and POLR2E in 2 pathways. Thirty genes showed significant differences between transitional cell cancer (TCC) and squamous cell cancer (SCC) samples. Unsupervised cluster analysis of DNA microarray data revealed a clear distinction between low and high grade tumors. In addition 26 genes showed significant differences between low and high tumor stages, including fragile histidine triad, Ras and sialyltransferase 8 (alpha) and 16 showed significant differences between low and high tumor grades, like methionine adenosyl transferase II, beta.
CONCLUSIONS: The present study identified some genes, that can be used as molecular biomarkers or target genes in Egyptian bladder cancer patients.
Cui A, Hua H, Shao T, et al.Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration.
Tumour Biol. 2015; 36(8):6507-13 [PubMed
] Related Publications
AflatoxinB1 (AFB1) is well known as a potent carcinogen. Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1-8,9-exo-epoxide, which acts as a mutagen to react with DNA. In addition, recent study demonstrates AFB1 positively regulates type I insulin-like growth factor receptor (IGF-IR) signaling in hepatoma cells. The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate (IRS) in lung cancer cells and the effects of AFB1 on lung cancer cell migration. To this end, the effects of AFB1 on IRS expression, Src, Akt, and ERK phosphorylation were measured by Western blot analysis. The migration of lung cancer cells was detected by wound-healing assay. AFB1 downregulates IRS1 but paradoxically upregulates IRS2 through positive regulation of the stability of IRS2 and the proteasomal degradation of IRS1 in lung cancer cell lines A549 and SPCA-1. In addition, AFB1 induces Src, Akt, and ERK1/2 phosphorylation. Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1-induced IRS2 accumulation. Moreover, AFB1 stimulates lung cancer cell migration, which can be inhibited by saracatinib. We conclude that AFB1 may upregulate IRS2 and stimulate lung cancer cell migration through Src.
Nunes M, Vrignaud P, Vacher S, et al.Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data.
Cancer Res. 2015; 75(8):1560-6 [PubMed
] Related Publications
Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies.
MicroRNAs (miRNAs) are dysregulated in many types of malignant diseases, including colorectal cancer. miRNA 30a (miR-30a) is a member of the miR-30 family and has been implicated in many types of cancers. In this study, we determined the expression of miR-30a in human colon cancer tissues and cell lines. miR-30a was found to be significantly downregulated in both the tissues and cell lines. Furthermore, overexpression of miR-30a inhibited, while silencing of miR-30a promoted, cell proliferation, migration, and invasion in vitro. Consistently, stable overexpression of miR-30a suppressed the growth of colon cancer cell xenografts in vivo. Moreover, bioinformatic algorithms and luciferase reporter assays revealed that insulin receptor substrate 2 (IRS2) is a direct target of miR-30a. Further functional studies suggested that repression of IRS2 by miR-30a partially mediated the tumor suppressor effect of miR-30a. In addition, miR-30a inhibited constitutive phosphorylation of Akt by targeting IRS2. Additionally, clinicopathological analysis indicated that miR-30a has an inverse correlation with the staging in patients with colon cancer. Taken together, our study provides the first evidence that miR-30a suppressed colon cancer cell growth through inhibition of IRS2. Thus, miR-30a might serve as a promising therapeutic strategy for colon cancer treatment.
Mahmoudi T, Majidzadeh-A K, Karimi K, et al.An exon variant in insulin receptor gene is associated with susceptibility to colorectal cancer in women.
Tumour Biol. 2015; 36(5):3709-15 [PubMed
] Related Publications
Given the role of insulin resistance in colorectal cancer (CRC), we explored whether genetic variants in insulin (INS), insulin receptor (INSR), insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), insulin-like growth factor 1 (IGF1), and insulin-like growth factor binding protein 3 (IGFBP3) genes were associated with CRC risk. A total of 600 subjects, including 261 cases with CRC and 339 controls, were enrolled in this case-control study. Six polymorphisms in INS (rs689), INSR (rs1799817), IRS1 (rs1801278), IRS2 (rs1805097), IGF1 (rs5742612), and IGFBP3 (rs2854744) genes were genotyped using PCR-RFLP method. No significant difference was observed for INS, INSR, IRS1, IRS2, IGF1, and IGFBP3 genes between the cases and controls. However, the INSR rs1799817 "TT + CT" genotype and "CT" genotype compared with "CC" genotype occurred more frequently in the women with CRC than women controls (P = 0.007; OR = 1.93, 95 %CI = 1.20-3.11 and P = 0.002, OR = 2.15, 95 %CI = 1.31-3.53, respectively), and the difference remained significant after adjustment for confounding factors including age, BMI, smoking status, NSAID use, and family history of CRC (P = 0.018; OR = 1.86, 95 %CI = 1.11-3.10 and P = 0.004, OR = 2.18, 95 %CI = 1.28-3.71, respectively). In conclusion, to our knowledge, this study indicated for the first time that the INSR rs1799817 TT + CT genotype and CT genotype compared with the CC genotype had 1.86-fold and 2.18-fold increased risks for CRC among women, respectively. Furthermore, this finding is in line with previous studies which found significant associations between other variants of the INSR gene and CRC risk. Nevertheless, further studies are required to confirm our findings.
Huang F, Chang H, Greer A, et al.IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines.
Mol Cancer Ther. 2015; 14(2):620-30 [PubMed
] Related Publications
Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS-754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand-stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit.
Lin MW, Huang MF, Wu MHAssociation of Gly972Arg variant of insulin receptor subtrate-1 and Gly1057Asp variant of insulin receptor subtrate-2 with polycystic ovary syndrome in the Chinese population.
J Ovarian Res. 2014; 7:92 [PubMed
] Free Access to Full Article Related Publications
OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrinologic disease in women. In the present study, we examined the relationship of the IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms to PCOS and phenotypic features of PCOS in a Chinese population from Taiwan.
MATERIALS AND METHODS: A total of three hundred and forty genetically unrelated women with age from 18 to 45 years, including two hundred and forty-eight PCOS patients and ninety-two control subjects, were recruited. The hormone and biochemical measurements were evaluated for each woman. Genotyping of the IRS-1 gene Gly972Arg variant and IRS-2 gene Gly1057Asp variant were performed by using direct sequencing.
RESULTS: We found significant difference in the genotypic distribution of IRS-2 gene Gly1057Asp between the PCOS group and the control group (p = 0.004). The carriers of homozygous IRS-2 Asp had an increased risk of PCOS compared with the carriers of Gly/Gly (OR 4.08, 95% C.I. 1.60-10.41, p = 0.003). No significant difference in genotype frequencies of IRS-1 Gly972Arg was observed between two groups. We further investigated the effect of interaction of IRS-1 Gly972Arg and IRS-2 Gly1057Asp on the risk of PCOS and found that women carried IRS-1 Gly/Arg or IRS-2 Asp/Asp or carried both IRS-1 Gly/Arg and IRS-2 Asp/Asp had a much higher risk of PCOS compared with their counterpart, respectively (OR 2.49, 95% C.I. 1.16-5.37, p = 0.019; OR 11.87, 95% C.I. 1.21-116.84, p = 0.034). We further found, the non-obese PCOS patients carried significantly higher frequency of IRS-2 Asp/Asp as compared with the control group (p = 0.004). A significant effect of interaction of carrying both IRS-1 Gly/Arg and IRS-2 Asp/Asp was also observed in the non-obese PCOS patients (p = 0.003), but not in the obese PCOS patients.
CONCLUSIONS: In this study, we found significant association of the variant of IRS-2 gene as well as the interaction of IRS-1 and IRS-2 genes with PCOS, especially in non-obese women. Women with IRS-2 homozygous Asp variant may be considered as a risk factor for PCOS that needs early detection to prevent further complication in the Chinese population from Taiwan.
Ibuki N, Ghaffari M, Reuveni H, et al.The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer.
Mol Cancer Ther. 2014; 13(12):2827-39 [PubMed
] Related Publications
Insulin-like growth factor (IGF) signaling is associated with castrate-resistant prostate cancer (CRPC) progression. Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from IGF1 receptor (IGF1R), insulin receptor, and other oncoproteins. This study demonstrates that IRS1/2 expression is increased in prostate cancer, and persists in CRPC. Furthermore, this study assesses the anticancer activity of NT157, a small molecule tyrphostin targeting IRS proteins, using androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. NT157 treatment resulted in dose-dependent inhibition of IGF1R activation, suppression of IRS protein expression, inhibition of IGF1-induced AKT activation, but increased ERK activation in NT157-treated cells in vitro. These effects were correlated with decreased proliferation and increasing apoptosis of LNCaP cells and increasing G2-M arrest in PC3 cells. NT157 also suppressed androgen-responsive growth, delayed CRPC progression of LNCaP xenografts, and suppressed PC3 tumor growth alone and in combination with docetaxel. This study reports the first preclinical proof-of-principle data that this novel small molecule tyrosine kinase inhibitor suppresses IRS1/2 expression, delays CRPC progression, and suppresses growth of CRPC tumors in vitro and in vivo. Demonstration that IRS expression can be increased in response to a variety of stressors that may lead to resistance or reduced effect of the therapies indicate that NT157-mediated IRS1/2 downregulation is a novel therapeutic approach for management of advanced prostate cancer.
Montales MT, Melnyk SB, Simmen FA, Simmen RCMaternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes.
Carcinogenesis. 2014; 35(9):2102-12 [PubMed
] Free Access to Full Article Related Publications
Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein, we evaluated mammary tumor risk in female mouse mammary tumor virus-Wnt-1 transgenic (Tg) offspring exposed to high-fat diet (HFD) or control diet (CD) (45% and 17% kcal from fat, respectively) during gestation and lactation, with CD provided to progeny at weaning. In Tg offspring, maternal HFD exposure increased mammary tumor incidence and decreased tumor latency without affecting tumor volume. Tumor risk was associated with higher tumor necrosis factor-α and insulin and altered oxidative stress biomarkers in sera and with early changes in mammary expression of genes linked to tumor promotion [interleukin 6 (Il6)] or inhibition [phosphatase and tensin homolog deleted on chromosome 10 (Pten), B-cell lymphoma 2 (Bcl2)]. Corresponding wild-type progeny exposed to maternal HFD displayed accelerated mammary development, higher mammary adiposity, increased insulin resistance and early changes in Pten, Bcl2 and Il6, than CD-exposed offspring. Dams-fed HFD showed higher serum glucose and oxidative stress biomarkers but comparable adiposity compared with CD-fed counterparts. In human breast cancer MCF-7 cells, sera from maternal HFD-exposed Tg offspring elicited changes in PTEN, BCL2 and IL6 gene expression, mimicking in vivo exposure; increased cell viability and mammosphere formation and induced measures [insulin receptor substrate-1 (IRS-1), IRS-2] of insulin sensitivity. Serum effects on IRS-1 were recapitulated by exogenous insulin and the PTEN-specific inhibitor SF1670. Hyperinsulinemia and PTEN loss-of-function may thus, couple maternal HFD exposure to enhanced insulin sensitivity via increased mammary IRS-1 expression in progeny, to promote breast cancer risk.
Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via 'crosstalk'). The 'molecular individuality' of these tumors suggests that a customized strategy, using an "N-of-One" model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.
Insulin-like growth factor (IGF) signaling is involved in oral squamous cell carcinoma (OSCC), but IGF-1 receptor (IGF-1R)-mediated intricate regulatory networks among molecular interactions and signalling path ways in OSCC remain unclear. Here, we found that overexpression of IGF-1R and insulin receptor substrate-2 (IRS-2) was negatively associated with histological differentiation. IGF signaling stimulated OSCC cell growth. Conversely, overexpression of let-7b inhibited proliferation and colony formation and triggered S/G2 cell cycle arrest by targeting IGF-1R and IRS-2 through the Akt pathway. Also, the inverse relationship between expression of let-7b and IGF-1R/IRS-2 was conﬁrmed in OSCC tumor xenografts and clinical specimens. Furthermore, by activating ERK1/2, IGF-1R transcriptionally upregulated IRS-2. Our results indicate that let-7b/IGF-1R-mediated crosstalk between IRS-2/Akt and MAPK is involved in OSCC and is a potential therapeutic target for therapy.
Rashad NM, El-Shal AS, Abd Elbary EH, et al.Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma.
Cytokine. 2014; 68(1):50-8 [PubMed
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BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population.
MATERIALS AND METHODS: Four hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA.
RESULTS: Serum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08-0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child-Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients.
CONCLUSION: IGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.
Multiple endocrine neoplasia type I (MEN1) is an inherited syndrome that includes susceptibility to pancreatic islet hyperplasia. This syndrome results from mutations in the MEN1 gene, which encodes menin protein. Menin interacts with several transcription factors, including JunD, and inhibits their activities. However, the precise mechanism by which menin suppresses gene expression is not well understood. Here, we show that menin interacts with arsenite-resistant protein 2 (ARS2), a component of the nuclear RNA CAP-binding complex that is crucial for biogenesis of certain miRNAs including let-7a. The levels of primary-let-7a (pri-let-7a) are not affected by menin; however, the levels of mature let-7a are substantially decreased upon Men1 excision. Let-7a targets, including Insr and Irs2, pro-proliferative genes that are crucial for insulin-mediated signaling, are up-regulated in Men1-excised cells. Inhibition of let-7a using anti-miRNA in wild type cells is sufficient to enhance the expression of insulin receptor substrate 2 (IRS2) to levels observed in Men1-excised cells. Depletion of menin does not affect the expression of Drosha and CBP80, but substantially impairs the processing of pri-miRNA to pre-miRNA. Ars2 knockdown decreased let-7a processing in menin-expressing cells but had little impact on let-7a levels in menin-excised cells. As IRS2 is known to mediate insulin signaling and insulin/mitogen-induced cell proliferation, these findings collectively unravel a novel mechanism whereby menin suppresses cell proliferation, at least partly by promoting the processing of certain miRNAs, including let-7a, leading to suppression of Irs2 expression and insulin signaling.
Akker M, Güldiken S, Sipahi T, et al.Investigation of insulin resistance gene polymorphisms in patients with differentiated thyroid cancer.
Mol Biol Rep. 2014; 41(5):3541-7 [PubMed
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We aimed to investigate insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), insulin-like growth factor binding protein-3 (IGFBP-3) genotypes, which are thought to be involved in the pathogenesis of many solid tumors and have thus far not been studied in patients with differentiated thyroid cancer (DTC). The study consisted of 93 patients diagnosed with DTC (79 females, 14 males) and 111 healthy control subjects (63 females, 48 males). The anthropometric measurements, lipid profiles, thyroid function tests and homeostatic model assessment (HOMA) as an indicator of insulin resistance (IR) of all patients were recorded. In addition IRS-1, IRS-2 and IGFBP-3 gene polymorphisms were determined by using polymerase chain reaction and restriction fragment length polymorphism. Hardy-Weinberg equilibrium was tested for each gene polymorphisms, and genetic effects were evaluated by the Chi Square test and multiple logistic regression. Homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, waist circumference and serum total cholesterol levels were significantly higher in patients with DTC than in the control group. There was no difference between the two groups with respect to IRS-1, IRS-2 and IGFBP-3 gene polymorphisms. In addition, these gene polymorphisms were found to have no effect on lymph node metastases or tumor staging. While, obesity and increased HOMA-IR may be risk factors in DTC development, we suggest that IRS-1, IRS-2 and IGFBP-3 gene polymorphisms do not play an important role in pathogenesis of DTC.
Karimi K, Mahmoudi T, Karimi N, et al.Is there an association between variants in candidate insulin pathway genes IGF-I, IGFBP-3, INSR, and IRS2 and risk of colorectal cancer in the Iranian population?
Asian Pac J Cancer Prev. 2013; 14(9):5011-6 [PubMed
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BACKGROUND: Several epidemiological studies have shown associations between colorectal cancer (CRC) risk and type 2 diabetes and obesity. Any effects would be expected to be mediated through the insulin pathway. Therefore it is possible that variants of genes encoding components of the insulin pathway play roles in CRC susceptibility. In this study, we hypothesized that polymorphisms in the genes involving the insulin pathway are associated with risk of CRC.
MATERIALS AND METHODS: The associations of four single nucleotide polymorphisms (SNPs) in IGF-I (rs6214), IGFBP-3 (rs3110697), INSR (rs1052371), and IRS2 (rs2289046) genes with the risk of CRC were evaluated using a case-control design with 167 CRC cases and 277 controls by the PCR-RFLP method.
RESULTS: Overall, we observed no significant difference in genotype and allele frequencies between the cases and controls for the IGF-I, IGFBP-3, INSR, IRS2 gene variants and CRC before or after adjusting for confounders (age, BMI, sex, and smoking status). However, we observed that the IRS2 (rs2289046) GG genotype compared with AA+AG genotypes has a protective effect for CRC in normal weight subjects (p=0.035, OR=0.259, 95%CI= 0.074-0.907).
CONCLUSIONS: These findings do not support plausible associations between polymorphic variations in IGF-I, IGFBP-3, INSR, IRS2 genes and risk of CRC. However, the evidence for a link between the IRS2 (rs2289046) variant and risk of CRC dependent on the BMI of the subjects, requires confirmation in subsequent studies with greater sample size.
Insulin receptor substrate 1 (IRS1) and IRS2 are well-characterized adapter proteins that relay signals from receptor tyrosine kinases to downstream components of signalling pathways. In contrast, the function of IRS4 is not well understood. IRS4 overexpression has been associated with acute lymphoblastic leukaemia and subungual exostosis, while point mutations of IRS4 have been found in melanomas. Here, we show that while IRS4 expression is low in most cancer cell lines, IRS4 mRNA and protein levels are markedly elevated in certain cells including the NCI-H720, DMS114, HEK293T and HEK293AAV lines. Surprisingly, IRS4 expression was also strongly induced when HEK293 cells were infected with retroviral particles and selected under puromycin, making IRS4 expression a potential off-target effect of retroviral expression vectors. Cells with high expression of IRS4 displayed high phosphatidylinositol (3,4,5)-trisphosphate (PIP3) levels, as well as elevated Akt and p70 S6 kinase activities, even in the absence of growth factors. PI 3-kinase (PI3K) signalling in these cells depends on IRS4, even though these cells also express IRS1/2. Knockdown of IRS4 also inhibited cell proliferation in cells with high levels of IRS4. Together, these findings suggest IRS4 as a potential therapeutic target for cancers with high expression of this protein.
Bizama C, Benavente F, Salvatierra E, et al.The low-abundance transcriptome reveals novel biomarkers, specific intracellular pathways and targetable genes associated with advanced gastric cancer.
Int J Cancer. 2014; 134(4):755-64 [PubMed
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Studies on the low-abundance transcriptome are of paramount importance for identifying the intimate mechanisms of tumor progression that can lead to novel therapies. The aim of the present study was to identify novel markers and targetable genes and pathways in advanced human gastric cancer through analyses of the low-abundance transcriptome. The procedure involved an initial subtractive hybridization step, followed by global gene expression analysis using microarrays. We observed profound differences, both at the single gene and gene ontology levels, between the low-abundance transcriptome and the whole transcriptome. Analysis of the low-abundance transcriptome led to the identification and validation by tissue microarrays of novel biomarkers, such as LAMA3 and TTN; moreover, we identified cancer type-specific intracellular pathways and targetable genes, such as IRS2, IL17, IFNγ, VEGF-C, WISP1, FZD5 and CTBP1 that were not detectable by whole transcriptome analyses. We also demonstrated that knocking down the expression of CTBP1 sensitized gastric cancer cells to mainstay chemotherapeutic drugs. We conclude that the analysis of the low-abundance transcriptome provides useful insights into the molecular basis and treatment of cancer.
The insulin/insulin-like growth factor pathway is involved in breast and colorectal cancer (CRC) development. In the present study, we analyzed the coding region and short intron-exon borders of the insulin receptor substrate 1 and 2 (IRS‑1 and IRS‑2) genes in 12 cell lines derived from breast cancer (BC), 14 cell lines derived from CRC and 33 primary CRCs. The nucleotide variants identified in BC were 3 in IRS‑1, 1 of which (p.Arg267Cys) was novel and with a pathogenic potential as predicted by in silico analysis and 6 in IRS‑2. Twenty‑one variants in IRS‑1 and 18 in IRS‑2 were identified in the CRC samples. These included 11 novel IRS‑1 variants detected exclusively in CRCs, which included 5 missense (p.Pro559Leu, p.Gln655His, p.Asp1014Gly, p.Asp1181His and pPro1203Ser) with a pathogenic potential as predicted by in silico analysis, 2 frameshifts predicted to generate a truncated protein, 1 splice-site mutation and 3 silent variants. In the CRC samples we also identified 7 novel IRS‑2 variants, including 4 missense variants, which included 2 (p.Asp782Asn and p.Gly1230Ser) with a pathogenic potential as predicted by in silico analysis, 2 frame insertion mutations and 1 silent variant. Most of the novel IRS‑1 and IRS‑2 variants may be involved in the modulation of IRS-1 or IRS‑2 functions and could be relevant to breast and colorectal tumorigenesis.
Copy number alterations are frequently found in colorectal cancer (CRC), and recurrent gains or losses are likely to correspond to regions harbouring genes that promote or impede carcinogenesis respectively. Gain of chromosome 13q is common in CRC but, because the region of gain is frequently large, identification of the driver gene(s) has hitherto proved difficult. We used array comparative genomic hybridization to analyse 124 primary CRCs, demonstrating that 13q34 is a region of gain in 35% of CRCs, with focal gains in 4% and amplification in a further 1.6% of cases. To reduce the number of potential driver genes to consider, it was necessary to refine the boundaries of the narrowest copy number changes seen in this series and hence define the minimal copy region (MCR). This was performed using molecular copy-number counting, identifying IRS2 as the only complete gene, and therefore the likely driver oncogene, within the refined MCR. Analysis of available colorectal neoplasia data sets confirmed IRS2 gene gain as a common event. Furthermore, IRS2 protein and mRNA expression in colorectal neoplasia was assessed and was positively correlated with progression from normal through adenoma to carcinoma. In functional in vitro experiments, we demonstrate that deregulated expression of IRS2 activates the oncogenic PI3 kinase pathway and increases cell adhesion, both characteristics of invasive CRC cells. Together, these data identify IRS2 as a likely driver oncogene in the prevalent 13q34 region of gain/amplification and suggest that IRS2 over-expression may provide an additional mechanism of PI3 kinase pathway activation in CRC.
Nishimura R, Takita J, Sato-Otsubo A, et al.Characterization of genetic lesions in rhabdomyosarcoma using a high-density single nucleotide polymorphism array.
Cancer Sci. 2013; 104(7):856-64 [PubMed
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Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes, embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited near-diploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS.
Minchenko DO, Kharkova AP, Hubenia OV, Minchenko OHInsulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation.
Endocr Regul. 2013; 47(1):15-26 [PubMed
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OBJECTIVE: The purpose of this study was to examine: 1) the association between the expression of the insulin receptor (INSR), insulin receptor substrate 1 (IRS1) and 2 (IRS2), insulin inducible gene 1 (INSIG1) and 2 (INSIG2), Ras-related associated with diabetes (RRAD), and brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) genes in glioma cells and 2) the function of the endoplasmic reticulum stress signaling, mediated by endoplasmic reticulum to nuclei-1 (ERN1) and regulation of these gene expressions by hypoxia and glucose or glutamine deprivation.
METHODS: The expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 genes in the glioma cell line U87 and its subline with ERN1 loss of function was studied by qPCR. The cells were exposed to a mix of 3 % oxygen and 5 % carbon dioxide and glucose or glutamine deprivation.
RESULTS: The blockade of the ERN1 signaling enzyme function in glioma cells leads to the gene expression increase in INSR, INSIG2, and IRS2 and decrease in the BAIAP2 and RRAD genes. Hypoxia affected the expression of the INSR, IRS1, IRS2, INSIG1, INSIG2, and BAIAP2 genes with more significant changes in INSIG2 and IRS2 genes. Furthermore, the effect of hypoxia on expression of these genes was mostly dependent on the ERN1 signaling enzyme function. The data also show that glucose or glutamine deprivation may change the expression of the genes studied and that the suppression of the ERN1 enzyme function usually modifies the effect of the glucose or glutamine deprivation.
CONCLUSIONS: Results of this study demonstrated the dependence of INSR and related to insulin receptor signaling gene expressions in U87 glioma cells on ERN1 enzyme function indicating its participation in the regulation of metabolic and proliferative processes via endoplasmic reticulum stress which is important component of tumor growth and metabolic diseases. Moreover, hypoxia and glucose or glutamine deprivation are controlled by the expression of insulin receptor and related to insulin signaling genes mostly via ERN1 enzyme signaling.