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IGF1; insulin-like growth factor 1 (somatomedin C) (12q23.2)

Gene Summary

Gene:IGF1; insulin-like growth factor 1 (somatomedin C)
Aliases: IGFI, IGF-I, IGF1A
Location:12q23.2
Summary:The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:insulin-like growth factor I
HPRD
Source:NCBI
Updated:14 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (81)

Pathways:

What pathways are this gene/protein implicaed in?
- Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK) BIOCARTA
- Erythrocyte Differentiation Pathway BIOCARTA
- Ghrelin BIOCARTA
- IGF-1 Signaling Pathway BIOCARTA
- NFAT and Hypertrophy of the heart (Transcription in the broken heart) BIOCARTA
- Regulation of BAD phosphorylation BIOCARTA
- Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway BIOCARTA
- The IGF-1 Receptor and Longevity BIOCARTA
- Focal adhesion KEGG
- Long-term depression KEGG
- mTOR signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (5)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerIGF1 and Breast Cancer View Publications40
Colorectal CancerIGF1 and Colorectal Cancer View Publications25
Lung CancerIGF1 and Lung Cancer View Publications13
Thyroid CancerIGF1 Expression in Thyroid Cancer View Publications5
Stomach CancerIGF1 and Stomach Cancer View Publications2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: IGF1 (cancer-related)

Philip PA, Goldman B, Ramanathan RK, et al.
Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727).
Cancer. 2014; 120(19):2980-5 [PubMed] Related Publications
BACKGROUND: Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance
METHODS: This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied
RESULTS: The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms.
CONCLUSIONS: Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.

Related: Monoclonal Antibodies Cancer of the Pancreas Pancreatic Cancer Signal Transduction Gemcitabine EGFR Erlotinib (Tarceva)


Heilmann AM, Perera RM, Ecker V, et al.
CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers.
Cancer Res. 2014; 74(14):3947-58 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
Loss-of-function mutations in p16(INK4A) (CDKN2A) occur in approximately 80% of sporadic pancreatic ductal adenocarcinoma (PDAC), contributing to its early progression. Although this loss activates the cell-cycle-dependent kinases CDK4/6, which have been considered as drug targets for many years, p16(INK4A)-deficient PDAC cells are inherently resistant to CDK4/6 inhibitors. This study searched for targeted therapies that might synergize with CDK4/6 inhibition in this setting. We report that the IGF1R/IR inhibitor BMS-754807 cooperated with the CDK4/6 inhibitor PD-0332991 to strongly block proliferation of p16(INK4A)-deficient PDAC cells in vitro and in vivo. Sensitivity to this drug combination correlated with reduced activity of the master cell growth regulator mTORC1. Accordingly, replacing the IGF1R/IR inhibitor with the rapalog inhibitor temsirolimus broadened the sensitivity of PDAC cells to CDK4/6 inhibition. Our results establish targeted therapy combinations with robust cytostatic activity in p16(INK4A)-deficient PDAC cells and possible implications for improving treatment of a broad spectrum of human cancers characterized by p16(INK4A) loss.

Related: CDK4 CDK6 gene Cancer of the Pancreas Pancreatic Cancer IGF1R RB1


Shahmoon S, Rubinfeld H, Wolf I, et al.
The aging suppressor klotho: a potential regulator of growth hormone secretion.
Am J Physiol Endocrinol Metab. 2014; 307(3):E326-34 [PubMed] Related Publications
Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice (kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.


Loddo M, Andryszkiewicz J, Rodriguez-Acebes S, et al.
Pregnancy-associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer.
J Pathol. 2014; 233(4):344-56 [PubMed] Related Publications
Aberrant mitosis is a common feature of cancer, yet little is known about the altered genes causing mitotic defects. We screened human tumours for cells with morphological signatures of highly specific mitotic defects previously assigned to candidate genes in a genome-wide RNA interference screen carried out in HeLa cells (www.mitocheck.org). We discovered a striking enrichment of early mitotic configurations indicative of prophase/prometaphase delay in breast cancer. Promoter methylation analysis of MitoCheck candidate genes assigned to the corresponding 'mitotic delay' class linked this defect to epigenetic silencing of the gene encoding pregnancy-associated plasma protein-A (PAPPA), a secreted protease. PAPPA silencing was highly prevalent in precursor lesions and invasive breast cancer. Experimental manipulation of PAPPA protein levels in human mammary epithelial cells and in breast cancer cell lines demonstrates that progression through early mitosis is dependent on PAPPA function, and that breast cancer cells become more invasive after down-regulation of this protease. PAPPA regulates mitotic progression through modulating the IGF-1 signalling pathway resulting in activation of the forkhead transcription factor FoxM1, which drives a transcriptional cluster of essential mitotic genes. Our results show that PAPPA has a critical function in normal cell division and is targeted early in breast cancer development.

Related: Breast Cancer Signal Transduction FOXM1


Cao Y, Lindström S, Schumacher F, et al.
Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival.
J Natl Cancer Inst. 2014; 106(6):dju085 [PubMed] Article available free on PMC after 01/06/2015 Related Publications
BACKGROUND: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.
METHODS: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.
RESULTS: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.
CONCLUSIONS: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

Related: Prostate Cancer Signal Transduction USA


Sciacca L, Cassarino MF, Genua M, et al.
Biological effects of insulin and its analogs on cancer cells with different insulin family receptor expression.
J Cell Physiol. 2014; 229(11):1817-21 [PubMed] Related Publications
Hyperinsulinemia is a likely cause of the increased cancer incidence and mortality in diabetic patients, but its role is difficult to define in vivo. Previous in vitro studies testing the mitogenic potential of insulin and its analogs provided incomplete and sometimes contradictory results. To better evaluate cancer cell responsiveness to insulin, to its analogs and to IGF-I, we measured under identical experimental conditions cell proliferation, invasiveness, and foci formation in six cancer cell lines with different insulin receptor family expression levels. The cancer cells studied have a different expression of insulin receptor (IR), its isoforms (IR-A and IR-B), and of the IGF-I receptor. The data indicate that insulin stimulates proliferation in all cancer cell lines, invasiveness in some, and foci formation in none. Cancer cell responses to insulin (and IGF-I) are not related to receptor expression levels; moreover, hormone-stimulated proliferation and invasiveness are not correlated. IGF-I is a more potent stimulator than insulin in most but not all cancer cell lines. Insulin analogs including M1 and M2 Glargine metabolites stimulate cancer cells similar to insulin. However, exceptions occur for specific analogs in particular cancer cells. In conclusion, in vitro insulin is an effective growth factor for all cancer cells but the biological response to insulin cannot be predicted on the basis of receptor expression levels. In the clinical setting, these observations should be taken in account when deciding treatment for diabetic patients who are at risk of undiscovered cancer or survivors of oncological diseases.

Related: Cancer Prevention and Risk Reduction IGF1R


Huang XP, Zhou WH, Zhang YF
Genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer.
Genet Mol Res. 2014; 13(1):2107-19 [PubMed] Related Publications
Recent evidence suggests that genetic variations in the insulin-like growth factor (IGF)-IGF receptor (IGFR)-IGF binding proteins (IGFBP) axis may impact an individual's susceptibility to lung and esophageal cancer, but individually published results are inconclusive. Our meta-analysis aimed at providing a more precise estimation of these associations. An extensive literature search was conducted for appropriate articles published before May 15th, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each study and then pooled using a random effect model. Twelve case-control studies were included with a total of 2686 lung cancer patients, 771 esophageal cancer patients, and 5918 healthy controls. Our meta-analysis indicated that genetic variations in the IGF-IGFR-IGFBP axis may be associated with increased risk of lung and esophageal cancer, especially among Asian populations. Further subgroup analysis by gene type indicated that common polymorphisms in the IGF1/2, IGF-1R, and IGFBP-3/5 genes may be the main determinants for lung cancer risk, while IGF-1, IGF-1R, and IGFBP-1 genetic polymorphisms may increase the risk of esophageal cancer. The current meta-analysis suggests that genetic variations in the IGF-IGFR-IGFBP axis confer susceptibility to lung and esophageal cancer, especially among Asian populations. Common polymorphisms in the IGF-IGFR-IGFBP axis may serve as useful biomarkers for predicting the risk of lung and esophageal cancer.

Related: Cancer of the Esophagus Esophageal Cancer Lung Cancer


Ikeda Y, Kajiyama K, Yamashita Y, et al.
Differential expression of insulin-like growth factor 1 in human primary liver cancer.
Fukuoka Igaku Zasshi. 2013; 104(10):334-8 [PubMed] Related Publications
Insulin-like Growth Factor 1 (IGF-1) antigen was immunohistochemically examined in 28 patients of the primary hepatocellular carcinoma with hepatectomy. IGF-1 was expressed in 93% (26/28) of the primary lesion and 100% (28/28) of the normal liver. Compared with expression in normal liver, decreased expressions in primary lesions were noted in 36% (10/28) for IGF-1. Histological examination revealed that there were significant correlations between patients with decreased expressions of IGF-1 in primary lesions and poor differentiated hepatocellular carcinoma, and portal vein infiltration. These results indicate that expression of IGF-1 has the relationship with the differentiation in human primary hepatocellular carcinoma.

Related: Liver Cancer


Tuna M, Itamochi H
Insulin-like growth factor I regulates the expression of isoforms of Wilms' tumor 1 gene in breast cancer.
Tumori. 2013 Nov-Dec; 99(6):715-22 [PubMed] Related Publications
AIM AND BACKGROUND: The Wilms' tumor 1 gene (WT1) is overexpressed in many cancers, including breast cancer, and its high expression is an adverse prognostic factor. However, the factors that regulate WT1 expression are poorly understood.
METHODS AND STUDY DESIGN: Expression of genes at the RNA and protein level was detected by reverse transcriptase-polymerase chain reaction, western blotting, and reverse-phase protein array assays in breast cancer cell lines and tumor samples.
RESULTS: In the study, we showed that the treatment of MCF-7 breast cancer cells with insulin-like growth factor I (IGF-I) increases WT1 protein expression by 77%. IGF-I uses Akt to up-regulate WT1 expression. Conversely, inhibition of IGF-I by IGF-binding protein 3 and of IGF-I receptor (IGF-IR) by anti-IGF-IR antibody (α-IR3) uses Akt to decrease WT1 protein levels in MCF-7 cells. We thus newly identified a mechanism by which IGF-I up-regulates WT1, especially the (+exon 5/-KTS) isoform, at the posttranscriptional level in MCF-7 cells and primary breast tumor samples.
CONCLUSIONS: The results indicate a novel posttranscriptional regulatory factor of WT1 in MCF-7 breast cancer cells.

Related: Breast Cancer WT1


Takeuchi A, Shiota M, Beraldi E, et al.
Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth.
Mol Cell Endocrinol. 2014; 384(1-2):117-25 [PubMed] Related Publications
Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis.

Related: CLU Signal Transduction TWIST1


Contaldo C, Myers TJ, Zucchini C, et al.
Expression levels of insulin receptor substrate-1 modulate the osteoblastic differentiation of mesenchymal stem cells and osteosarcoma cells.
Growth Factors. 2014; 32(1):41-52 [PubMed] Related Publications
The insulin-like growth factor-1 system, including its critical mediator insulin receptor substrate-1 (IRS-1), is involved in regulating osteosarcoma (OS) cell proliferation or differentiation. The aim of this study is to define the role of IRS-1 in OS cells by assessing the contribution of IRS-1 in the differentiation of human and murine OS cell lines and mouse mesenchymal stem cells (MSCs) and found that the basal level of IRS-1 is important for the initiation of differentiation. Both down-regulation and over-expression of IRS-1 inhibited osteoblastic differentiation. In vivo studies showed that OS cells over-expressing IRS-1 have increased metastatic potential and tumor growth. The proteasome inhibitor MG-132 led to an increase in IRS-1 protein level that inhibited osteoblastic differentiation, suggesting a role for proteasomal regulation in maintaining the appropriate expression level of IRS-1. Thus, precise regulation of IRS-1 expression level is critical for determining the differentiating capacity of MSCs and OS cells, and that derangement of IRS-1 levels can be a critical step in OS transformation.

Related: Osteosarcoma Signal Transduction


Malaguarnera R, Sacco A, Morcavallo A, et al.
Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling.
Endocrinology. 2014; 155(4):1207-21 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
We have previously demonstrated that, in prostate cancer cells, androgens up-regulate IGF-I receptor (IGF-IR) by inducing cAMP-response element-binding protein (CREB) activation and CREB-dependent IGF-IR gene transcription through androgen receptor (AR)-dependent membrane-initiated effects. This IGF-IR up-regulation is not blocked by classical antiandrogens and sensitizes cells to IGF-I-induced biological effects. Metformin exerts complex antitumoral functions in various models and may inhibit CREB activation in hepatocytes. We, therefore, evaluated whether metformin may affect androgen-dependent IGF-IR up-regulation. In the AR(+) LNCaP prostate cancer cells, we found that metformin inhibits androgen-induced CRE activity and IGF-IR gene transcription. CRE activity requires the formation of a CREB-CREB binding protein-CREB regulated transcription coactivator 2 (CRTC2) complex, which follows Ser133-CREB phosphorylation. Metformin inhibited Ser133-CREB phosphorylation and induced nuclear exclusion of CREB cofactor CRTC2, thus dissociating the CREB-CREB binding protein-CRTC2 complex and blocking its transcriptional activity. Similarly to metformin action, CRTC2 silencing inhibited IGF-IR promoter activity. Moreover, metformin blocked membrane-initiated signals of AR to the mammalian target of rapamycin/p70S6Kinase pathway by inhibiting AR phosphorylation and its association with c-Src. AMPK signals were also involved to some extent. By inhibiting androgen-dependent IGF-IR up-regulation, metformin reduced IGF-I-mediated proliferation of LNCaP cells. These results indicate that, in prostate cancer cells, metformin inhibits IGF-I-mediated biological effects by disrupting membrane-initiated AR action responsible for IGF-IR up-regulation and suggest that metformin could represent a useful adjunct to the classical antiandrogen therapy.

Related: Prostate Cancer IGF1R Signal Transduction


Jardim-Perassi BV, Arbab AS, Ferreira LC, et al.
Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer.
PLoS One. 2014; 9(1):e85311 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.

Related: Breast Cancer MKI67 Angiogenesis and Cancer VEGFA


Yen YC, Shiah SG, Chu HC, et al.
Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells.
Mol Cancer. 2014; 13:6 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
BACKGROUND: MicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%.
METHODS: The expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors.
RESULTS: We observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3'UTR of IGF1R mRNA into the 3'UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3'UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling.
CONCLUSION: Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation.

Related: Oral Cancer IGF1R Signal Transduction


Mahmoud AM, Yang W, Bosland MC
Soy isoflavones and prostate cancer: a review of molecular mechanisms.
J Steroid Biochem Mol Biol. 2014; 140:116-32 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Soy isoflavones are dietary components for which an association has been demonstrated with reduced risk of prostate cancer (PCa) in Asian populations. However, the exact mechanism by which these isoflavones may prevent the development or progression of PCa is not completely understood. There are a growing number of animal and in vitro studies that have attempted to elucidate these mechanisms. The predominant and most biologically active isoflavones in soy products, genistein, daidzein, equol, and glycetin, inhibit prostate carcinogenesis in some animal models. Cell-based studies show that soy isoflavones regulate genes that control cell cycle and apoptosis. In this review, we discuss the literature relevant to the molecular events that may account for the benefit of soy isoflavones in PCa prevention or treatment. These reports show that although soy isoflavone-induced growth arrest and apoptosis of PCa cells are plausible mechanisms, other chemo protective mechanisms are also worthy of consideration. These possible mechanisms include antioxidant defense, DNA repair, inhibition of angiogenesis and metastasis, potentiation of radio- and chemotherapeutic agents, and antagonism of estrogen- and androgen-mediated signaling pathways. Moreover, other cells in the cancer milieu, such as the fibroblastic stromal cells, endothelial cells, and immune cells, may be targeted by soy isoflavones, which may contribute to soy-mediated prostate cancer prevention. In this review, these mechanisms are discussed along with considerations about the doses and the preclinical models that have been used.

Related: Angiogenesis Inhibitors Apoptosis Prostate Cancer Signal Transduction


Jones H, Crombleholme T, Habli M
Regulation of amino acid transporters by adenoviral-mediated human insulin-like growth factor-1 in a mouse model of placental insufficiency in vivo and the human trophoblast line BeWo in vitro.
Placenta. 2014; 35(2):132-8 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
Previous work in our laboratory demonstrated that over-expression of human insulin-like growth factor-11 (hIGF-1) in the placenta corrects fetal weight deficits in mouse, rat, and rabbit models of intrauterine growth restriction without changes in placental weight. The underlying mechanisms of this effect have not been elucidated. To investigate the effect of intra-placental IGF-1 over-expression on placental function we examined amino acid transporter expression and localization in both a mouse model of placental Insufficiency (PI) and a model of human trophoblast, the BeWo Choriocarcinoma cell line. For in vitro human studies, BeWo Choriocarcinoma cells were maintained in F12 complete medium + 10%FBS. Cells were incubated in serum-free control media ± Ad-IGF-1 or Ad-LacZ for 48 h. MOIs of 10:1 and 100:1 were utilized. In BeWo, transfection efficiency was 100% at an MOI of 100:1 and Ad-IGF-1 significantly increased IGF-1 secretion, proliferation and invasion but reduced apoptosis compared to controls. In vitro, amino acid uptake was increased following Ad-IGF-1 treatment and associated with significantly increased RNA expression of SNAT1, 2, LAT1 and 4F2hc. Only SNAT2 protein expression was increased but LAT1 showed relocalization from a perinuclear location to the cytoplasm and cell membrane. For in vivo studies, timed-pregnant animals were divided into four groups on day 18; sham-operated controls, uterine artery branch ligation (UABL), UABL + Ad-hIGF-1 (10(8) PFU), UABL + Ad-LacZ (10(8) PFU). At gestational day 20, pups and placentas were harvested by C-section. Only LAT1 mRNA expression changed, showing that a reduced expression of the transporter levels in the PI model could be partially rectified with Ad-hIGF1 treatment. At the protein level, System L was reduced in PI but remained at control levels following Ad-hIGF1. The System A isoforms were differentially regulated with SNAT2 expression diminished but SNAT1 increased in PI and Ad-hIGF1 groups. Enhanced amino acid isoform transporter expression and relocalization to the membrane may be an important mechanism contributing to Ad-hIGF-1 mediated correction of placental insufficiency.


Jeon HM, Kim do H, Jung WH, Koo JS
Expression of cell metabolism-related genes in different molecular subtypes of triple-negative breast cancer.
Tumori. 2013 Jul-Aug; 99(4):555-64 [PubMed] Related Publications
AIMS AND BACKGROUND: We evaluated the difference in and significance of cancer cell metabolism by molecular subtyping of triple-negative breast carcinoma.
METHODS: Tissue microarrays from 122 surgical specimens of triple-negative breast carcinoma patients and immunohistochemical staining for CK5/6, epidermal growth factor receptor, claudin 3, claudin 4, claudin 7, E-cadherin, androgen receptor, and gamma-glutamyltransferase 1 were used to classify triple-negative breast carcinoma as follows: basal-like type, molecular apocrine type, claudin low type, mixed type and null type. In addition, immunohistochemical staining for metabolism-related proteins such as c-myc, insulin-like growth factor (g)-1, hypoxia-inducible factor 1-1α, glucose transporter 1, carbonic anhydrase IX antibody, macrophage migration inhibitory factor, and pyruvate dehydrogenase kinase 1 was used to compare the differences according to molecular subtype and clinicopathological factors.
RESULTS: The basal-like type showed the highest proportion of high glucose transporter 1 expression (P = 0.049) and carbonic anhydrase IX antibody expression (P = 0.008). Hypoxia-inducible factor 1-1α expression was associated with lymph node metastasis (P = 0.001) and central fibrotic zone (P = 0.012), and high glucose transporter 1 expression was related to high histologic grade (P = 0.007), cytokeratin 5/6 positivity (P = 0.002), and central fibrotic zone (P = 0.017). Finally, carbonic anhydrase IX antibody was associated with cytokeratin 5/6 positivity (P = 0.001) and central fibrotic zone (P = 0.048).
CONCLUSIONS: Our study revealed the different characteristics of cancer cell metabolism according to the molecular subtypes of triple-negative breast carcinoma. Among them, basal-like type was the most glycolytic and acid-resistant phenotype.

Related: SLC2A1 HIF1A MIF


Sun F, Chen HG, Li W, et al.
Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors.
J Biol Chem. 2014; 289(3):1529-39 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
Deregulation of androgen receptor (AR) splice variants has been implicated to play a role in prostate cancer development and progression. To understand their functions in prostate, we established a transgenic mouse model (AR3Tg) with targeted expression of the constitutively active and androgen-independent AR splice variant AR3 (a.k.a. AR-V7) in prostate epithelium. We found that overexpression of AR3 modulates expression of a number of tumor-promoting autocrine/paracrine growth factors (including Tgfβ2 and Igf1) and expands prostatic progenitor cell population, leading to development of prostatic intraepithelial neoplasia. In addition, we showed that some epithelial-mesenchymal transition-associated genes are up-regulated in AR3Tg prostates, suggesting that AR3 may antagonize AR activity and halt the differentiation process driven by AR and androgen. This notion is supported by our observations that the number of Ck5(+)/Ck8(+) intermediate cells is increased in AR3Tg prostates after castration, and expression of AR3 transgene in these intermediate cells compromises prostate epithelium regeneration upon androgen replacement. Our results demonstrate that AR3 is a driver of prostate cancer, at least in part, through modulating multiple tumor-promoting autocrine/paracrine factors.

Related: Prostate Cancer AR: androgen receptor


Xu CZ, Shi RJ, Chen D, et al.
Potential biomarkers for paclitaxel sensitivity in hypopharynx cancer cell.
Int J Clin Exp Pathol. 2013; 6(12):2745-56 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
Paclitaxel has been proved to be active in treatment and larynx preservation of HNSCC, however, the fact that about 20-40% patients do not respond to paclitaxel makes it urgent to figure out the biomarkers for paclitaxel-based treatment in Hypopharynx cancer (HPC) patients to improve the therapy effect. In this work, Fadu cells, treated or untreated with low dose of paclitaxel for 24 h, were applied to DNA microarray chips. The differential expression in mRNAs and miRs was analyzed and the network between expression-altered mRNAs and miRs was constructed. Differentially expressed genes were mainly enriched in superpathway of cholesterol biosynthesis (ACAT2, MSMO1, LSS, FDFT1 and FDPS etc.), complement system (C3, C1R, C1S, CFR and CFB etc.), interferon signaling (IFIT1, IFIT3, IFITM1 and MX1 etc.), mTOR signaling (MRAS, PRKAA2, PLD1, RND3 and EIF4A1 etc.) and IGF1 signaling (MRAS, IGFBP7, JUN and FOS etc.), most of these pathways are implicated in tumorigenesis or chemotherapy resistance. The first three pathways were predicted to be suppressed, while the last two pathways were predicted to be induced by paclitaxel, suggesting the combination therapy with mTOR inhibition and paclitaxel might be better than single one. The dramatically expression-altered miRs were miR-112, miR-7, miR-1304, miR-222*, miR-29b-1* (these five miRs were upregulated) and miR-210 (downregulated). The 26 putative target genes mediated by the 6 miRs were figured out and the miR-gene network was constructed. Furthermore, immunoblotting assay showed that ERK signaling in Fadu cells was active by low dose of paclitaxel but repressed by high dose of paclitaxel. Collectively, our data would provide potential biomarkers and therapeutic targets for paclitaxel-based therapy in HPC patients.

Related: Hypopharyngeal Cancer Paclitaxel Signal Transduction


Okon IS, Coughlan KA, Zou MH
Liver kinase B1 expression promotes phosphatase activity and abrogation of receptor tyrosine kinase phosphorylation in human cancer cells.
J Biol Chem. 2014; 289(3):1639-48 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
Aberrant receptor tyrosine kinase phosphorylation (pRTK) has been associated with diverse pathological conditions, including human neoplasms. In lung cancer, frequent liver kinase B1 (LKB1) mutations correlate with tumor progression, but potential links with pRTK remain unknown. Heightened and sustained receptor activation was demonstrated by LKB1-deficient A549 (lung) and HeLaS3 (cervical) cancer cell lines. Depletion (siRNA) of endogenous LKB1 expression in H1792 lung cancer cells also correlated with increased pRTK. However, ectopic LKB1 expression in A549 and HeLaS3 cell lines, as well as H1975 activating-EGF receptor mutant lung cancer cell resulted in dephosphorylation of several tumor-enhancing RTKs, including EGF receptor, ErbB2, hepatocyte growth factor receptor (c-Met), EphA2, rearranged during transfection (RET), and insulin-like growth factor I receptor. Receptor abrogation correlated with attenuation of phospho-Akt and increased apoptosis. Global phosphatase inhibition by orthovanadate or depletion of protein tyrosine phosphatases (PTPs) resulted in the recovery of receptor phosphorylation. Specifically, the activity of SHP-2, PTP-1β, and PTP-PEST was enhanced by LKB1-expressing cells. Our findings provide novel insight on how LKB1 loss of expression or function promotes aberrant RTK signaling and rapid growth of cancer cells.

Related: Cancer Prevention and Risk Reduction AKT1 Signal Transduction


Huang YF, Cheng WF, Wu YP, et al.
Circulating IGF system and treatment outcome in epithelial ovarian cancer.
Endocr Relat Cancer. 2014; 21(2):217-29 [PubMed] Related Publications
Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy are performed. Thus, the early detection of high-risk subgroups is important in order to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating IGF system components and their relationship with treatment outcome in EOC. We included 228 patients with a median follow-up time of 44 months at two tertiary centers. There were 68 cancer deaths and 108 cases of cancer progression in the cohort. Preoperative serum levels of total IGF1, IGF2, IGF-binding protein 2 (IGFBP2), and IGFBP3 were analyzed using an ELISA and were then converted into an IGF1:IGFBP3 molar ratio. The risks of mortality and progression were estimated using Cox regression models in univariate and multivariate analyses. Our results showed that high IGF1, IGF2, and IGFBP3 levels were significantly associated with an early cancer stage, non-serous histology, and optimal cytoreduction. High IGFBP2 levels were associated with an advanced stage and serous histology. Overall and progression-free survival durations were significantly better among patients with high IGF1 (P=0.003 and P=0.001), IGF2 (P=0.003 and P=0.02), or IGFBP3 levels (P=0.02 and P=0.008). In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratio=1.84, 95% CI: 1.07-3.18, P=0.03), indicating that IGFBP2 could be used as an early predictor of EOC-related mortality. The combination of elevated IGFBP2 and reduced IGF1 levels at diagnosis could further facilitate the identification of a patient subgroup with the worst prognosis.

Related: IGF2 Ovarian Cancer


Rosenberg EE, Prudnikova TY, Zabarovsky ER, et al.
D-glucuronyl C5-epimerase cell type specifically affects angiogenesis pathway in different prostate cancer cells.
Tumour Biol. 2014; 35(4):3237-45 [PubMed] Related Publications
D-glucuronyl C5-epimerase (GLCE) is involved in breast and lung carcinogenesis as a potential tumor suppressor gene, acting through inhibition of tumor angiogenesis and invasion/metastasis pathways. However, in prostate tumors, increased GLCE expression is associated with advanced disease, suggesting versatile effects of GLCE in different cancers. To investigate further the potential cancer-promoting effect of GLCE in prostate cancer, GLCE was ectopically re-expressed in morphologically different LNCaP and PC3 prostate cancer cells. Transcriptional profiles of normal PNT2 prostate cells, LNCaP, PC3 and DU145 prostate cancer cells, and GLCE-expressing LNCaP and PC3 cells were determined. Comparative analysis revealed the genes whose expression was changed in prostate cancer cells compared with normal PNT2 cells, and those differently expressed between the cancer cell lines (ACTA2, IL6, SERPINE1, TAGLN, SEMA3A, and CDH2). GLCE re-expression influenced mainly angiogenesis-involved genes (ANGPT1, SERPINE1, IGF1, PDGFB, TNF, IL8, TEK, IFNA1, and IFNB1) but in a cell type-specific manner (from basic deregulation of angiogenesis in LNCaP cells to significant activation in PC3 cells). Invasion/metastasis pathway was also affected (MMP1, MMP2, MMP9, S100A4, ITGA1, ITGB3, ERBB2, and FAS). The obtained results suggest activation of angiogenesis as a main molecular mechanism of pro-oncogenic effect of GLCE in prostate cancer. GLCE up-regulation plus expression pattern of a panel of six genes, discriminating morphologically different prostate cancer cell sub-types, is suggested as a potential marker of aggressive prostate cancer.

Related: Angiogenesis and Cancer Prostate Cancer


Lindner R, Sullivan C, Offor O, et al.
Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy.
PLoS One. 2013; 8(11):e71915 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.

Related: Breast Cancer Angiogenesis and Cancer


Koti M, Gooding RJ, Nuin P, et al.
Identification of the IGF1/PI3K/NF κB/ERK gene signalling networks associated with chemotherapy resistance and treatment response in high-grade serous epithelial ovarian cancer.
BMC Cancer. 2013; 13:549 [PubMed] Article available free on PMC after 17/01/2015 Related Publications
BACKGROUND: Resistance to platinum-based chemotherapy remains a major impediment in the treatment of serous epithelial ovarian cancer. The objective of this study was to use gene expression profiling to delineate major deregulated pathways and biomarkers associated with the development of intrinsic chemotherapy resistance upon exposure to standard first-line therapy for ovarian cancer.
METHODS: The study cohort comprised 28 patients divided into two groups based on their varying sensitivity to first-line chemotherapy using progression free survival (PFS) as a surrogate of response. All 28 patients had advanced stage, high-grade serous ovarian cancer, and were treated with standard platinum-based chemotherapy. Twelve patient tumours demonstrating relative resistance to platinum chemotherapy corresponding to shorter PFS (< eight months) were compared to sixteen tumours from platinum-sensitive patients (PFS > eighteen months). Whole transcriptome profiling was performed using an Affymetrix high-resolution microarray platform to permit global comparisons of gene expression profiles between tumours from the resistant group and the sensitive group.
RESULTS: Microarray data analysis revealed a set of 204 discriminating genes possessing expression levels which could influence differential chemotherapy response between the two groups. Robust statistical testing was then performed which eliminated a dependence on the normalization algorithm employed, producing a restricted list of differentially regulated genes, and which found IGF1 to be the most strongly differentially expressed gene. Pathway analysis, based on the list of 204 genes, revealed enrichment in genes primarily involved in the IGF1/PI3K/NF κB/ERK gene signalling networks.
CONCLUSIONS: This study has identified pathway specific prognostic biomarkers possibly underlying a differential chemotherapy response in patients undergoing standard platinum-based treatment of serous epithelial ovarian cancer. In addition, our results provide a pathway context for further experimental validations, and the findings are a significant step towards future therapeutic interventions.

Related: Ovarian Cancer Signal Transduction


Hawsawi Y, El-Gendy R, Twelves C, et al.
Insulin-like growth factor - oestradiol crosstalk and mammary gland tumourigenesis.
Biochim Biophys Acta. 2013; 1836(2):345-53 [PubMed] Related Publications
Development and differentiation of the mammary gland are dependent on the appropriate temporal expression of both systemically acting hormones and locally produced growth factors. A large body of evidence suggests that molecular crosstalk between these hormonal and growth factor axes is crucial for appropriate cell and tissue function. Two of the most important trophic factors involved in this process are the oestrogen (E) and insulin-like growth factor (IGF) molecular axes. The reciprocal crosstalk that exists between these pathways occurs at transcriptional/post-transcriptional and translational/post-translational levels regulate the expression and activity of genes involved in this process. In a clinical context an important consequence of such crosstalk in the mammary gland is the role which it may play in the aetiology, maintenance and development of breast tumours. Although oestradiol (E2) acting through oestrogen receptors α and β (ERα/β) is important for normal mammary gland function it can also provide a mitogenic drive to ER+ breast tumours. Therefore over several years anti-oestrogen therapeutic regimens in the form of selective oestrogen receptor modulators (SERMs - e.g. tamoxifen), aromatase inhibitors (AI e.g. anastrozole) or selective oestrogen receptor down regulators (SERDs - e.g. fulvestrant) have been used in an adjuvant setting to control tumour growth. Although initial response is usually encouraging, large cohorts of patients eventually develop resistance to these treatments leading to tumour recurrence and poor prognosis. There are potentially many routes by which breast cancer (BC) cells could escape anti-oestrogen based therapeutic strategies and one of the most studied is the possible growth factor mediated activation of ER(s). Because of this, growth factor modulation of ER activity has been an intensively studied route of molecular crosstalk in the mammary gland. The insulin-like growth factors (IGF-1 and -2) are amongst the most potent mitogens for mammary epithelial cells and there is accumulating evidence that they interact with the E2 axis to regulate mitogenesis, apoptosis, adhesion, migration and differentiation of mammary epithelial cells. Such interactions are bi-directional and E2 has been shown to regulate the expression and activity of IGF axis genes with the general effect of sensitising breast epithelial cells to the actions of IGFs and insulin. In this short review we discuss the evidence for the involvement of crosstalk between the insulin-like growth factor (IGF) and oestrogen axes in the mammary gland and comment on the relevance of such studies in the aetiology and treatment of BC.

Related: Breast Cancer Signal Transduction


Ellis BC, Graham LD, Molloy PL
CRNDE, a long non-coding RNA responsive to insulin/IGF signaling, regulates genes involved in central metabolism.
Biochim Biophys Acta. 2014; 1843(2):372-86 [PubMed] Related Publications
Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that is activated early in colorectal cancer but whose regulation and functions are unknown. CRNDE transcripts are recognized as long non-coding RNAs (lncRNAs), which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Complex alternative splicing results in numerous transcripts from this gene, and we have identified novel transcripts containing a highly-conserved sequence within intron 4 ("gVC-In4"). In colorectal cancer cells, we demonstrate that treatment with insulin and insulin-like growth factors (IGF) repressed CRNDE nuclear transcripts, including those encompassing gVC-In4. These repressive effects were negated by use of inhibitors against either the PI3K/Akt/mTOR pathway or Raf/MAPK pathway, suggesting CRNDE is a downstream target of both signaling cascades. Expression array analyses revealed that siRNA-mediated knockdown of gVC-In4 transcripts affected the expression of many genes, which showed correlation with insulin/IGF signaling pathway components and responses, including glucose and lipid metabolism. Some of the genes are identical to those affected by insulin treatment in the same cell line. The results suggest that CRNDE expression promotes the metabolic changes by which cancer cells switch to aerobic glycolysis (Warburg effect). This is the first report of a lncRNA regulated by insulin/IGFs, and our findings indicate a role for CRNDE nuclear transcripts in regulating cellular metabolism which may correlate with their upregulation in colorectal cancer.

Related: Colorectal (Bowel) Cancer IGF2 AKT1 Signal Transduction


Chen Y, Li T, Yu X, et al.
The RTK/ERK pathway is associated with prostate cancer risk on the SNP level: a pooled analysis of 41 sets of data from case-control studies.
Gene. 2014; 534(2):286-97 [PubMed] Related Publications
Prostate cancer (PCa) is a malignant disease influencing numerous men worldwide every year. However, the exact pathogenesis and the genes, environment, and other factors involved have not been explained clearly. Some studies have proposed that cell signaling pathways might play a key role in the development and progression of PCa. According to our previous study, the RTK/ERK pathway containing nearly 40 genes was associated with PCa risk. On the basis of these genes, we conducted a meta-analysis with our own Chinese Consortium for Prostate Cancer Genetics (ChinaPCa) study and available studies in the databases to describe the association between the pathway and PCa on the SNP level. The results suggested that rs4764695/IGF1 (recessive model: pooled OR=0.92, 95%CI=0.852-0.994, P=0.034; I(2)=0%, P=0.042; allele analysis: pooled OR=0.915, 95%CI=0.874-0.958, P=0; I(2)=0%, P=0.424; codominant model: OR=0.835, 95%CI=0.762-0.916, P=0; I(2)=0%, P=0.684) and rs1570360/VEGF (recessive model: OR=0.596, 95%CI=0.421-0.843, P=0.003; I(2)=23.9%, P=0.269; codominant model: OR=0.576, 95%CI=0.404-0.820, P=0.002; I(2)=49.1%, P=0.140) were significantly associated with PCa. In subgroup analysis, the relationship was also found in Caucasians for IGF1 (dominant model: OR=0.834, 95%CI=0.769-0.904, P=0; allele analysis: OR=0.908, 95%CI=0.863-0.955, P=0; AA vs CC: OR=0.829, 95%CI=0.750-0.916, P=0; AC vs CC: OR=0.837, 95%CI=0.768-0.912, P=0). In addition, in Asians (allele analysis: OR=0.21, 95%CI=0.168-0.262, P=0) and Caucasians (recessive model: OR=0.453, 95%CI: 0.240-0.855, P=0.015; codominant model: OR=0.464, 95%CI=0.240-0.898, P=0.023) for VEGF, the association was significant. The results indicated that rs4764695/IGF1 and rs1570360/VEGF might play a key role in the development and progression of PCa. On the SNP level, we suggest that the study gives us a new view of gene-pathway analysis and targeted therapy for PCa.

Related: Prostate Cancer


Galet C, Gollapudi K, Stepanian S, et al.
Effect of a low-fat fish oil diet on proinflammatory eicosanoids and cell-cycle progression score in men undergoing radical prostatectomy.
Cancer Prev Res (Phila). 2014; 7(1):97-104 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
We previously reported that a 4- to 6-week low-fat fish oil (LFFO) diet did not affect serum insulin-like growth factor (IGF)-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared with a Western diet. In this post hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, leukotriene B4 (LTB4) and 15-S-hydroxyeicosatetraenoic acid [15(S)-HETE], and the cell-cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by quantitative real-time reverse transcriptase PCR (RT-PCR). Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the Western diet group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared with the Western diet group. The 15(S)-HETE change correlated with tissue Ki67 (R = 0.48; P < 0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r = 0.4; P = 0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, an LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a Western diet. Further studies are warranted to determine whether the LFFO diet antiproliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways.

Related: MKI67 Prostate Cancer


Barcellos-Hoff MH, Kleinberg DL
Breast cancer risk in BRCA1 mutation carriers: insight from mouse models.
Ann Oncol. 2013; 24 Suppl 8:viii8-viii12 [PubMed] Related Publications
Since its identification 20 years ago, the biological basis for the high breast cancer risk in women who have germline BRCA1 mutations has been an area of intense study for three reasons. First, BRCA1 was the first gene shown to associate with breast cancer risk, and therefore serves as model for understanding genetic susceptibility. Second, the type of breast cancer that occurs in these women has specific features that have engendered new hypotheses about the cancer biology. Third, it is hoped that understanding the origins of this disease may provide the means to prevent disease. Resolving this question has proven extremely challenging because the biology controlled by BRCA1 is complex. Our working model is that the high frequency of basal-like breast cancer in BRCA1 mutation carriers is the result of a self-perpetuating triad of cellular phenotypes consisting of: (i) intrinsic defects in DNA repair and centrosome regulation that lead to genomic instability and increases spontaneous transformation; (ii) aberrant lineage commitment; and (iii) increased proliferation due to in large part to increased IGF-1 activity. We propose that the last is key and is a potential entree for preventing breast cancer in BRCA1 mutation carriers.

Related: Breast Cancer


Fogarty FM, O'Keeffe J, Zhadanov A, et al.
HRG-1 enhances cancer cell invasive potential and couples glucose metabolism to cytosolic/extracellular pH gradient regulation by the vacuolar-H(+) ATPase.
Oncogene. 2014; 33(38):4653-63 [PubMed] Related Publications
Haeme-responsive gene (HRG)-1 encodes a 16-kDa transmembrane protein that is induced by insulin-like growth factor-1 (IGF-1) and associates with the vacuolar-(H(+)) ATPase (V-ATPase). We previously reported that HRG-1 is essential for V-ATPase activity in endosomal acidification and receptor trafficking. Here, we show that in highly invasive and migratory cancer cell lines, HRG-1 and the V-ATPase are co-expressed at the plasma membrane, whereas in less invasive cell lines and non-transformed cells HRG-1 over-expression remains confined to intracellular compartments. Stable suppression of HRG-1 in invasive breast cancer MDA-MB-231 cells decreases extracellular pH, cell growth, migration and invasion. Ectopic expression of HRG-1 in non-invasive MCF-7 cells enhances V-ATPase activity, lowers the extracellular pH and increases the pH-dependent activity of MMP2 and MMP9 matrix metalloproteinases. HRG-1 enhances trafficking of the glucose transporter-1 (GLUT-1) with a concomitant increase in glucose uptake and lactate production. HRG-1 also promotes trafficking of the insulin-like growth factor I receptor (IGF-1R), β1-integrin and IGF-1 signalling. Taken together, our findings indicate that HRG-1 expression at the plasma membrane enhances V-ATPase activity, drives glycolytic flux and facilitates cancer cell growth, migration and invasion. Thus, HRG-1 may represent a novel target for selectively disrupting V-ATPase activity and the metastatic potential of cancer cells.

Related: SLC2A1 MMP2 MMP9: matrix metallopeptidase 9


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Cite this page: Cotterill SJ. IGF1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/IGF1.htm Accessed: date

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