IGF2

Gene Summary

Gene:IGF2; insulin like growth factor 2
Aliases: GRDF, IGF-II, PP9974, C11orf43
Location:11p15.5
Summary:This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:insulin-like growth factor II
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
Show (42)

Cancer Overview

The loss of imprinting of insulin-like growth factor 2 (IGF2) and an overexpression of this growth factor gene have been reported in a wide range of cancers, particularly in Wilms' tumour.

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 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 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (9)

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).

Latest Publications: IGF2 (cancer-related)

Gümus M, Ozgur A, Tutar L, et al.
Design, Synthesis, and Evaluation of Heat Shock Protein 90 Inhibitors in Human Breast Cancer and Its Metastasis.
Curr Pharm Biotechnol. 2016; 17(14):1231-1245 [PubMed] Related Publications
BACKGROUND: Despite development of novel cancer drugs, invasive ductal breast carcinoma and its metastasis are still highly morbid. Therefore, new therapeutic approaches are being developed and Hsp90 is an important target for drug design. For this purpose, a series of benzodiazepine derivatives were designed and synthesized as novel Hsp90 inhibitor.
METHODS: Benzodiazepine derivatives anticancer activities were determined by XTT cell proliferation assay against human breast cancer cell line (MCF-7). Effects of the compounds on endothelial function were monitored on human vascular endothelium (HUVEC) cell line as well. In order to determine the anti-proliferative mechanism of the compounds, in silico molecular docking studies were performed between Hsp90 ATPase domain and the benzodiazepine derivatives. Further, these compounds perturbation on Hsp90 ATPase function were tested. Fluorescence binding experiments showed that the derivatives bind Hsp90 effectively. Expression analysis of known cancer drug target genes by PCR array experiments suggest that the benzodiazepine derivatives have remarkable anticancer activity.
RESULTS: A representative Benzodiazepine derivative D5 binds Hsp90 with Kd value of 3,93 μM and with estimated free energy of binding -7.99 (kcal/mol). The compound decreases Hsp90 ATPase function and inhibit Hsp90 client protein folding activity. The compound inhibits expression of both Hsp90 isoforms and key proteins (cell cycle receptors; PLK2 and TERT, kinases; PI3KC3 and PRKCE, and growth factors; IGF1, IGF2, KDR, and PDGFRA) on oncogenic pathways.
CONCLUSION: Benzodiazepine derivatives presented here display anticancer activity. The compounds effect on both breast cancer and endothelial cell lines show their potential as drug templates to inhibit breast cancer and its metastasis.

Piyamongkol W, Suprasert P
Allelic Characterization of IGF2 and H19 Gene Polymorphisms in Molar Tissues.
Asian Pac J Cancer Prev. 2016; 17(9):4405-4408 [PubMed] Related Publications
BACKGROUND: To investigate the characteristics of allelic distribution of IGF2 and H19 gene polymorphisms in molar tissues compared to normal placentas.
MATERIALS AND METHODS: Forty-nine specimens of molar tissues as well as 100 control normal placental tissues, delivered on the same days, were collected. Polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) on 2% agarose gel electrophoresis was conducted to determine the allelic distribution. The ApaI polymorphism within exon 9 of IGF2 and the RsaI polymorphism within exon 5 of H19 were employed to identify the allelic distribution of the IGF2 and H19 genes, respectively. Then the data for these genes in the molar and normal placenta tissues were compared.
RESULTS: The allelic distribution of IGF2 genes found in molar tissue were 21 (42.9%) aa (undigested), 10 (20.4%) ab (heterozygous) and 18 (36.7%) bb (digested), while in normal placenta tissue the values were 22 (22%) aa, 51 (51%) ab, and 27 (27%) bb. The allelic distribution of H19 in molar tissues was 8 (16.2%) aa (undigested), 8 (16.3%) ab (heterozygous) and 33 (67.4%) bb (digested) and in normal placental tissue was 16 (16%) aa, 36 (36%) ab and 48 (48%) bb in normal placenta tissue. These results were significantly different with P values of 0.001 and 0.037 for the allelic distribution of IGF2 and H19, respectively.
CONCLUSIONS: Molar tissues showed significant differences of allelic distribution of IGF2 and H19 from normal placenta tissues.

Rogers MA, Kalter V, Strowitzki M, et al.
IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.
Tumour Biol. 2016; 37(9):12485-12495 [PubMed] Related Publications
Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T. The cells were analyzed for changes in proliferation, cell cycle, apoptosis, adhesion, and invasion. Expression profiling analysis was performed, and, for a subset of the identified genes, expression was validated by qRT-PCR and Western blot. IGF2 knockdown inhibited cell proliferation in both cell lines induced G1 cell cycle blockade and decreased adhesion to several extracellular matrix proteins. Knockdown of IGF2 did not alter invasiveness in SW480 cells, while a slight increase in apoptosis was seen only in the LS174T cell line. Knockdown of IGF2 in SW480 deregulated 58 genes, several of which were associated with proliferation and cell-cell/cell-ECM contacts. A subset of these genes, including CDK2, YAP1, and BIRC5 (Survivin), are members of a common network. This study supports the concept of direct autocrine/paracrine tumor cell activation through IGF2 and a shows role of IGF2 in CRC proliferation, adhesion and, to a limited extent, apoptosis.

Minchenko DO, Kharkova AP, Halkin OV, et al.
Effect of hypoxia on the expression of genes encoding insulin-like growth factors and some related proteins in U87 glioma cells without IRE1 function.
Endocr Regul. 2016; 50(2):43-54 [PubMed] Related Publications
OBJECTIVE: The aim of the present study was to investigate the effect of hypoxia on the expression of genes encoding insulin-like growth factors (IGF1 and IGF2), their receptor (IGF1R), binding protein-4 (IGFBP4), and stanniocalcin 2 (STC2) in U87 glioma cells in relation to inhibition of endoplasmic reticulum stress signaling mediated by IRE1 (inositol requiring enzyme 1) for evaluation of their possible significance in the control of tumor growth.
METHODS: The expression of IGF1, IGF2, IGF1R, IGFBP4, and STC2 genes in U87 glioma cells transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia was studied by qPCR.
RESULTS: The expression of IGF1 and IGF2 genes is down-regulated in glioma cells without IRE1 signaling enzyme function in comparison with the control cells. At the same time, the expression of IGF1R, IGFBP4, and STC2 genes was up-regulated in glioma cells upon inhibition of IRE1, with more significant changes for IGFBP4 and STC2 genes. We also showed that hypoxia does not change significantly the expression of IGF1, IGF2, and IGF1R genes but up-regulated IGFBP4 and STC2 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells does not change significantly the effect of hypoxia on the expression of IGF1, IGF1R, and IGFBP4 genes but introduces sensitivity of IGF2 gene to hypoxic condition. Thus, the expression of IGF2 gene is resistant to hypoxia only in control glioma cells and significantly down-regulated in cells without functional activity of IRE1 signaling enzyme, which is central mediator of the unfolded protein response and an important component of the tumor growth as well as metabolic diseases.
CONCLUSIONS: Results of this study demonstrate that the expression of IGF1 and IGF1R genes is resistant to hypoxic condition both in control U87 glioma cells and cells without IRE1 signaling enzyme function. However, hypoxia significantly up-regulates the expression of IGFBP4 gene independently on the inhibition of IRE1 enzyme. These data show that proteins encoded by these genes are resistant to hypoxia except IGFBP4 and participate in the regulation of metabolic and proliferative processes through IRE1 signaling.

Sumida T, Kamata YU, Kobayashi Y, et al.
ID1 Controls Aggressiveness of Salivary Gland Cancer Cells via Crosstalk of IGF and AKT Pathways.
Anticancer Res. 2016; 36(8):3865-70 [PubMed] Related Publications
BACKGROUND: Inhibitor of differentiation or DNA binding 1 (ID1) is overexpressed in human salivary gland cancer (SGC). The insulin growth factor (IGF) system is an attractive target in cancer control because it is associated with various cancer progressions.
MATERIALS AND METHODS: The human SGC cell line HSY with abundant ID1 was used. ID1 knockdown and its effect on the IGF system were investigated. Cell proliferation and invasion, as well as associated protein expression, were analyzed. Phospho-AKT was also evaluated.
RESULTS: ID1 knockdown reduced cell proliferation and invasion, while the expression of proteins associated with malignant phenotypes was altered. IGF-II expression was suppressed, suggesting that this system is one of the mechanisms underlying effects of ID1 in SGC cells. c-Myc was up-regulated, whereas p21 and p27 were down-regulated. Moreover, phospho-AKT was reduced in ID1-knockeddown cells.
CONCLUSION: ID1 down-regulation induced parallel changes in the IGF and AKT pathways. The crosstalk of these pathways may enhance malignant phenotypes in SGCs.

Kim TH, Chang JH, Lee HJ, et al.
mRNA expression of CDH3, IGF2BP3, and BIRC5 in biliary brush cytology specimens is a useful adjunctive tool of cytology for the diagnosis of malignant biliary stricture.
Medicine (Baltimore). 2016; 95(27):e4132 [PubMed] Free Access to Full Article Related Publications
Although advances have been made in diagnostic tools, the distinction between malignant and benign biliary strictures still remains challenging. Intraductal brush cytology is a convenient and safe method that is used for the diagnosis of biliary stricture, but, low sensitivity limits its usefulness. This study aimed to demonstrate the usefulness of mRNA expression levels of target genes in brush cytology specimens combined with cytology for the diagnosis of malignant biliary stricture. Immunohistochemistry for cadherin 3 (CDH3), p53, insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), and baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) was performed in 4 benign and 4 malignant bile duct tissues. Through endoscopic or interventional radiologic procedures, brush cytology specimens were prospectively obtained in 21 and 35 paitents with biliary strictures. In the brush cytology specimens, the mRNA expressions levels of 5 genes were determined by real-time polymerase chain reaction. Immunohistochemistry for CDH3, p53, IGF2BP3, HOXB7, and BIRC5 all showed positive staining in malignant tissues in contrast to benign tissues, which were negative. In the brush cytology specimens, the mRNA expression levels of CDH3, IGF2BP3, HOXB7, and BIRC5 were significantly higher in cases of malignant biliary stricture compared with cases of benign stricture (P = 0.006, P < 0.001, P < 0.001, and P = 0.001). The receiver-operating characteristic curves of these 4 mRNAs demonstrated that mRNA expression levels are useful for the prediction of malignant biliary stricture (P = 0.006, P < 0.001, P < 0.001, and P = 0.002). The sensitivity and specificity, respectively, for malignant biliary stricture were 57.1% and 100% for cytology, 57.1% and 64.3% for CDH3, 76.2% and 100% for IGF2BP3, 71.4% and 57.1% for HOXB7, and 76.2% and 64.3% for BIRC5. When cytology was combined with the mRNA levels of CDH3, IGF2BP3, or BIRC5, the sensitivity for malignant biliary stricture improved to 90.5%. The measurement of the mRNA expression levels of CDH3, IGF2BP3, and BIRC5 by real-time polymerase chain reaction combined with cytology was useful for the differentiation of malignant and benign biliary strictures in brush cytology specimens.

Gadducci A, Biglia N, Tana R, et al.
Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning.
Crit Rev Oncol Hematol. 2016; 105:73-83 [PubMed] Related Publications
Metformin exerts antitumor effects mainly through AMP-activated protein kinase [AMPK] activation and phosphatidylinositol 3-kinase [PI3K]-Akt-mammalian target of rapamycin [mTOR] inhibition. This drug leads to activation of the cellular energy-sensing liver kinase B1 [LKB1]/AMPK pathway. LKB1 is implicated as a tumor suppressor gene in molecular pathogenesis of different malignancies. AMPK is a serine/threonine protein kinase that acts as an ultra-sensitive cellular energy sensor maintaining the energy balance within the cell. AMPK activation inhibits mRNA translation and proliferation in cancer cells via down-regulation of PI3K/Akt/mTOR pathway. Moreover, metformin decreases the production of insulin, insulin-like growth factor, inflammatory cytokines and vascular endothelial growth factor, and therefore it exerts anti-mitotic, anti-inflammatory and anti-angiogenetic effects. Recent in vitro and experimental data suggest that metformin electively targets cancer stem cells, and acts together with chemotherapy to block tumor growth in different cancers. Several epidemiological studies and meta-analysis have shown that metformin use is associated with decreased cancer risk and/or reduced cancer mortality for different malignancies. The present review analyzes the recent biological and clinical data suggesting a possible growth-static effect of metformin also in gynecological cancers. The large majority of available clinical data on the anti-cancer potential of metformin are based on observational studies. Therefore long-term phase II-III clinical trials are strongly warranted to further investigate metformin activity in gynecological cancers.

Wang J, Zhao M, Xiao J, et al.
E-Cadherin, CD44v6, and Insulin-Like Growth Factor-II mRNA-Binding Protein 3 Expressions in Different Stages of Hydatidiform Moles.
J Biochem Mol Toxicol. 2016; 30(9):455-61 [PubMed] Related Publications
E-cadherin, CD44v6, and IMP3 expression in partial, complete, and invasive hydatidiform moles (HMs) was evaluated. High E-cadherin expression with low CD44v6 expression was observed in partial, complete, and invasive HMs, as well as in normal placental tissues; and there was no significant difference in E-cadherin and CD44v6 expression among the four groups. However, IMP3 expression was gradually decreased in the order of normal placental tissues, partial HMs, complete HMs, and invasive HMs; wherein, invasive HMs had the lowest level. Low IMP3 expression may serve as a prognostic biomarker for HMs, and IMP3 may play a certain role in HMs progression.

Hsu CM, Lin PM, Lin HC, et al.
Altered Expression of Imprinted Genes in Squamous Cell Carcinoma of the Head and Neck.
Anticancer Res. 2016; 36(5):2251-8 [PubMed] Related Publications
BACKGROUND: Genomic imprinting is associated with many human diseases, including various types of cancers, however, no studies on gene imprinting are related to squamous cell carcinoma of the head and neck (SCCHN) directly.
MATERIALS AND METHODS: In this study, the expression of a panel of 15 imprinted genes in cancerous and non-cancerous tissues from 73 patients with SCCHN were investigated.
RESULTS: Altered expression of carboxypeptidase A4 (CPA4); protein phosphatase 1 regulatory subunit 9A (PPP1R9A); H19, imprinted maternally expressed transcript (non-protein coding) (H19); paternally expressed gene 3 antisense RNA 1 (PEG3-AS1); retrotransposon-like 1 (RTL1), insulin-like growth factor 2 (IGF2); solute carrier family 22 member 3 (SLC22A3); and gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) was observed. Down-regulation of PPP1R9A (p<0.05) and GABRB3 (p<0.05) was correlated with more advanced cancer stages. Down-regulation of PEG3-AS1 (p<0.05) and GABRB3 (p<0.01) was correlated with lymph node metastasis. Poor survival was related to higher expression of CPA4 (p<0.01) and lower expression of PEG3-AS1 (p<0.05) and IGF2 (p<0.05). Chemotherapy was also found to have an impact on the expression of imprinted genes.
CONCLUSION: Loss of imprinting is involved in tumorigenesis of SCCHN.

Merritt MA, Strickler HD, Einstein MH, et al.
Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors.
Cancer Causes Control. 2016; 27(6):737-48 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology.
METHODS: We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively.
RESULTS: In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01).
CONCLUSIONS: These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.

El Ghorayeb N, Rondeau G, Latour M, et al.
Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.
Medicine (Baltimore). 2016; 95(13):e3180 [PubMed] Free Access to Full Article Related Publications
Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients.

Sabet JA, Park LK, Iyer LK, et al.
Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring.
PLoS One. 2016; 11(3):e0151579 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well.
OBJECTIVE: In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content.
METHODS: Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden.
RESULTS: No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid-metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring.
CONCLUSIONS: In this animal model, modulation of paternal B vitamin intake prior to mating alters offspring weight gain, lipid metabolism and tumor growth in a sex-specific fashion. These results highlight the need to better define how paternal nutrition affects the health of offspring.

Fujisawa Y, Sakaguchi K, Ono H, et al.
Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma.
J Steroid Biochem Mol Biol. 2016; 159:86-93 [PubMed] Related Publications
Although childhood adrenocortical carcinomas (c-ACCs) with a TP53 mutation are known to produce androgens, detailed steroidogenic characters have not been clarified. Here, we examined steroid metabolite profiles and expression patterns of steroidogenic genes in a c-ACC removed from the left adrenal position of a 2-year-old Brazilian boy with precocious puberty, using an atrophic left adrenal gland removed at the time of tumorectomy as a control. The c-ACC produced not only abundant dehydroepiandrosterone-sulfate but also a large amount of testosterone via the Δ5 pathway with Δ5-androstenediol rather than Δ4-androstenedione as the primary intermediate metabolite. Furthermore, the c-ACC was associated with elevated expressions of CYP11A1, CYP17A1, POR, HSD17B3, and SULT2A1, a low but similar expression of CYB5A, and reduced expressions of AKR1C3 (HSD17B5) and HSD3B2. Notably, a Leydig cell marker INSL3 was expressed at a low but detectable level in the c-ACC. Furthermore, molecular studies revealed a maternally inherited heterozygous germline TP53 mutation, and several post-zygotic genetic aberrations in the c-ACC including loss of paternally derived chromosome 17 with a wildtype TP53 and loss of maternally inherited chromosome 11 and resultant marked hyperexpression of paternally expressed growth promoting gene IGF2 and drastic hypoexpression of maternally expressed growth suppressing gene CDKN1C. These results imply the presence of combined steroidogenic properties of fetal adrenal and Leydig cells in this patient's c-ACC with a germline TP53 mutation and several postzygotic carcinogenic events.

Huang L, Mokkapati S, Hu Q, et al.
Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation.
Neoplasia. 2016; 18(2):71-81 [PubMed] Free Access to Full Article Related Publications
Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes β-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage.

Altinoz MA, Elmaci I, Ince B, et al.
Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and İmmunity with Special Emphasis for Brain Tumors.
J Neurol Surg A Cent Eur Neurosurg. 2016; 77(3):247-57 [PubMed] Related Publications
In systemic cancers, increased hemolysis leads to extracellular hemoglobin (HB), and experimental studies have shown its provoking role on tumor growth and metastasis. However, investigations have shown that HB chains presented by tumor vascular pericytes or serum protein complexes of HB could also induce antitumor immunity, which may be harnessed to treat refractory cancers and brain tumors. Mounting recent evidence shows that expression of HBs is not restricted to erythrocytes and that HBs exist in the cells of lung and kidney, in macrophages, and in neurons and glia of the central nervous system (CNS). HBs mediate coping with hypoxia and free radical stress in normal and tumor cells, and they are increased in certain tumors including breast, lung, colon, and squamous cell cancers. Recent studies showed HBs in meningioma, in the cyst fluid of craniopharyngioma, in the cerebrospinal fluid (CSF) of pediatric patients with posterior fossa tumors, and in glioblastoma cell lines. Hemorphins, abundant brain peptides formed via HB-chain cleavage, exert opioid activity and antiproliferative and immunomodifier effects. Hence mutations in HBs may modify brain tumorigenesis via influencing hemorphins and perturbing regulations of immune surveillance and cell growth in the neuroectodermal tissues. The β-globin gene cluster resides in the chromosome region 11p15.5, harboring important immunity genes and IGF2, H19, PHLDA2/TSSC3, TRIM3, and SLC22A18 genes associated with cancers and gliomas. 11p15.5 is a prominent region subject to epigenetic regulation. Thus the β-globin loci may exert haplotypal interactions with these. Some clues support this theory. It is well established that iron load induces liver cancer in thalassemia major; however iron load-independent associations also exist. Enhanced rates of hematologic malignancies are associated with HB Lepore, association of hemoglobin E with cholangiocarcinoma, and enhanced gastric cancer rates in the thalassemia trait. In the African Herero population, a mutant form of δ-globin is very prevalent, and this population has higher rates of pediatric brain tumors. Globins are also expressed in healthy endothelia and in tumoral vessels, indicating potential involvement in angiogenesis. Studies on HBs and their cleavage peptides in cancers and brain tumors may lead to innovative treatment strategies.

Stoskus M, Vaitkeviciene G, Eidukaite A, Griskevicius L
ETV6/RUNX1 transcript is a target of RNA-binding protein IGF2BP1 in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia.
Blood Cells Mol Dis. 2016; 57:30-4 [PubMed] Related Publications
The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) is overexpressed in a subset of cancers and promotes cell cycle, migration and aggressive phenotype by regulating post-transcriptionally a number of key mRNAs (e. g, ACTB, CD44, CTNNB1, KRAS, MAPK4, MYC, PTEN and others). IGF2BP1 is also overexpressed in t(12;21)(p13;q22)-positive acute lymphoblastic leukemia (ALL), but the biological significance of this phenomenon has not been addressed so far. We have identified leukemia fusion gene ETV6/RUNX1 mRNA to be highly enriched in immunoprecipitated fraction of endogenous IGF2BP1 from a model cell line REH and t(12;21)(p13;q22)-positive ALL samples. Furthermore, downregulation of IGF2BP1 by two-fold has resulted in a corresponding decrease of ETV6/RUNX1 mRNA validating this transcript as a target of IGF2BP1 protein in t(12;21)(p13;q22)-positive ALL. These data infer that IGF2BP1 is a potent regulator of ETV6/RUNX1 mRNA stability and potentially link this evolutionary-highly conserved protein to cell transformation events in ETV6/RUNX1-mediated leukemogenesis of t(12;21)(p13;q22)-positive ALL.

Murayama T, Nakaoku T, Enari M, et al.
Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit.
Cancer Res. 2016; 76(4):974-83 [PubMed] Related Publications
The CD74-Neuregulin1 (NRG1) fusion gene was recently identified as novel driver of invasive mucinous adenocarcinoma, a malignant form of lung cancer. However, the function of the CD74-NRG1 fusion gene in adenocarcinoma pathogenesis and the mechanisms by which it may impart protumorigenic characteristics to cancer stem cells (CSC) is still unclear. In this study, we found that the expression of the CD74-NRG1 fusion gene increased the population of lung cancer cells with CSC-like properties. CD74-NRG1 expression facilitated sphere formation not only of cancer cells, but also of nonmalignant lung epithelial cells. Using a limiting dilution assay in a xenograft model, we further show that the CD74-NRG1 fusion gene enhanced tumor initiation. Mechanistically, we found that CD74-NRG1 expression promoted the phosphorylation of ErbB2/3 and activated the PI3K/Akt/NF-κB signaling pathway. Furthermore, the expression of the secreted insulin-like growth factor 2 (IGF2) and phosphorylation of its receptor, IGF1R, were enhanced in an NF-κB-dependent manner in cells expressing CD74-NRG1. These findings suggest that CD74-NRG1-induced NF-κB activity promotes the IGF2 autocrine/paracrine circuit. Moreover, inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation. Therefore, our study provides a preclinical rationale for developing treatment approaches based on these identified pathways to suppress CSC properties that promote tumor progression and recurrence.

Chen J, Yao ZX, Chen JS, et al.
TGF-β/β2-spectrin/CTCF-regulated tumor suppression in human stem cell disorder Beckwith-Wiedemann syndrome.
J Clin Invest. 2016; 126(2):527-42 [PubMed] Free Access to Full Article Related Publications
Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder, and individuals with this disease have a substantially increased risk (~800-fold) of developing tumors. Epigenetic silencing of β2-spectrin (β2SP, encoded by SPTBN1), a SMAD adaptor for TGF-β signaling, is causally associated with BWS; however, a role of TGF-β deficiency in BWS-associated neoplastic transformation is unexplored. Here, we have reported that double-heterozygous Sptbn1+/- Smad3+/- mice, which have defective TGF-β signaling, develop multiple tumors that are phenotypically similar to those of BWS patients. Moreover, tumorigenesis-associated genes IGF2 and telomerase reverse transcriptase (TERT) were overexpressed in fibroblasts from BWS patients and TGF-β-defective mice. We further determined that chromatin insulator CCCTC-binding factor (CTCF) is TGF-β inducible and facilitates TGF-β-mediated repression of TERT transcription via interactions with β2SP and SMAD3. This regulation was abrogated in TGF-β-defective mice and BWS, resulting in TERT overexpression. Imprinting of the IGF2/H19 locus and the CDKN1C/KCNQ1 locus on chromosome 11p15.5 is mediated by CTCF, and this regulation is lost in BWS, leading to aberrant overexpression of growth-promoting genes. Therefore, we propose that loss of CTCF-dependent imprinting of tumor-promoting genes, such as IGF2 and TERT, results from a defective TGF-β pathway and is responsible at least in part for BWS-associated tumorigenesis as well as sporadic human cancers that are frequently associated with SPTBN1 and SMAD3 mutations.

Mishima C, Kagara N, Tanei T, et al.
Loss of imprinting of IGF2 in fibroadenomas and phyllodes tumors of the breast.
Oncol Rep. 2016; 35(3):1511-8 [PubMed] Related Publications
Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is thought to be implicated in the pathogenesis of some tumors by upregulating IGF2 mRNA but its role in the pathogenesis of fibroadenomas (FAs) and phyllodes tumors (PTs) of the breast is yet to be studied. LOI of IGF2 was investigated in 25 FAs and 17 PTs which were heterozygous for Apa I polymorphism, and was found to be present in 13 FAs and 12 PTs. IGF2 mRNA expression was more upregulated in FAs and PTs than in paired surrounding normal tissues and laser microdissection showed that IGF2 mRNA expression was significantly higher in the stromal than the epithelial cells. LOI was not associated with upregulation of IGF2 mRNA, nor were MED12 mutations and methylation status of the differentially methylated region 0 (DMR0) of IGF2. These results demonstrate that IGF2 mRNA expression is more upregulated in FAs and PTs than in normal tissues, especially in their stromal cells, but such an upregulation is not related to LOI of IGF2, and that hypomethylation of DMR0 is unlikely to be involved in induction of LOI.

Matà R, Palladino C, Nicolosi ML, et al.
IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway.
Oncotarget. 2016; 7(7):7683-700 [PubMed] Free Access to Full Article Related Publications
Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer. In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 upregulation required the activation of the PI3K/AKT pathway while the ERK1/2, the p70/mTOR and the PKC pathways were not involved. Moreover, we observed that DDR1 protein upregulation was induced by translational mechanisms involving miR-199a-5p suppression through PI3K/AKT activation. This effect was confirmed by both IGF-II produced by cancer-associated fibroblasts from human breast cancer and by stable transfection of breast cancer cells with a human IGF-II expression construct. Transfection with a constitutively active form of AKT was sufficient to decrease miR-199a-5p and upregulate DDR1. Accordingly, IGF-I-induced DDR1 upregulation was inhibited by transfection with pre-miR-199a-5p, which also impaired AKT activation and cell migration and proliferation in response to IGF-I. These results demonstrate that, in breast cancer cells, a novel pathway involving AKT/miR-199a-5p/DDR1 plays a role in modulating IGFs biological responses. Therefore, this signaling pathway may represent an important target for breast cancers with over-activation of the IGF-IR axis.

Kanojia D, Nagata Y, Garg M, et al.
Genomic landscape of liposarcoma.
Oncotarget. 2015; 6(40):42429-44 [PubMed] Free Access to Full Article Related Publications
Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.

Zhang H, Zhang T, You Z, Zhang Y
Positive Surgical Margin, HPV Persistence, and Expression of Both TPX2 and PD-L1 Are Associated with Persistence/Recurrence of Cervical Intraepithelial Neoplasia after Cervical Conization.
PLoS One. 2015; 10(12):e0142868 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To determine the clinicopathologic and immunohistochemical predictors of the persistence/recurrence of cervical intraepithelial neoplasia (CIN) after cervical conization.
METHODS: Medical records of 502 patients who received cervical conization treatment of CIN between 2005 and 2012 were reviewed. The clinicopathologic parameters were analyzed using Cox hazard regression. Fifty patients with CIN persistence/recurrence were matched to 50 cases without CIN persistence/recurrence. These 100 cervical specimens were assessed for expression of insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3), targeting protein for xenopus kinesin-like protein 2 (TPX2), and programmed cell death-1 ligand-1 (PD-L1) using immunohistochemical staining.
RESULTS: Multivariate analysis found that the independent predictors of CIN persistence/recurrence were positive surgical margin (hazard ratio 5.777, 95% confidence interval 2.334-14.301, p < 0.001) and human papilloma virus persistence for 6 months (hazard ratio 20.685, 95% confidence interval 7.350-57.657, p < 0.001). Co-expression of TPX2 and PD-L1 was significantly higher in CIN persistence/recurrence group than the group without CIN persistence/recurrence (p = 0.013). The depth of glandular involvement (GI) was less than 3mm in about 86.8% (59/68) CIN2-3 lesions, However, No statistically significant associations between GI and persistence/recurrence were observed (P = 0.58).
CONCLUSION: Positive surgical margin, HPV persistence, and expression of both TPX2 and PD-L1 are associated with persistence/recurrence of cervical intraepithelial neoplasia after cervical conization.

Melmed S
New therapeutic agents for acromegaly.
Nat Rev Endocrinol. 2016; 12(2):90-8 [PubMed] Related Publications
The currently available somatostatin receptor ligands (SRLs) and growth hormone (GH) antagonists are used to control levels of GH and insulin-like growth factor 1 (IGF-1) in patients with acromegaly. However, these therapies are limited by wide variations in efficacy, associated adverse effects and the need for frequent injections. A phase III trial of oral octreotide capsules demonstrated that this treatment can safely sustain suppressed levels of GH and IGF-1 and reduce the severity of symptoms in patients with acromegaly previously controlled by injectable SRL therapy, with the added benefit of no injection-site reactions. Phase I and phase II trials of the pan-selective SRL DG3173, the liquid crystal octreotide depot CAM2029 and an antisense oligonucleotide directed against the GH receptor have shown that these agents can be used to achieve biochemical suppression in acromegaly and have favourable safety profiles. This Review outlines the need for new therapeutic agents for patients with acromegaly, reviews clinical trial data of investigational agents and considers how these therapies might best be integrated into clinical practice.

Yan J, Wei Q, Jian W, et al.
IMP3 Predicts Invasion and Prognosis in Human Lung Adenocarcinoma.
Lung. 2016; 194(1):137-46 [PubMed] Related Publications
PURPOSE: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with several aggressive and advanced cancers. Whether IMP3 can predict invasion, and prognosis in patients with human lung adenocarcinoma (LAC) remains unclear.
METHODS: Ninety-five LAC and 75 non-tumor lung tissue samples were included in a tissue microarray. IMP3 expression was assessed by immunohistochemical examination. Correlation between IMP3 expression levels, clinicopathological characteristics, and overall prognosis was evaluated. In a separate in vitro study, RNA interference method was applied for knockdown of IMP3 gene in human LAC cell lines. Invasive potential of LAC cells was then evaluated by transwell migration assay.
RESULTS: IMP3 immunoreactivity was observed in 39 out of 95 (41.1 %) LAC patients, but not in non-tumor lung tissues. IMP3 expression levels were closely associated with histological grade (P = 0.037), TNM stage (P = 0.034), and lymph node metastasis (P = 0.011). Patients presenting with positive IMP3 expression (P = 0.000), an advanced TNM stage (P = 0.000), and lymph node metastasis (P = 0.001) had a worse overall survival, compared to those lacking these characteristics. Both IMP3 expression (hazard ratio [HR], 2.310; 95 % confidence interval [CI] 1.192-4.476; P = 0.013) and TNM stage (HR 2.338; 95 % CI 1.393-3.925; P = 0.001) were independent predictors of poor prognosis. The invasive potential of LAC cells was significantly inhibited by IMP3 knockdown.
CONCLUSION: IMP3 appears to play an important role in tumor invasion in patients with LAC and may serve as a useful prognostic biomarker in these patients.

Qu Y, Pan S, Kang M, et al.
MicroRNA-150 functions as a tumor suppressor in osteosarcoma by targeting IGF2BP1.
Tumour Biol. 2016; 37(4):5275-84 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary malignant bone tumor with high morbidity in young adults and adolescents. Increasing evidence has demonstrated that aberrant microRNA (miRNA) expression is involved in OS occurrence and development. miR-150 has been recently widely studied in many cancers, but not including OS. This study is aimed to investigate the expression and biological role of miR-150 in OS. Here, we found that miR-150 expression was consistently downregulated in OS tissues and cell lines compared with the matched adjacent normal tissues and human normal osteoblast cells (NHOst), and its expression was significantly correlated with lymph node metastasis and tumor-node-metastasis (TNM) stage. Functional study showed that restoration of miR-150 expression in OS cells could inhibit cell proliferation, migration, and invasion and induced apoptosis in vitro as well as suppressed tumor growth of OS in vivo. Mechanistically, IGF2 mRNA-binding protein 1(IGF2BP1) was confirmed to act as a direct target of miR-150, and the IGF2BP1 mRNA expression was inversely correlated with the level of miR-150 in OS tissues. In addition, downregulation of endogenous IGF2BP1 exhibited similar effects of overexpression of miR-150. Taken together, these findings suggest that miR-150 functions as a tumor suppressor in OS partially by targeting IGF2BP1.

Schultz B, Yao X, Deng Y, et al.
A Common Polymorphism within the IGF2 Imprinting Control Region Is Associated with Parent of Origin Specific Effects in Infantile Hemangiomas.
PLoS One. 2015; 10(10):e0113168 [PubMed] Free Access to Full Article Related Publications
Infantile hemangioma (IH) is the most common tumor of the pediatric age group, affecting up to 4% of newborns ranging from inconsequential blemishes, to highly aggressive tumors. Following well defined growth phases (proliferative, plateau involutional) IH usually regress into a fibro-fatty residuum. Despite the high prevalence of IH, little is known regarding the pathogenesis of disease. A reported six fold decrease in IGF2 expression (correlating with transformation of proliferative to involuted lesions) prompted us to study the IGF-2 axis further. We demonstrate that IGF2 expression in IH is strongly related to the expression of a cancer testes and suspected oncogene BORIS (paralog of CTCF), placing IH in the unique category of being the first known benign BORIS positive tumor. IGF2 expression was strongly and positively related to BORIS transcript expression. Furthermore, a stronger association was made when comparing BORIS levels against the expression of CTCF via either a percentage or difference between the two. A common C/T polymorphism at CTCF BS6 appeared to modify the correlation between CTCF/BORIS and IGF2 expression in a parent of origin specific manner. Moreover, these effects may have phenotypic consequences as tumor growth also correlates with the genotype at CTCF BS6. This may provide a framework for explaining the clinical variability seen in IH and suggests new insights regarding CTCF and BORIS related functionality in both normal and malignant states.

Frassanito MA, De Veirman K, Desantis V, et al.
Halting pro-survival autophagy by TGFβ inhibition in bone marrow fibroblasts overcomes bortezomib resistance in multiple myeloma patients.
Leukemia. 2016; 30(3):640-8 [PubMed] Related Publications
Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) β. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3)-II and inhibiting p62 and phospho-mammalian target of rapamycin. The small-interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFβ mediates bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.

Mukherjee A, Ma Y, Yuan F, et al.
Lysophosphatidic Acid Up-Regulates Hexokinase II and Glycolysis to Promote Proliferation of Ovarian Cancer Cells.
Neoplasia. 2015; 17(9):723-34 [PubMed] Free Access to Full Article Related Publications
Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the human HK2 gene promoter identified the sterol regulatory element-binding protein as the primary mediator of LPA-induced HK2 transcription. The effects of LPA on HK2 and glycolysis rely on LPA2, an LPA receptor subtype overexpressed in ovarian cancer and many other malignancies. We further examined the general role of growth factor-induced glycolysis in cell proliferation. Like LPA, epidermal growth factor (EGF) elicited robust glycolytic and proliferative responses in ovarian cancer cells. Insulin-like growth factor 1 (IGF-1) and insulin, however, potently stimulated cell proliferation but only modestly induced glycolysis. Consistent with their differential effects on glycolysis, LPA and EGF-dependent cell proliferation was highly sensitive to glycolytic inhibition while the growth-promoting effect of IGF-1 or insulin was more resistant. These results indicate that LPA- and EGF-induced cell proliferation selectively involves up-regulation of HK2 and glycolytic metabolism. The work is the first to implicate LPA signaling in promotion of glucose metabolism in cancer cells.

Li B, Xu WW, Guan XY, et al.
Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance.
Clin Cancer Res. 2016; 22(5):1243-55 [PubMed] Related Publications
PURPOSE: Chemoresistance is a major obstacle in cancer therapy. We found that fluorouracil (5-FU)-resistant esophageal squamous cell carcinoma cell lines, established through exposure to increasing concentrations of 5-FU, showed upregulation of Id1, IGF2, and E2F1. We hypothesized that these genes may play an important role in cancer chemoresistance.
EXPERIMENTAL DESIGN: In vitro and in vivo functional assays were performed to study the effects of Id1-E2F1-IGF2 signaling in chemoresistance. Quantitative real-time PCR, Western blotting, immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays were used to investigate the molecular mechanisms by which Id1 regulates E2F1 and by which E2F1 regulates IGF2. Clinical specimens, tumor tissue microarray, and Gene Expression Omnibus datasets were used to analyze the correlations between gene expressions and the relationships between expression profiles and patient survival outcomes.
RESULTS: Id1 conferred 5-FU chemoresistance through E2F1-dependent induction of thymidylate synthase expression in esophageal cancer cells and tumor xenografts. Mechanistically, Id1 protects E2F1 protein from degradation and increases its expression by binding competitively to Cdc20, whereas E2F1 mediates Id1-induced upregulation of IGF2 by binding directly to the IGF2 promoter and activating its transcription. The expression level of E2F1 was positively correlated with that of Id1 and IGF2 in human cancers. More importantly, concurrent high expression of Id1 and IGF2 was associated with unfavorable patient survival in multiple cancer types.
CONCLUSIONS: Our findings define an intricate E2F1-dependent mechanism by which Id1 increases thymidylate synthase and IGF2 expressions to promote cancer chemoresistance. The Id1-E2F1-IGF2 regulatory axis has important implications for cancer prognosis and treatment.

Li Y, Francia G, Zhang JY
p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer.
Oncotarget. 2015; 6(32):32656-68 [PubMed] Free Access to Full Article Related Publications
p62/IMP2 is an oncofetal protein that is overexpressed in several types of cancer, and is a member of the family of insulin-like growth factor 2 mRNA binding proteins. We previously reported that high levels of p62/IMP2 autoantibody are present in sera from cancer patients, compared to healthy individuals. Here, we report the overexpression of p62/IMP2 in tumor tissues of 72 out of 104 cases of human breast cancer, and high levels of p62/IMP2 autoantibody in patients' sera (in 63 out of 216 cases). To explore the role of p62/IMP2 in breast cancer progression, we generated p62/IMP2 transfected variants of two human breast cancer cell lines: MDA-MB-231 and LM2-4. Using in vitro assays we found that overexpression of p62/IMP2 can increase cell migration, and reduce cell adhesion to extracellular matrix (ECM) proteins. A Human Extracellular Matrix and Adhesion Molecules qPCR array was performed with our generated variants, and it identified a group of mRNAs whose expression was altered with p62/IMP2 overexpression, including connective tissue growth factor (CTGF) mRNA - which we show to be a p62/IMP2 binding partner. Overall, our results provide new insights into the molecular mechanism by which p62/IMP2 can contribute to breast cancer progression.

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