IGF2 MRNA Binding Protein-2 is a Tumor Promoter That Drives Cancer Proliferation Through Its Client MRNAs IGF2 and HMGA1

Overview

Journal Elife

Specialty Biology

Date 2017 Jul 29

PMID 28753127

Citations 58

Authors

Ning Dai

Fei Ji

Jason Wright

Liliana Minichiello

Ruslan Sadreyev

Joseph Avruch

Affiliations

Soon will be listed here.

Abstract

The gene encoding the Insulin-like Growth Factor 2 mRNA binding protein 2/IMP2 is amplified and overexpressed in many human cancers, accompanied by a poorer prognosis. Mice lacking IMP2 exhibit a longer lifespan and a reduced tumor burden at old age. Herein we show in a diverse array of human cancer cells that IMP2 overexpression stimulates and IMP2 elimination diminishes proliferation by 50-80%. In addition to its known ability to promote the abundance of Insulin-like Growth Factor 2/IGF2, we find that IMP2 strongly promotes IGF action, by binding and stabilizing the mRNA encoding the DNA binding protein , a known oncogene. HMGA1 suppresses the abundance of IGF binding protein 2/IGFBP2 and Grb14, inhibitors of IGF action. IMP2 stabilization of mRNA plus IMP2 stimulated IGF2 production synergistically drive cancer cell proliferation and account for IMP2's tumor promoting action. IMP2's ability to promote proliferation and IGF action requires IMP2 phosphorylation by mTOR.

Citing Articles

Insulin-Like Growth Factor 2 mRNA-Binding Protein 2 (IGF2BP2) Promotes Castration-Resistant Prostate Cancer Progression by Regulating AR-V7 mRNA Stability.

Saini T, Srivastava D, Raut R, Mishra P, Misra A Cancer Rep (Hoboken). 2025; 8(2):e70096.

PMID: 39948708 PMC: 11825379. DOI: 10.1002/cnr2.70096.

Ouabain-mediated downregulation of ALKBH5 and IGF2BP2 inhibits the malignant progression of DLBCL.

Hong Y, Ma H, Yang H, Zhu Y, Wei Y, Xu Z Front Pharmacol. 2024; 15:1447830.

PMID: 39281280 PMC: 11392878. DOI: 10.3389/fphar.2024.1447830.

The RNA binding protein IGF2BP2/IMP2 alters the cargo of cancer cell-derived extracellular vesicles supporting tumor-associated macrophages.

Mashayekhi V, Schomisch A, Rasheed S, Aparicio-Puerta E, Risch T, Yildiz D Cell Commun Signal. 2024; 22(1):344.

PMID: 38937789 PMC: 11212187. DOI: 10.1186/s12964-024-01701-y.

IGF2BP2 regulates the proliferation and migration of endometrial stromal cells through the PI3K/AKT/mTOR signaling pathway in Hu sheep.

Deng K, Li X, Liu Z, Su Y, Sun X, Wei W J Anim Sci. 2024; 102.

PMID: 38727196 PMC: 11151927. DOI: 10.1093/jas/skae129.

lncRNA SNHG1 promotes the progression of hepatocellular carcinoma by regulating the miR-7-5p/IGF2BP2 axis.

Zhu X, Yu H, Li H, Zhang W, Sun L, Dou T Heliyon. 2024; 10(6):e27631.

PMID: 38545199 PMC: 10966585. DOI: 10.1016/j.heliyon.2024.e27631.

References

Aiello A, Pandini G, Sarfstein R, Werner H, Manfioletti G, Vigneri R . HMGA1 protein is a positive regulator of the insulin-like growth factor-I receptor gene. Eur J Cancer. 2010; 46(10):1919-26. DOI: 10.1016/j.ejca.2010.02.050. View

Saxena R, Voight B, Lyssenko V, Burtt N, de Bakker P, Chen H . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007; 316(5829):1331-6. DOI: 10.1126/science.1142358. View

Degrauwe N, Schlumpf T, Janiszewska M, Martin P, Cauderay A, Provero P . The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing. Cell Rep. 2016; 15(8):1634-47. DOI: 10.1016/j.celrep.2016.04.086. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Davidson B, Rosenfeld Y, Holth A, Hellesylt E, Trope C, Reich R . VICKZ2 protein expression in ovarian serous carcinoma effusions is associated with poor survival. Hum Pathol. 2014; 45(7):1520-8. DOI: 10.1016/j.humpath.2014.03.005. View

Li Y, Francia G, Zhang J . p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer. Oncotarget. 2015; 6(32):32656-68. PMC: 4741720. DOI: 10.18632/oncotarget.5328. View

Yisraeli J . VICKZ proteins: a multi-talented family of regulatory RNA-binding proteins. Biol Cell. 2004; 97(1):87-96. DOI: 10.1042/BC20040151. View

Chiefari E, Tanyolac S, Paonessa F, Pullinger C, Capula C, Iiritano S . Functional variants of the HMGA1 gene and type 2 diabetes mellitus. JAMA. 2011; 305(9):903-12. DOI: 10.1001/jama.2011.207. View

Froguel P, Marquez M, Cauchi S . Response to comment on: Marquez et al. Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. Diabetes 2012;61:524-530. Diabetes. 2012; 61(9):e15. PMC: 3425425. DOI: 10.2337/db12-0800. View

10.

Degrauwe N, Suva M, Janiszewska M, Riggi N, Stamenkovic I . IMPs: an RNA-binding protein family that provides a link between stem cell maintenance in normal development and cancer. Genes Dev. 2016; 30(22):2459-2474. PMC: 5159662. DOI: 10.1101/gad.287540.116. View

11.

Nielsen J, Christiansen J, Johnsen A, Wewer U, Nielsen F . A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol. 1999; 19(2):1262-70. PMC: 116055. DOI: 10.1128/MCB.19.2.1262. View

12.

Fujii Y, Kishi Y, Gotoh Y . IMP2 regulates differentiation potentials of mouse neocortical neural precursor cells. Genes Cells. 2013; 18(2):79-89. DOI: 10.1111/gtc.12024. View

13.

Kessler S, Pokorny J, Zimmer V, Laggai S, Lammert F, Bohle R . IGF2 mRNA binding protein p62/IMP2-2 in hepatocellular carcinoma: antiapoptotic action is independent of IGF2/PI3K signaling. Am J Physiol Gastrointest Liver Physiol. 2012; 304(4):G328-36. DOI: 10.1152/ajpgi.00005.2012. View

14.

Janiszewska M, Suva M, Riggi N, Houtkooper R, Auwerx J, Clement-Schatlo V . Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev. 2012; 26(17):1926-44. PMC: 3435496. DOI: 10.1101/gad.188292.112. View

15.

Pollak M . The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012; 12(3):159-69. DOI: 10.1038/nrc3215. View

16.

Balogh K, Asa S, Zheng L, Cassol C, Cheng S, Ezzat S . The insulin resistance Grb14 adaptor protein promotes thyroid cancer ret signaling and progression. Oncogene. 2011; 31(36):4012-21. PMC: 3954818. DOI: 10.1038/onc.2011.569. View

17.

Hoeflich A, Wu M, Mohan S, Foll J, Wanke R, Froehlich T . Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology. 1999; 140(12):5488-96. DOI: 10.1210/endo.140.12.7169. View

18.

Diehl D, Hessel E, Oesterle D, Renner-Muller I, Elmlinger M, Langhammer M . IGFBP-2 overexpression reduces the appearance of dysplastic aberrant crypt foci and inhibits growth of adenomas in chemically induced colorectal carcinogenesis. Int J Cancer. 2009; 124(9):2220-5. DOI: 10.1002/ijc.24193. View

19.

Morrione A, Valentinis B, Xu S, Yumet G, Louvi A, Efstratiadis A . Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci U S A. 1997; 94(8):3777-82. PMC: 20517. DOI: 10.1073/pnas.94.8.3777. View

20.

Shen X, Xi G, Wai C, Clemmons D . The coordinate cellular response to insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-2 (IGFBP-2) is regulated through vimentin binding to receptor tyrosine phosphatase β (RPTPβ). J Biol Chem. 2015; 290(18):11578-90. PMC: 4416861. DOI: 10.1074/jbc.M114.620237. View