IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2

Perry S. Mongroo, Felicite K. Noubissi, Miriam Cuatrecasas, Jiri Kalabis, Catrina E. King, Cameron N. Johnstone, Mark J. Bowser, Antoni Castells, Vladimir S. Spiegelman, Anil K. Rustgi

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

Insulin-like growth factor 2 mRNA-binding protein-1 (IMP-1) is an oncofetal protein that binds directly to and stabilizes oncogenic c-Myc and regulates, in turn, its posttranscriptional expression and translation. In contrast to normal adult tissue, IMP-1 is reexpressed and/or overexpressed in human cancers. We show that knockdown of c-Myc in human colon cancer cell lines increases the expression of mature let-7 miRNA family members and downregulates several of its mRNA targets: IMP-1, Cdc34, and K-Ras. We further show that loss of IMP-1 inhibits Cdc34, Lin-28B, and K-Ras, suppresses SW-480 cell proliferation and anchorage-independent growth, and promotes caspase- and lamin-mediated cell death. We also found that IMP-1 binds to the coding region and 3′UTR of K-Ras mRNA. RNA microarray profiling and validation by reverse transcription PCR reveals that the p53-inducible proapoptotic protein CYFIP2 is upregulated in IMP-1 knockdown SW480 cells, a novel finding. We also show that overexpression of IMP-1 increases c-Myc and K-Ras expression and LIM2405 cell proliferation. Furthermore, we show that loss of IMP-1 induces Caspase-3- and PARP-mediated apoptosis, and inhibits K-Ras expression in SW480 cells, which is rescued by CYFIP2 knockdown. Importantly, analysis of 228 patients with colon cancers reveals that IMP-1 is significantly upregulated in differentiated colon tumors (P ≤ 0.0001) and correlates with K-Ras expression (r = 0.35, P ≤ 0.0001) relative to adjacent normal mucosa. These findings indicate that IMP-1, interrelated with c-Myc, acts upstream of K-Ras to promote survival through a novel mechanism that may be important in colon cancer pathogenesis.

Original languageEnglish (US)
Pages (from-to)2172-2182
Number of pages11
JournalCancer Research
Volume71
Issue number6
DOIs
StatePublished - Mar 15 2011

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Mongroo, P. S., Noubissi, F. K., Cuatrecasas, M., Kalabis, J., King, C. E., Johnstone, C. N., Bowser, M. J., Castells, A., Spiegelman, V. S., & Rustgi, A. K. (2011). IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. Cancer Research, 71(6), 2172-2182. https://doi.org/10.1158/0008-5472.CAN-10-3295