IMP-1 Displays Cross-Talk with K-Ras and Modulates Colon Cancer Cell Survival through the Novel Proapoptotic Protein CYFIP2

Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Research (Impact Factor: 9.33). 03/2011; 71(6):2172-82. DOI: 10.1158/0008-5472.CAN-10-3295
Source: PubMed


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.

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Available from: Cameron N Johnstone, Mar 24, 2014
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    • "Furthermore, silencing of CYFIP1 interferes with normal epithelial morphogenesis and cooperates with Ras to produce invasive carcinomas in vivo (Silva et al., 2009). A proapoptotic role was also proposed for CYFIP2 by interacting with the Insulin-like growth factor 2 mRNA-binding protein-1 (IMP-1; Mongroo et al., 2011). "
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    • "CRD-BP/IMP1 in human cancers has been extensively studied. While CRD-BP is virtually absent or undetectable in normal adult tissues, it is over-expressed in many types of human cancers including cancers of the breast [9], colon [10]–[12], brain [13], lung [13], [14], testicular [15], skin [16], ovarian [17], and chorion [18]. Furthermore, transgenic mice carrying targeted expression of CRD-BP develop mammary tumours [19], further implicating this RNA-binding protein in the development of cancer. "
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    • "Unlike immunostaining of the protein isolated from the blood (Figure 3d), staining for CYFIP2 in the brain revealed two bands of closely related size, one at the predicted size (~145 kD) and one slightly larger (Figure 4h). Several reports have identified CYFIP2 with a single band (Jackson et al., 2007, Mayne et al., 2004, Mongroo et al., 2011) consistent with what we observe in lymphocytes. However, multiple bands for CYFIP2 have also been reported (Derivery et al., 2009). "
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