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

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 0 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 ¼ 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. Cancer Res; 71(6); 2172-82. Ó2011 AACR.

DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

“…Also with roles in nervous system development, CYFIP2 is a p53-inducible gene that leads to caspase activation and apoptosis (35,36). Similarly, CYFIP2 has been shown to negatively modulate survival of colon cancer cells (37). Epigenetic inactivation of SPOCK2 gene is involved in malignant transformation of ovarian endometriosis (38,39).…”

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

“…We (23,(28)(29)(30)(31). Using quantitative PCR (qPCR), we validated these genes as being hypoxia inducible in a p53-dependent manner in the HCT116 isogenic cell lines (p53 +/+ and p53 -/-) ( Figure 2A).…”

Inhibition of GLI1 Expression by Targeting the CRD-BP–GLI1 mRNA Interaction Using a Specific Oligonucleotide

“…In addition to GLI1, CRD-BP also has high affinity for several mRNAs whose protein products have been implicated in cancer. These include mRNAs for c-myc (Prokipcak et al, 1994), CD44 (Vikesaa et al, 2006;King et al, 2014), K-Ras (Mongroo et al, 2011), bTrCP1 (Noubissi et al, 2006), microphthalmiaassociated transcription factor (Goswami et al, 2015), mitogenactivated protein kinase 4 (Stohr et al, 2012), b-catenin (Gu et al, 2008), and multi-drug resistance 1 (Sparanese and Lee, 2007). The role of CRD-BP in cancer is further supported by the following findings: 1) Overexpression of CRD-BP in various human cancers, which include colon and breast cancers (Bell et al, 2013), and 2) mice genetically engineered to overproduce CRD-BP in their mammary glands developed mammary adenocarcinoma (Tessier et al, 2004).…”

“…The role of CRD-BP in cancer is further supported by the following findings: 1) Overexpression of CRD-BP in various human cancers, which include colon and breast cancers (Bell et al, 2013), and 2) mice genetically engineered to overproduce CRD-BP in their mammary glands developed mammary adenocarcinoma (Tessier et al, 2004). Studies on various mRNA targets of CRD-BP have now confirmed that the oncogenic function of CRD-BP results from its physical association with the corresponding mRNAs, leading to their stabilization, increased expression, and ultimately the presentation of the cancerous phenotypes (Noubissi et al, 2006(Noubissi et al, , 2009Vikesaa et al, 2006;Gu et al, 2008;Mongroo et al, 2011). Hence, the ability to disrupt specific CRD-BP-RNA interaction could represent a novel therapeutic approach for the treatment of cancer.…”