Identification and analysis of functional RNAs regulated by p53 family members in gastrointestinal tumorigenesis

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The miR-200 family includes two clusters: miR-200b-200a-429 located on chromosome 1; and miR-200c-141 located on chromosome 12. We identified response elements located around both clusters that are responsive to p53 family. Here, in silico miRNA target prediction identified the v-crk sarcoma virus CT10 oncogene homolog-like (CRKL) as a potential miR-200b/200c/429 target. MiR-200b/200c/429 inhibits the expression of CRKL by directly targeting its 3'-UTR region. Importantly, CRKL expression was decreased in cancer cells with introduction of wild-type p53 and TAp63. Oncomine database shows that CRKL levels are significantly overexpressed in multiple cancer types compared with the corresponding normal tissues. We also found that CRKL was overexpressed in primary breast cancer tissues harboring mutant p53 genes. Our results indicate that a p53-inducible miRNA, 200b/200c/429 is a negative regulator of the CRKL oncoprotein and suggest a new p53-miR-200-CRKL pathway in carcinogenesis.