Abstract 3687: p53 downregulates CRKL oncogene through miR-200

Abstract

Abstract Tumor suppressive miRNAs targeting oncogenes are frequently downregulated in cancers, which leads to the activation of the oncogene pathways. Thus, tumor suppressive miRNAs as well as their target oncogenes are proposed to be useful for cancer treatment. The downregulation of the miR-200 family has been involved in the progression and metastasis in cancers. The miR-200 family consists of two gene clusters: miR-200b/200a/429 and miR-200c/141 are located on human chromosome 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of miR-200s and confirmed miR-200s as transcriptional targets of p53. in silico analysis of miRNA target predicted an oncogene CRKL as a potential target for miR-200b/200c/429. Moreover, miR-200b/200c/429 inhibit the expression of CRKL mRNA and protein by directly targeting its 3’-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells with introduction of wild-type p53. Moreover, downregulation of CRKL by siRNA in cancer cells inhibits cell growth. Oncomine database shows that CRKL levels are overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP53. Our results demonstrate that p53-target miRNAs, miR-200b/200c/429 are negative regulators of the CRKL oncogene. Citation Format: Takashi Tokino, Miyuki Tamura, Masashi Idogawa, Yasushi Sasaki. p53 downregulates CRKL oncogene through miR-200. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3687.