RREB1 repressed miR-143/145 modulates KRAS signaling through downregulation of multiple targets

• Published in: Oncogene Vol. 32; no. 20; pp. 2576 - 2585
• Main Authors: Kent, O A, Fox-Talbot, K, Halushka, M K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2013; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/208/200; 631/67/1504/1885; 631/80/86; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Apoptosis; Cancer cells; Cell Biology; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Gene Expression Regulation, Neoplastic; Gene mutations; Genetic aspects; HCT116 Cells; Human Genetics; Humans; Internal Medicine; K-Ras protein; MAP kinase; MAP Kinase Signaling System - genetics; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs - genetics; Oncology; original-article; Pancreatic cancer; Physiological aspects; Promoter Regions, Genetic; Proteins; ras Proteins - genetics; ras Proteins - metabolism; Signal transduction; Signal Transduction - genetics; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor cell lines; Tumors; miRNA; miR-143; colorectal; RREB1; miR-145
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.266

A lack of expression of miR-143 and miR-145 has been demonstrated to be a frequent feature of colorectal tumors. Activating KRAS mutations have been reported in 30–60% of colorectal cancers and an inverse correlation between Kras and miR-143/145 expression has been observed. Previously, we have demonstrated that oncogenic Kras leads to repression of the miR-143/145 cluster in pancreatic cancer and is dependent on the Ras responsive element (RRE) binding protein (RREB1), which negatively regulates miR-143/145 expression. In the present study, we have found that RREB1 is overexpressed in colorectal adenocarcinoma tumors and cell lines, and the expression of the miR-143/145 primary transcript is inversely related to RREB1 expression. In colorectal cancer cell lines, the miR-143/145 cluster is repressed by RREB1 downstream of constitutively active KRAS . RREB1 is activated by the MAPK pathway and negatively represses the miR-143/145 promoter through interaction with two RREs. In addition, overexpression of miR-143 or miR-145 in HCT116 cells abrogates signaling through the MAPK, PI3K and JNK pathways by downregulation of both KRAS and RREB1 in addition to downregulation of a cohort of genes in the MAPK signaling cascade. These results establish a complex network of regulation through which the miR-143/145 cluster is able to modulate KRAS signaling in colorectal cancer.