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

機譯：RREB1抑制的miR-143 / 145通過下調多個靶標來調節(jié)KRAS信號傳導

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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鈥?0% 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.
機譯：已證明缺乏miR-143和miR-145的表達是結直腸腫瘤的常見特征。據報道，在30％至0％的結直腸癌中存在激活的KRAS突變，并且還觀察到Kras與miR-143 / 145表達呈負相關。以前，我們已經證明，致癌性Kras會導致胰腺癌中miR-143 / 145簇的阻遏，并且依賴于Ras反應元件（RRE）結合蛋白（RREB1），后者負調控miR-143 / 145的表達。在本研究中，我們發(fā)現(xiàn)RREB1在大腸腺癌腫瘤和細胞系中過表達，而miR-143 / 145初級轉錄本的表達與RREB1的表達負相關。在結腸直腸癌細胞系中，組成性活性KRAS下游的RREB1抑制了miR-143 / 145簇。 RREB1被MAPK途徑激活，并通過與兩個RRE的相互作用負抑制miR-143 / 145啟動子。另外，HTC116細胞中miR-143或miR-145的過表達除了下調MAPK信號傳導級聯(lián)中的一組基因外，還通過下調KRAS和RREB1來消除通過MAPK，PI3K和JNK途徑的信號傳導。這些結果建立了復雜的調節(jié)網絡，通過該網絡miR-143 / 145簇能夠調節(jié)大腸癌中的KRAS信號傳導。

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