Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway

被引：253

作者：

Kent, Oliver A. ^{[1
,2
]}

Chivukula, Raghu R. ^{[1
,2
]}

Mullendore, Michael ^{[3
]}

Wentzel, Erik A. ^{[1
,2
]}

Feldmann, Georg ^{[3
]}

Lee, Kwang H. ^{[3
]}

Liu, Shu ^{[4
]}

Leach, Steven D. ^{[2
,4
]}

Maitra, Anirban ^{[2
,3
,5
,6
]}

Mendell, Joshua T. ^{[1
,2
,7
,8
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Res Ctr, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

来源：

GENES & DEVELOPMENT | 2010年 / 24卷 / 24期

关键词：

Pancreatic cancer; Ras; miR-143/145; microRNA; primary transcript; ZINC-FINGER PROTEIN; PANCREATIC DUCTAL ADENOCARCINOMA; MICRORNA EXPRESSION; C-MYC; CANCER; LET-7; TUMORIGENESIS; MOUSE; CELLS; DIFFERENTIATION;

D O I：

10.1101/gad.1950610

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.

引用

页码：2754 / 2759

页数：6

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