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

Oliver A. Kent; Raghu R. Chivukula; Michael Mullendore; Erik A. Wentzel; Georg Feldmann; Kwang H. Lee; Shu Liu; Steven D. Leach; Anirban Maitra; Joshua T. Mendell

doi:10.1101/gad.1950610

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

Oliver A. Kent, Raghu R. Chivukula, Michael Mullendore, Erik A. Wentzel, Georg Feldmann, Kwang H. Lee, Shu Liu, Steven D. Leach, Anirban Maitra, Joshua T. Mendell

Research output: Contribution to journal › Article › peer-review

277 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2754-2759
Number of pages	6
Journal	Genes and Development
Volume	24
Issue number	24
DOIs	https://doi.org/10.1101/gad.1950610
State	Published - Dec 15 2010

Keywords

Pancreatic cancer
Primary transcript
Ras
miR-143/145
microRNA

ASJC Scopus subject areas

General Medicine

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10.1101/gad.1950610

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

abstract = "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.",

keywords = "Pancreatic cancer, Primary transcript, Ras, miR-143/145, microRNA",

author = "Kent, {Oliver A.} and Chivukula, {Raghu R.} and Michael Mullendore and Wentzel, {Erik A.} and Georg Feldmann and Lee, {Kwang H.} and Shu Liu and Leach, {Steven D.} and Anirban Maitra and Mendell, {Joshua T.}",

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AU - Kent, Oliver A.

AU - Chivukula, Raghu R.

AU - Mullendore, Michael

AU - Wentzel, Erik A.

AU - Feldmann, Georg

AU - Lee, Kwang H.

AU - Liu, Shu

AU - Leach, Steven D.

AU - Maitra, Anirban

AU - Mendell, Joshua T.

PY - 2010/12/15

Y1 - 2010/12/15

N2 - 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.

AB - 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.

KW - Pancreatic cancer

KW - Primary transcript

KW - Ras

KW - miR-143/145

KW - microRNA

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

Abstract

Keywords

ASJC Scopus subject areas

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