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

Oliver A Kent1, Raghu R Chivukula, Michael Mullendore

  • 1Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Genes & Development
|December 17, 2010
PubMed

Insights

Ras activation represses miR-143/145 microRNAs, crucial for preventing tumor growth. Restoring these microRNAs halts tumorigenesis in KRAS-mutant cancers, revealing a new therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • Activating mutations in RAS oncogenes drive aberrant signaling pathways.
  • The specific role of microRNAs (miRNAs) in the Ras oncogenic program is not well understood.

Purpose of the Study:

  • To investigate the role of microRNAs in Ras-driven oncogenesis.
  • To characterize the regulatory mechanisms of miRNA expression in response to Ras activation.

Main Methods:

  • Analysis of miR-143/145 cluster expression in human, murine, and zebrafish cells with Ras activation.
  • Assessment of miR-143/145 expression in KRAS-mutant pancreatic cancers.
  • Functional studies involving restoration of miR-143/145 expression.
  • Identification of transcription factors regulating miR-143/145 promoter activity.
  • Validation of KRAS and RREB1 as targets of miR-143/miR-145.

Main Results:

  • Ras activation leads to the repression of the miR-143/145 cluster across species.
  • Loss of miR-143/145 expression is a frequent event in KRAS-mutant pancreatic cancers.
  • Restoration of miR-143/145 expression abrogates tumorigenesis.
  • Ras-responsive element-binding protein (RREB1) represses the miR-143/145 promoter.
  • A feed-forward loop exists where miR-143/145 targets KRAS and RREB1, further potentiating Ras signaling.

Conclusions:

  • miR-143/145 plays a critical tumor-suppressive role in Ras-driven cancers.
  • The repression of miR-143/145 by RREB1 is a key mechanism in Ras oncogenesis.
  • Targeting the miR-143/145 cluster represents a potential therapeutic strategy for KRAS-mutant cancers.

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