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

O A Kent1, K Fox-Talbot, M K Halushka

  • 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. kent@lunenfeld.ca

Oncogene
|July 4, 2012
PubMed

Insights

MicroRNAs miR-143 and miR-145 are underexpressed in colorectal cancer. The Ras responsive element binding protein 1 (RREB1) represses these microRNAs, offering a new therapeutic target for KRAS-driven colorectal tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • miR-143 and miR-145 are frequently downregulated in colorectal tumors.
  • Activating KRAS mutations are common in colorectal cancer, with an observed inverse correlation to miR-143/145 expression.
  • Oncogenic KRAS was previously shown to repress miR-143/145 in pancreatic cancer via RREB1.

Purpose of the Study:

  • To investigate the role of RREB1 in the repression of miR-143/145 in colorectal cancer.
  • To elucidate the regulatory network involving KRAS, RREB1, and miR-143/145 in colorectal adenocarcinoma.
  • To explore the therapeutic potential of miR-143/145 in modulating signaling pathways in colorectal cancer.

Main Methods:

  • Assessed RREB1 and miR-143/145 expression in colorectal tumors and cell lines.
  • Investigated the regulatory relationship between RREB1, KRAS, and miR-143/145 using colorectal cancer cell lines.
  • Utilized reporter assays to confirm RREB1's interaction with the miR-143/145 promoter.
  • Overexpressed miR-143 or miR-145 in HCT116 cells to analyze downstream signaling pathway modulation.

Main Results:

  • RREB1 is overexpressed in colorectal adenocarcinoma, inversely correlating with miR-143/145 primary transcript expression.
  • RREB1, activated by the MAPK pathway, represses the miR-143/145 promoter in colorectal cancer cell lines downstream of active KRAS.
  • Overexpression of miR-143/145 abrogated MAPK, PI3K, and JNK signaling by downregulating KRAS, RREB1, and other MAPK pathway genes.

Conclusions:

  • RREB1 acts as a key repressor of the miR-143/145 cluster in KRAS-driven colorectal cancer.
  • A complex regulatory network exists where miR-143/145 modulates KRAS signaling.
  • These findings highlight the miR-143/145 cluster as a potential therapeutic target in colorectal cancer treatment.

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