Transcriptional regulation of miR-31 by oncogenic KRAS mediates metastatic phenotypes by repressing RASA1

Oliver A. Kent, Joshua T. Mendell, Robert Rottapel

Research output: Contribution to journalArticle

Abstract

Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. miRNAs are small noncoding RNAs that regulate gene expression by binding sequences within the 3'UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to the expression of oncogenic KRAS and activity of the MAPK pathway. miR-31 is highly expressed in patient-derived xenografts and a panel of pancreatic and colorectal cancer cells harboring activating KRAS mutations. The miR-31 host gene is a large noncoding RNA that correlates with miR-31 expression and enabled identification of the putative miR-31 promoter. Using luciferase reporters, a minimal RAS-responsive miR-31 promoter was found to drive robust luciferase activity dependent on expression of mutant KRAS and the transcription factor ELK1. Furthermore, ELK1 interacts directly with the endogenous miR-31 promoter in a MAPK-dependent manner. Expression of enforced miR-31 significantly enhanced invasion and migration of multiple pancreatic cancer cells resulting from the activation of RhoA through regulation of the miR-31 target gene RASA1. Importantly, acute knockdown of RASA1 phenocopied enforced miR-31 expression on the migratory behavior of pancreatic cancer cells through increased RhoA activation. Implications: Oncogenic KRAS can activate Rho through the miR-31-mediated regulation of RASA1 indicating miR-31 acts as a KRAS effector to modulate invasion and migration in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)267-277
Number of pages11
JournalMolecular Cancer Research
Volume14
Issue number3
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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Pancreatic Neoplasms
Phenotype
MicroRNAs
Luciferases
Small Untranslated RNA
Untranslated RNA
Mutation
3' Untranslated Regions
Heterografts
Genes
Colorectal Neoplasms
Carcinogenesis
Transcription Factors
Gene Expression
Messenger RNA
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Transcriptional regulation of miR-31 by oncogenic KRAS mediates metastatic phenotypes by repressing RASA1. / Kent, Oliver A.; Mendell, Joshua T.; Rottapel, Robert.

In: Molecular Cancer Research, Vol. 14, No. 3, 01.03.2016, p. 267-277.

Research output: Contribution to journalArticle

Kent, Oliver A. ; Mendell, Joshua T. ; Rottapel, Robert. / Transcriptional regulation of miR-31 by oncogenic KRAS mediates metastatic phenotypes by repressing RASA1. In: Molecular Cancer Research. 2016 ; Vol. 14, No. 3. pp. 267-277.
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