Dataset Information

Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.

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.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.

SUBMITTER: Kent OA

PROVIDER: S-EPMC4794362 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.

Kent Oliver A OA Mendell Joshua T JT Rottapel Robert R

Molecular cancer research : MCR 20160108 3

<h4>Unlabelled</h4>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 ...[more]

PMID: 26747707

Similar Datasets

Project description:BackgroundCrohn's disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity.MethodsWe performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes.ResultsSmall RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgeryCONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies.FundingThis work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS).

Dataset Information

Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.

Publications

Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets