title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto Medical Discovery Tower, University of Toronto, Toronto, Ontario, Canada. kent.uhn@gmail.com.
authors.forename: Oliver A
authors.initials: OA
authors.lastname: Kent
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas. Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mendell
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto Medical Discovery Tower, University of Toronto, Toronto, Ontario, Canada. Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. Department of Medical Biophysics, St. Michael's Hospital, Toronto, Ontario, Canada. Department of Immunology, St. Michael's Hospital, Toronto, Ontario, Canada. Division of Rheumatology, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism; D020729:p120 GTPase Activating Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C494112:ELK1 protein, human; C117307:KRAS protein, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C557248:RASA1 protein, human; D050807:ets-Domain Protein Elk-1; D020729:p120 GTPase Activating Protein; D016283:Proto-Oncogene Proteins p21(ras)