title: MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer.
abstract: OBJECTIVE
  MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples.
  
  
  METHODS
  The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition.
  
  
  RESULTS
  MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation.
  
  
  CONCLUSIONS
  This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells.
authors.affiliation: IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Migliore
authors.forename: Valentina
authors.initials: V
authors.lastname: Martin
authors.forename: Vera P
authors.initials: VP
authors.lastname: Leoni
authors.forename: Angelo
authors.initials: A
authors.lastname: Restivo
authors.forename: Luigi
authors.initials: L
authors.lastname: Atzori
authors.forename: Annalisa
authors.initials: A
authors.lastname: Petrelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Isella
authors.forename: Luigi
authors.initials: L
authors.lastname: Zorcolo
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Casula
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000368:Aged; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C544162:MACC1 protein, human; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; D015534:Trans-Activators; D014157:Transcription Factors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met