MiR-1 downregulation cooperates with MACC1 in promoting MET overexpression in human colon cancer

Cristina Migliore, Valentina Martin, Vera P. Leoni, Angelo Restivo, Luigi Atzori, Annalisa Petrelli, Claudio Isella, Luigi Zorcolo, Ivana Sarotto, Giuseppe Casula, Paolo M. Comoglio, Amedeo Columbano, Silvia Giordano

Research output: Contribution to journalArticlepeer-review


Purpose: 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. Experimental Design: The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by realtime 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.

Original languageEnglish
Pages (from-to)737-747
Number of pages11
JournalClinical Cancer Research
Issue number3
Publication statusPublished - Feb 1 2012

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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