MiR-1 Downregulation Cooperates with MACC1 in Promoting MET Overexpression in Human Colon Cancer.
Articolo
Data di Pubblicazione:
2012
Abstract:
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 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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
HEPATOCYTE GROWTH-FACTOR; MUSCLE-SPECIFIC MICRORNA; COLORECTAL-CANCER; INVASIVE GROWTH; STIMULATES INVASION; LIVER METASTASES; GENE; EXPRESSION; STAGE; PROTOONCOGENE
Elenco autori:
Migliore C;Martin V;Leoni VP;Restivo A;Atzori L;Petrelli A;Isella C;Zorcolo L;Sarotto I;Casula G;Comoglio PM;Columbano A;Giordano S
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