MET, the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF), is frequently over-expressed in colon cancers with high metastatic tendency. We aimed at evaluating 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.

The expression of MET, miR-1, miR-199a* and MACC1 was evaluated by Real Time PCR in 52 matched-pairs of colorectal cancers and non tumoral 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.

MiR-1 was down-regulated in 84.6% of the tumors and its decrease significantly correlated with MET over-expression, particularly in metastatic tumors. We found that concurrent MACC1 up-regulation and miR-1 down-regulation is required to elicit a significant 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 feed-back loop between miR-1 and MET, resulting in their mutual regulation.

The present study identifies an oncosuppressive role of miR-1 in colorectal cancer where it acts by controlling MET expression through a feed-back loop. Concomitant down-regulation of miR-1 and increase of MACC1 can thus contribute to MET over-expression and to the metastatic behavior of colon cancer cells.

PMID: 22179665 [PubMed - as supplied by publisher] Source: National Library of Medicine.