MiR-1 Downregulation Cooperates with MACC1 in Promoting MET Overexpression in Human Colon Cancer

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 à , 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 à , 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.

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

“…The MET oncogene encodes a tyrosine kinase receptor that binds hepatocyte growth factor (HGF) and drives the malignant progression of several tumour types (Reid et al 2012). Experiments in CRC cells have confirmed the tumour-suppressive ability of miR-1, as enforced expression impairs cell scattering, migration, wound-healing and proliferation in response to HGF (Migliore et al 2012). Thus, activation of MET, due to a decrease in miR-1 is likely to be associated to cancer progression and to the acquisition of an invasive phenotype and metastatic dissemination (Migliore et al 2012, Reid et al 2012.…”

“…Experiments in CRC cells have confirmed the tumour-suppressive ability of miR-1, as enforced expression impairs cell scattering, migration, wound-healing and proliferation in response to HGF (Migliore et al 2012). Thus, activation of MET, due to a decrease in miR-1 is likely to be associated to cancer progression and to the acquisition of an invasive phenotype and metastatic dissemination (Migliore et al 2012, Reid et al 2012. Interestingly, our bioinformatic analyses revealed HGF to also be targeted by miR-1 and we found HGF levels significantly increased in LN and liver metastases compared with primary SBNETs (Supplementary Fig.…”

“…Deep sequencing has also found miR-1 levels to be reduced in colorectal cancers (CRCs) and a case of colorectal NET (Hamfjord et al 2012). miR-1 downregulation in human CRCs has been correlated with over-expression of the MET gene, especially in advanced stages of progression (Migliore et al 2012). The MET oncogene encodes a tyrosine kinase receptor that binds hepatocyte growth factor (HGF) and drives the malignant progression of several tumour types (Reid et al 2012).…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Clinical data show that MET overexpression, in the absence of gene amplifi cation, is the most frequent cause of constitutive MET activation in human tumors and often correlates with poor prognosis. Overexpression can be caused by several factors, such as hypoxia ( 19 ), activation of upstream oncogenes ( 20,21 ), inactivation of tumor suppressor genes ( 22 ), or loss of miRNAs ( 23,24 ). MET gene amplifi cation, which drives increased expression and constitutive receptor activation, has been described in selected histotypes such as gastroesophageal, colorectal, endometrial, and lung carcinomas, glioblastomas, and medulloblastomas (reviewed in ref.…”

Aberrant Expression of Pim-3 Promotes Proliferation and Migration of Ovarian Cancer Cells

“…Metastasis-associated in colon cancer-1 (MACC1) has been reported to promote tumor proliferation and invasion mediated via hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-Met) signaling in colorectal cancer (Stein et al, 2009;Galimi et al, 2011;Migliore et al, 2012). Recently, a clinical study showed that aberrant overexpression of MACC1 may indicate poor prognosis of ovarian cancer patients for early recurrence and distance metastasis (Zhang et al, 2014).…”