Oncotarget

Research Papers:

Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer

Conor A. Bradley, Philip D. Dunne, Victoria Bingham, Stephen McQuaid, Hajrah Khawaja, Stephanie Craig, Jackie James, Wendy L. Moore, Darragh G. McArt, Mark Lawler, Sonali Dasgupta, Patrick G. Johnston and Sandra Van Schaeybroeck _

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Oncotarget. 2016; 7:78932-78945. https://doi.org/10.18632/oncotarget.12933

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Abstract

Conor A. Bradley1,*, Philip D. Dunne1,*, Victoria Bingham1, Stephen McQuaid1,2, Hajrah Khawaja1, Stephanie Craig1, Jackie James1,2, Wendy L. Moore1, Darragh G. McArt1, Mark Lawler1, Sonali Dasgupta1, Patrick G. Johnston1, Sandra Van Schaeybroeck1

1Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, UK

2Tissue Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK

*Joint first authors

Correspondence to:

Sandra Van Schaeybroeck, email: s.vanschaeybroeck@qub.ac.uk

Keywords: c-MET, colorectal cancer (CRC), tumor budding, invasion, metastasis

Received: July 06, 2016     Accepted: October 19, 2016     Published: October 26, 2016

ABSTRACT

c-MET and its ligand HGF are frequently overexpressed in colorectal cancer (CRC) and increased c-MET levels are found in CRC liver metastases. This study investigated the role of the HGF/c-MET axis in regulating migration/invasion in CRC, using pre-clinical models and clinical samples. Pre-clinically, we found marked upregulation of c-MET at both protein and mRNA levels in several invasive CRC cells. Down-regulation of c-MET using RNAi suppressed migration/invasion of parental and invasive CRC cells. Stimulation of CRC cells with rh-HGF or co-culture with HGF-expressing colonic myofibroblasts, resulted in significant increases in their migratory/invasive capacity. Importantly, HGF-induced c-MET activation promoted rapid downregulation of c-MET protein levels, while the MET transcript remained unaltered. Using RNA in situ hybridization (RNA ISH), we further showed that MET mRNA, but not protein levels, were significantly upregulated in tumor budding foci at the invasive front of a cohort of stage III CRC tumors (p < 0.001). Taken together, we show for the first time that transcriptional upregulation of MET is a key molecular event associated with CRC invasion and tumor budding. This data also indicates that RNA ISH, but not immunohistochemistry, provides a robust methodology to assess MET levels as a potential driving force of CRC tumor invasion and metastasis.


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