title: Transcriptional upregulation of c-MET is associated with invasion and tumor budding in colorectal cancer.
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.
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Conor A
authors: CA
authors: Bradley
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Philip D
authors: PD
authors: Dunne
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Victoria
authors: V
authors: Bingham
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK.
authors: Stephen
authors: S
authors: McQuaid
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Hajrah
authors: H
authors: Khawaja
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Stephanie
authors: S
authors: Craig
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.|Tissue Pathology, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, UK.
authors: Jackie
authors: J
authors: James
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Wendy L
authors: WL
authors: Moore
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Darragh G
authors: DG
authors: McArt
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Mark
authors: M
authors: Lawler
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Sonali
authors: S
authors: Dasgupta
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Patrick G
authors: PG
authors: Johnston
authors: Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
authors: Sandra
authors: S
authors: Van Schaeybroeck
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D019899:Paracrine Communication; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: c-MET; colorectal cancer (CRC); invasion; metastasis; tumor budding