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Title: Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer.
Austin Authors: Dopeso, Higinio;Rodrigues, Paulo;Bilic, Josipa;Bazzocco, Sarah;Cartón-García, Fernando;Macaya, Irati;de Marcondes, Priscila Guimarães;Anguita, Estefanía;Masanas, Marc;Jiménez-Flores, Lizbeth M;Martínez-Barriocanal, Águeda;Nieto, Rocío;Segura, Miguel F;Schwartz, Simo;Mariadason, John M ;Arango, Diego
Affiliation: Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain
Drug Delivery and Targeting Group, CIBBIM Nanomedicine, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Zaragoza, Spain
La Trobe University School of Cancer Medicine, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Issue Date: Jan-2018 2017-12-05
Publication information: British Journal of Cancer 2018; 118(1): 106-116
Abstract: Reduced RHOA signalling has been shown to increase the growth/metastatic potential of colorectal tumours. However, the mechanisms of inactivation of RHOA signalling in colon cancer have not been characterised. A panel of colorectal cancer cell lines and large cohorts of primary tumours were used to investigate the expression and activity of RHOA, as well as the presence of RHOA mutations/deletions and promoter methylation affecting RHOA. Changes in RHOA expression were assessed by western blotting and qPCR after modulation of microRNAs, SMAD4 and c-MYC. We show here that RHOA point mutations and promoter hypermethylation do not significantly contribute to the large variability of RHOA expression observed among colorectal tumours. However, RHOA copy number loss was observed in 16% of colorectal tumours and this was associated with reduced RHOA expression. Moreover, we show that miR-200a/b/429 downregulates RHOA in colorectal cancer cells. In addition, we found that TGF-β/SMAD4 upregulates the RHOA promoter. Conversely, RHOA expression is transcriptionally downregulated by canonical Wnt signalling through the Wnt target gene c-MYC that interferes with the binding of SP1 to the RHOA promoter in colon cancer cells. We demonstrate a complex pattern of inactivation of the tumour suppressor gene RHOA in colon cancer cells through genetic, transcriptional and post-transcriptional mechanisms.
DOI: 10.1038/bjc.2017.420
PubMed URL: 29206819
Type: Journal Article
Appears in Collections:Journal articles

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