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Cited by 30Mechanisms of cancer metastasisProtein Kinase Regulation and GTPase SignalingGenetic factors in colorectal cancer

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

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Dopeso, Higinio, Rodrigues, Paulo, Bilic, Josipa, Bazzocco, Sarah, Cartón-García, Fernando, Macaya, Irati, de Marcondes, Priscila Guimarães, Anguita, Estefanía +8 more·2018·British Journal of Cancer
DOI 10.1038/bjc.2017.420PMC PMC5765235
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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: We demonstrate a complex pattern of inactivation of the tumour suppressor gene RHOA in colon cancer cells through genetic, transcriptional and post-transcriptional mechanisms.

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  • In colon cancer cells, SMAD4 and SP1 activated RHOA expression, while c-Myc interfered with SP1 binding to the RHOA promoter, downregulating RHOA expression.

    “In colon cancer cells, the transcription factors SMAD family member 4 (SMAD4) and specific protein 1 (SP1) activated RHOA expression, while c-Myc was reported to interfere with the binding of SP1 to the RHOA promoter, leading to downregulation of RHOA expression [85].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [85]

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Authors
Dopeso, H., Rodrigues, P., Bilic, J., Bazzocco, S., Cartón-García, F., Macaya, I., de Marcondes, P. G., Anguita, E., Masanas, M., Jiménez-Flores, L. M., Martínez-Barriocanal, Á., Nieto, R., Segura, M. F., Schwartz Jr, S., Mariadason, J. M., & Arango, D.
Affiliations
  • Universitat Autònoma de Barcelona (ES)
  • La Trobe University (AU)
Corresponding author
Arango, Diego
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2017-12-05
Volume
118
Issue
1
Pages
106-116
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/bjc.2017.420
PMC
PMC5765235
OpenAlex
W2775577499
Cited by
30
References
0
Citations by year
2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 6 · 2018: 1
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-sa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
  • Figshare (submittedVersion, cc-by-nc-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-sa)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, other-oa)
  • La Trobe University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
RhoA, colorectal cancer, tumor suppressor inactivation, copy number loss, promoter hypermethylation, RHOA mutations, microRNA downregulation, Wnt signaling, c-Myc
MeSH terms
Female, Humans, Male, Colorectal Neoplasms, Cohort Studies, Signal Transduction, Transcriptional Activation, Down-Regulation, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Point Mutation, Gene Dosage, DNA Methylation, rhoA GTP-Binding Protein, MicroRNAs, Cell Line, Tumor, Smad4 Protein, DNA Copy Number Variations, Wnt Signaling Pathway

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