BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study

Molecular Cancer

Research

Senji Shirasawa¹  Takehiko Sasazuki²  Ladislav Andera³  Michal Koc³  Eftychia Oikonomou⁴  Alexander Pintzas⁴  Eleni Makrodouli⁴ 

[1] Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan;Department of Pathology, International Medical Center of Japan, Tokyo, Japan;Laboratory of Cell Signaling and Apoptosis, Institute of Molecular Genetics, v.v.i., Czech Academy of Sciences, 1083 Videnska, CZ-14220, Prague 4, Czech Republic;Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Vas. Constantinou Ave. 48, 11635, Athens, Greece;

关键词: Focal Adhesion Kinase;    HT29 Cell;    PI3K Pathway;    RhoA Activation;    Mutant BRAFV600E;   

DOI  :  10.1186/1476-4598-10-118

 received in 2011-04-10, accepted in 2011-09-23,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundColorectal cancer is a common disease that involves genetic alterations, such as inactivation of tumour suppressor genes and activation of oncogenes. Among them are RAS and BRAF mutations, which rarely coexist in the same tumour. Individual members of the Rho (Ras homology) GTPases contribute with distinct roles in tumour cell morphology, invasion and metastasis. The aim of this study is to dissect cell migration and invasion pathways that are utilised by BRAFV600Eas compared to KRASG12V and HRASG12V oncoproteins. In particular, the role of RhoA (Ras homolog gene family, member A), Rac1 (Ras-related C3 botulinum toxin substrate 1) and Cdc42 (cell division cycle 42) in cancer progression induced by each of the three oncogenes is described.MethodsColon adenocarcinoma cells with endogenous as well as ectopically expressed or silenced oncogenic mutations of BRAFV600E, KRASG12V and HRASG12V were employed. Signalling pathways and Rho GTPases were inhibited with specific kinase inhibitors and siRNAs. Cell motility and invasion properties were correlated with cytoskeletal properties and Rho GTPase activities.ResultsEvidence presented here indicate that BRAFV600E significantly induces cell migration and invasion properties in vitro in colon cancer cells, at least in part through activation of RhoA GTPase. The relationship established between BRAFV600E and RhoA activation is mediated by the MEK-ERK pathway. In parallel, KRASG12V enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation. Ultimately increased cell migration and invasion, mediated by Rac1, along with the mesenchymal morphology obtained through the Epithelial-Mesenchymal Transition (EMT) were the main characteristics rendered by HRASG12V in Caco-2 cells. Moreover, BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming properties.ConclusionThis study discriminates oncogene-specific cell migration and invasion pathways mediated by Rho GTPases in colon cancer cells and reveals potential new oncogene-specific characteristics for targeted therapeutics.

【 授权许可】

Unknown   
© Makrodouli et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.