BRAFV600E Efficient Transformation and Induction of Microsatellite Instability Versus KRASG12V Induction of Senescence Markers in Human Colon Cancer Cells12

• Published in: Neoplasia (New York, N.Y.) Vol. 11; no. 11; pp. 1116 - 1131
• Main Authors: Oikonomou, Eftychia, Makrodouli, Eleni, Evagelidou, Maria, Joyce, Tobias, Probert, Lesley, Pintzas, Alexander
• Format: Journal Article
• Language: English
• Published: Neoplasia Press Inc 01.11.2009
• ISSN: 1522-8002; 1476-5586

In colorectal cancer, BRAF and KRAS oncogenes are mutated in about 15% and 35% respectively at approximately the same stage of the adenoma-carcinoma sequence. Since these two mutations rarely coexist, further analysis to dissect their function of transformation in colon cancer is required. Caco-2 human colon adenocarcinoma cells were stably transfected with BRAF V600E (Caco-BR cells) or KRAS G12V (Caco-K cells) oncogenes. BRAF V600E is more efficient in transforming Caco-2 cells and altering their morphology. The dominant nature of BRAF V600E is evident by its ability to render Caco-2 cells tumorigenic in vivo all be it through selective extracellular signal-related kinase (ERK) 2 phosphorylation and high levels of cyclin D1. As a consequence, the cell cycle distribution of parental cells is altered and microsatellite instability is introduced. Attenuated ERK activation observed correlated with KSR downregulation by BRAF V600E without further implications to signaling. Highly activated ERK in case of KRAS G12V (Caco-K cells) leads to mild transformation causing Caco-K cells to express premature senescence-related markers and acquire growth factor-dependent viability. Interestingly, BRAF WT gets equally activated by upstream KRAS mutations present in colon adenocarcinoma cells such as DLD-1 and SW620. Taken together, these results suggest that the two oncogenes have different transforming capability in colon cancer, although they both use the mitogen-activated protein (MAP) kinase pathway to carry out their effect. In general, BRAF V600E presents greater potential in mediating tumorigenic effect as compared to KRAS G12V both in vivo and in vitro . These findings may have implications in personalised diagnosis and targeted therapeutics.