BRAF(V600E) Efficient Transformation and Induction of Microsatellite Instability Versus KRAS(G12V) Induction of Senescence Markers in Human Colon Cancer Cells

Evagelidou, Maria

Pintzas, Alexander

Makrodouli, Eleni

Probert, Lesley

Joyce, Tobias

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(G12)V both in vivo and in vitro. These findings may have implications in personalised diagnosis and targeted therapeutics.

Article

Εθνικό Ίδρυμα Ερευνών (ΕΙΕ)

Ήλιος - Αποθετήριο Εθνικού Ιδρύματος Ερευνών

Άρθρο σε περιοδικό

EC_fundedresources set

Ινστιτούτο Βιολογικών Ερευνών και Βιοτεχνολογίας (ΙΒΕΒ) (έως 2012)

Driver

Video

Αγγλική γλώσσα

2012-10-01

2012-10-01T15:25:20Z

2009-11

http://hdl.handle.net/10442/12233

DOI: http://dx.doi.org/10.1593/neo.09514

Τύποι Τεκμηρίων

Άρθρο σε περιοδικό

Συλλογές του Ήλιος

Ινστιτούτο Βιολογικών Ερευνών και Βιοτεχνολογίας (ΙΒΕΒ) (έως 2012)

Ινστιτούτο Bιολογίας, Φαρμακευτικής Χημείας και Βιοτεχνολογίας (ΙΒΦΧΒ)