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  • Title: B-Raf(V600E) cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival.
    Author: Matos P, Oliveira C, Velho S, Gonçalves V, da Costa LT, Moyer MP, Seruca R, Jordan P.
    Journal: Gastroenterology; 2008 Sep; 135(3):899-906. PubMed ID: 18602919.
    Abstract:
    BACKGROUND & AIMS: In colorectal tumors, activating BRAF mutations occur alternative to KRAS oncogenic mutations, but in cell culture possess a much lower transforming capacity. Rac1b, a hyperactive Rac1 spliced variant, is over expressed in some colorectal tumors and activates the transcription factor nuclear factor-kappaB, which initiates a transcriptional response that promotes cell cycle progression and inhibits apoptosis. The aim of this study was to determine whether Rac1b overexpression is associated with B-Raf(V600E) in primary colorectal tumors and whether a functional cooperation between these 2 proteins exists in colorectal cells with a wild-type KRAS genotype. METHODS: Screening of BRAF and KRAS mutations by direct sequencing and Rac1b mRNA expression analysis by quantitative real-time polymerase chain reaction were conducted in 74 samples (13 normal colonic mucosa, 45 primary colorectal tumors, and 16 colorectal cancer [CRC] cell lines). RNA interference and focus formation assays were used to assess the cooperation between Rac1b and B-Raf(V600E) in cancer cell viability. RESULTS: Rac1b overexpression and B-Raf(V600E) are significantly associated in primary colorectal tumors (P = .008) and colorectal cell lines. The simultaneous suppression of both proteins dramatically decreased CRC cell viability through impaired cell-cycle progression and increased apoptosis. CONCLUSIONS: Our data demonstrate that Rac1b and B-Raf(V600E) functionally cooperate to sustain colorectal cell viability and suggest they constitute an alternative survival pathway to oncogenic K-Ras. These results reveal a novel molecular characteristic of colon tumors containing B-Raf mutations and should help in defining novel targets for cancer therapy.
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