ERBB4 is over-expressed in human colon cancer and enhances cellular transformation
A partir de bases de données portant sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, puis menée in vitro et in vivo, cette étude identifie des niveaux élevés de la protéine ERBB4 dans les tumeurs et met en évidence des mécanismes par lesquels cette protéine favorise la survie et la croissance des cellules cancéreuses
The ERBB4 receptor tyrosine kinase promotes colonocyte survival. Herein, we tested whether ERBB4’s anti-apoptotic signaling promotes transformation and colorectal tumorigenesis. ERBB4 alterations in a TCGA colorectal cancer (CRC) dataset stratified survival, and in a combined Moffit Cancer Center & Vanderbilt Medical Center CRC expression dataset, ERBB4 message levels were increased at all tumor stages. Similarly, western blot and immunohistochemistry on additional CRC tissue banks showed elevated ERBB4 protein in tumors. ERBB4 was highly expressed in aggressive, dedifferentiated CRC cell lines, and its knockdown in LIM2405 cells reduced anchorage-independent colony formation. In nude mouse xenograft studies, ERBB4 alone was insufficient to induce tumor establishment of non-transformed mouse colonocytes, but its over-expression in cells harboring Apcmin and v-Ha-Ras caused a doubling of tumor size. ERBB4-expressing xenografts displayed increased activation of survival pathways, including EGFR and Akt phosphorylation and COX-2 expression, and decreased apoptotic signals. Finally, ERBB4 deletion from mouse intestinal epithelium impaired stem cell replication and in vitro enteroid establishment. In summary, we report that ERBB4 is over-expressed in human CRC, and in experimental systems enhances the survival and growth of cells driven by Ras and/or WNT signaling. Chronic ERBB4 over-expression, for example in the context of inflammation, may contribute to colorectal carcinogenesis. Tumors with high receptor levels are likely to have enhanced cell survival signaling through EGFR, PI3K, and COX-2. These results suggest ERBB4 as a novel therapeutic target in a subset of CRC.
http://carcin.oxfordjournals.org/content/early/2015/04/27/carcin.bgv049.abstract