Down-regulation of the tumor suppressor gene C-terminal Src kinase: An early event during premalignant colonic epithelial hyperproliferation☆

Abstract 

Hyperproliferation of the premalignant epithelium is critical for colonic carcinogenesis; however the mechanisms remain largely unexplored. We report herein that prior to occurrence of neoplastic lesions in the azoxymethane-rat model of colon carcinogenesis; the tumor suppressor gene C-terminal Src kinase (Csk) was down-regulated with a concomitant increase in Src activity. Furthermore, pharmacological or genetic (RNA interference) inhibition of Csk resulted in increased proliferation in colon cancer cell lines through the mitogen-activated protein kinase dependent pathway. Thus, we demonstrate, for the first time, that Csk suppression is an important early event in colorectal cancer pathogenesis.

Abbreviations: CRC, colorectal cancer, Csk, C-terminal Src kinase, AOM, azoxymethane, BrDu, 5′bromo 2′deoxyuridine, MAP kinase, mitogen-activated protein kinase, MEK, MAP kinase kinase, PCNA, proliferating cell nuclear antigen, shRNA, short hairpin-loop RNA

Keywords: Csk, Colon cancer, Src, Colonic hyperproliferation