Abstract
BackgroundKras mutations and increased Notch activation occur frequently in gallbladder cancer. However, their roles in gallbladder carcinogenesis have not been defined. This study was aimed at determining whether expression of mutant Kras was sufficient to induce gallbladder carcinoma and whether Notch deregulation played a role in this context.MethodsWe determined Cre recombination activity of Pdx1-Cre in the gallbladder using a reporter strain and examined gallbladder tumor development in the KrasLSL- G12D/+;Pdx1-Cre mice. We analyzed expression of Notch pathway genes in the mouse gallbladder by immunohistochemistry, quantitative RT-PCR, and Western blot analysis. We also determined the effect of Jag1 deletion on Kras-induced gallbladder tumor development.ResultsPdx1-Cre exhibits robust recombination activity in the gallbladder epithelium. KrasLSL-G12D/+;Pdx1-Cre mice form early onset adenoma in the gallbladder and adjacent biliary tract with complete penetrance, albeit short of invasive adenocarcinoma. KrasG12D upregulates expressions of Notch2, Notch3, Notch4, Jag1 and downstream target genes Hes1, Hey1 and Hey2, and deletion of Jag1 partially suppresses KrasG12D-induced adenoma development.ConclusionsKrasG12D induces gallbladder adenoma and Notch plays a key role in Kras-initiated gallbladder tumorigenesis.
Highlights
Gallbladder cancer is the most common malignancy of the biliary tract, associated with late diagnosis, unsatisfactory treatment and poor prognosis
KrasG12D induces gallbladder adenoma and Notch plays a key role in Kras-initiated gallbladder tumorigenesis
KRAS mutations are frequent and early events in tumors associated with anomalous pancreatobiliary duct junction (APBDJ), but less frequent in carcinomas associated with gallstones [1]
Summary
Gallbladder cancer is the most common malignancy of the biliary tract, associated with late diagnosis, unsatisfactory treatment and poor prognosis. Gallbladder cancers evolved through these two pathways demonstrate differences in demographic distribution, clinical outcome, gender bias and molecular changes. KRAS mutations are frequent and early events in tumors associated with APBDJ, but less frequent in carcinomas associated with gallstones [1]. Other molecular changes of gallbladder cancers include somatic mutations of TP53, ErbB signaling pathway genes, and cell cycle regulator CDKN2A [2, 3]. Overexpression of Erbb in the basal epithelium of the mouse gallbladder resulted in the development of adenoma and progression to adenocarcinoma characterized by papillary structures, demonstrating a functional role of Erbb in gallbladder carcinogenesis [4]. Kras mutations and increased Notch activation occur frequently in gallbladder cancer. Their roles in gallbladder carcinogenesis have not been defined. This study was aimed at determining whether expression of mutant Kras was sufficient to induce gallbladder carcinoma and whether Notch deregulation played a role in this context
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