Kras(G12D) upregulates Notch signaling to induce gallbladder tumorigenesis in mice

BACKGROUND: Kras 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. METHODS: We determined Cre recombination activity of Pdx1-Cre in the gallbladder using a reporter strain and examined gallbladder tumor development in the Kras(LSL- 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. RESULTS: Pdx1-Cre exhibits robust recombination activity in the gallbladder epithelium. Kras(LSL-G12D/+);Pdx1-Cre mice form early onset adenoma in the gallbladder and adjacent biliary tract with complete penetrance, albeit short of invasive adenocarcinoma. Kras(G12D) upregulates expressions of Notch2, Notch3, Notch4, Jag1 and downstream target genes Hes1, Hey1 and Hey2, and deletion of Jag1 partially suppresses Kras(G12D)-induced adenoma development. CONCLUSIONS: Kras(G12D) induces gallbladder adenoma and Notch plays a key role in Kras-initiated gallbladder tumorigenesis.