Oncoscience

KrasG12D upregulates Notch signaling to induce gallbladder tumorigenesis in mice

Wen-Cheng Chung1, Junqing Wang2, Yunyun Zhou3 and Keli Xu1,4

1Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

2Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

3Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA

4Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence to:

Keli Xu, email: kxu@umc.edu

Keywords: gallbladder tumorigenesis, Kras mutation, Notch signaling, mouse model, adenoma

Received: August 04, 2017     Accepted: September 17, 2017     Published: October 23, 2017

ABSTRACT

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 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.

Results: Pdx1-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.

Conclusions: KrasG12D induces gallbladder adenoma and Notch plays a key role in Kras-initiated gallbladder tumorigenesis.


PII: 368