Abstract
Abstract BACKGROUND & AIMS: SAG, a small ring finger protein, a component of CRLs, might be involved in pancreatic tumorigenesis. SAG overexpression in human pancreatic ductal adenocarcinomas indicating that SAG could be promotes pancreatic tumorigenesis. We investigated how manipulated SAG (overexpression or disruption of SAG) cooperate KRAS to regulate pancreatic cancer progression in mice. METHODS: We disrupted or overexpressed SAG specifically in pancreata of mice (Sagfl/fl;P48-Cre or SagTG;P48-Cre mice) and crossed them with LSL-KRASG12D mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Sagfl/fl;LSL-KRASG12D;P48-Cre or SagTG;LSL-KRASG12D;P48-Cre mice were monitored; Pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. Protein was isolated from mouse tissues and primary acinar cells were prepared and cultured in 3D condition. Human PDA TMA was analyzed by immunohistochemistry. RESULTS: Overexpression of Sag with KRASG12D in pancreata of mice increased the proliferation of pancreatic epithelial cells, lead to formation of acinar to ductal metaplasia and pancreatic intraepithelial neoplasias (mPanINs) and shorten mice survival. Disruption of Sag in LSL-KRASG12D;P48-Cre mice accelerated the growth of pancreatic cystic lesions compared to LSL-KRASG12D;P48-Cre mice, but did not change mouse survival. In mechanism, Sag promotes pancreatic tumorigenesis by regulating Deptor/mTOR/S6K axis and EGFR signaling pathway. CONCLUSION: Sag is an oncogenic cooperator of activated KRAS for pancreatic tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with mutant KRAS. Citation Format: Mingjia Tan, Qiang Zhang, Yi Sun. SAG/RBX2/ROC2 regulates pancreatic cancer initiation, cystic formation in mice driven by KrasG12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4012.
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