Abstract B09: Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis

Abstract

Abstract Liver cancer is one of the most common solid tumors with poor prognosis and high mortality. Mutation or deletion of the tumor suppressor PTEN is strongly correlated with human liver cancer. Glucose-regulated protein 94 (GRP94) is a major endoplasmic reticulum (ER) chaperone protein, but its in vivo function is still emerging. To study the role of GRP94 in maintaining liver homeostasis and tumor development, we created two liver-specific knockout mouse models with the deletion of Grp94 alone, or in combination with Pten, using the albumin-cre system. We demonstrated that while deletion of GRP94 in the liver led to hyperproliferation of liver progenitor cells, deletion of both GRP94 and PTEN accelerated development of liver tumors, including both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) suggestive of progenitor cell origin. Furthermore, at the premalignant stage, we observed disturbance of cell adhesion proteins but no detectable overt liver injury. We further discovered that when GRP94 was deleted in PTEN-null livers, ERK was selectively activated, suggesting that this could be a potential molecular mechanism for enhanced liver tumorigenesis in this mouse model. Conclusion: We identify GRP94 as a novel regulator of cell adhesion, liver homeostasis, and tumorigenesis. Citation Format: Wan-Ting Chen, Chun-Chih Tseng, Kyle Pfaffenbach, Gary Kanel, Biquan Luo, Bangyan L. Stiles, Amy S. Lee. Liver-specific knockout of GRP94 in mice disrupts cell adhesion, activates liver progenitor cells, and accelerates liver tumorigenesis. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B09.