Abstract 2293: Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and tumorigenesis

Background: Tid1, DnaJ cochaperone protein, is a mammalian homolog of the Drosophila tumor suppressor Tid56 whose anti-tumor function is through its capacity to regulate cell differentiation in imaginal discs. In our previous studies, we found Tid1 regulates early mouse embryogenesis and T cell development. In addition, it has been identified that Tid1 can act as a tumor suppressor in breast, colon, lung and head and neck cancer. Tid1 protein is highly expressed in mouse and human hepatocyte. However, the physiological role of Tid1 in hepatocyte development and hepatic tumorigenesis remains elusive. Methods: Mice with loss of Tid1 lead to embryonic lethality as early as E4.5. Therefore; we generated a hepatocyte specific Tid1 knockout mice by crossing the Tid1flx/flx mice generated in our lab with transgenic mice expressing Cre recombinase activity driven by albumin promoter. Both spontaneous or carcinogen (diethylnitrosamine; DEN) mediated hepatocellular carcinoma (HCC) in Tid1 deficiency mice will be monitored. In addition, the physiological function of hepatocytes including albumin, plasma alanine aminotransferase (ALT), triglyceride (TG) and cholesterol collected from the control and mutant mice will be examined. Results: We have successfully established mice with hepatocyte specific ablation of Tid1 mice. Immunohistochemistry staining and western blot showed that conditional knockout mice were deficient on Tid1 expression in hepatocyte. Deletion of Tid1 in hepatocyte caused the hepatic steatosis and fibrosis. Consequently, spontaneous HCC tumor was found in thirteen-month-old Tid1 knockout mice. In DEN-treated mice model, deletion of Tid1 also enhanced the induction of HCC accompanying with elevatiof of plasma ALT and cholesterol. Conclusion: The progression of steatosis, fibrosis to HCC was observed in Tid1 deficient mice, which similarly reflects to those observed in tumorigenesis of human HCC. Therefore, we could further characterize the molecular mechanisms to understand how human HCC is developed through our Tid1-deficent HCC mice model. Ultimately, therapeutic regime for HCC could be developed from the Tid1-deficent mice for improving future HCC therapy. Citation Format: Yu-Syuan Chen, Jeng-Fan Lo. Deletion of Tid1 in hepatocyte promotes steatosis, fibrosis, and tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2293. doi:10.1158/1538-7445.AM2015-2293