Abstract 1821: SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma

Abstract Background: Nonalcoholic steatohepatitis (NASH) is a risk factor for the development of hepatocellular carcinoma (HCC). β-spectrin, encoded by SPTBN1, is associated with HCC. The goal of this study was to evaluate the hepatocyte-specific roles of SPTBN1 in NASH and HCC using mouse models. Methods: We investigated the effect of knocking out Sptbn1 specifically in the liver in mice (LSKO mice). We examined the effect of diets that promote NASH—a high-fat diet (HFD) or Western diet (WD)— and the outcomes of HCC induced by diethylnitrosamine (DEN). Based on the phenotypes of these mice, we examined the therapeutic effects of knocking down Sptbn1 using siRNA. Results: We found LSKO mice were protected from HFD-induced obesity and NASH. Control mice administered siRNA targeting Sptbn1 were protected from developing NASH when placed on a HFD, and NASH phenotypes triggered by WD were reduced by administration of siRNA targeting Sptbn1. LSKO mice appeared to be protected from HFD-induced HCC: One of four HFD control mice developed liver tumors, but none of the three LSKO mice did. HFD-induced HCC is rare in mice, therefore we evaluated DEN-induced HCC. LSKO mice subjected to DEN with or without WD had less severe cancer than did wild-type mice. Compared to the HCC in the control mice, the number of liver tumors in the LSKO mice was lower, the size of the tumors was smaller, and the tumors were less proliferative based on KI67 staining intensity. Furthermore, overall liver pathology was reduced. Conclusions: These data suggest that SPTBN1 is a potential target for therapeutic intervention to treat NASH and prevent progression to HCC. Because other injected siRNA therapies are approved to treat liver diseases, a siRNA-based therapy targeting SPTBN1 could translate into clinical trials. Citation Format: Xiaochun Yang, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Patricia Latham, Kirti Shetty, Lopa Mishra. SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1821.