Abstract 5747: Lack of FGF21 accelerates the Th17-IL-17 axis-mediated transition from nonalcoholic steatohepatitis to hepatocellular carcinoma
Authors: Zheng Qianqian , Pandit Harshul , Liu Xingkai , Yu Youxi , Li Suping , Turner Shelby , Meng Xin , Martin Robert , Li Yan 
Published: August 2018

Background: Hepatocellular carcinoma (HCC) has been increasingly recognized in nonalcoholic steatohepatitis (NASH) before cirrhosis stage and the estimated annual HCC incidence in NASH patients is about 0.3%. Accumulating evidence shows that T helper (Th) 17-Interleukin (IL)-17 axis mediates the transition from NASH to HCC, while fibroblast growth factor 21 (FGF21) exerts pharmacologic efficacy in downregulation of Th17- IL-17 axis. In fact, FGF21 has recently emerged as a promising therapeutic candidate for the treatment of obesity and diabetes. However, the NASH-related carcinogenesis and role of FGF21 played during NASH-HCC transition are largely unknown.

Aim: To investigate the effect of FGF21 on Th17-IL-17 axis during the NASH-HCC carcinogenetic transformation and to reveal the potential NASH-HCC mechanism.

Methods: NASH-HCC was induced in FGF21 knockout (KO) mice treated with DEN at age 2 weeks at 100 mg/kg body weight (i.p.), and followed feeding with high-fat diet (HFD,60% kcal% fat) or methionine/choline-deficient diet (MCD). In an orthotopic HCC model with inoculation of 106 hepal-6 cells into 10 week-old male C57L/J mice, fenofibrate (50 mg/kg) was administered to induce FGF21. In vitro studies were performed using shRNA-FGF21 knockdown hepatocyte and HCC cell lines. The cellular and molecular events, in turn, white adipose tissue (WAT) lipolysis, insulin resistance (IR), release of free fatty acids (FFAs), Th17 cell infiltration and IL-17A production, and NASH-HCC initiation, were determined both in vivo and in vitro.

Results: Early HCC detection and increased HCC incidence were found in the FGF21 knockout (KO) mice (P&lt;0.05 versus wild-type controls). Increased WAT lipolysis, hepatic FFAs uptake, Th17 cells/IL-17A, and aberrant NF-κB and p53 signaling were found in NASH and HCC tissues (adipose, spleen and liver) from in FGF21-KO mice by flow cytometry, immunohistochemistry (IHC) and Western blot. IL-17A significantly induced FFAs uptake in the shRNA-FGF21 knockdown hepal-6 cells and FL83B cells. IL-17A promoted the shRNA-FGF21 knockdown hepal-6 cells spheroid formation through Wnt/β-catenin pathway. Fenofibrate treatment significantly increased PPAR-α and native FGF21 protein levels in the liver tissues, and decreased the tumor volumes.

Conclusions: 1) Lack of FGF21 played a key role in hepatic lipid accumulation and subsequent upregulated Th17-IL-17 signaling in liver; 2) lack of FGF21 accelerated the Th17-IL-17 axis promoted NASH-HCC transition; 3) upregulation of native FGF21 not only attenuates NASH, but also prevents HCC carcinogenetic transformation via downregulation of Th17-IL-17 axis.

This work was supported by an Institutional Development Award (IDeA) from the NIGMS of the National Institutes of Health under grant number P20GM113226.

Citation Format: Qianqian Zheng, Harshul Pandit, Xingkai Liu, Youxi Yu, Suping Li, Shelby Turner, Xin Meng, Robert Martin, Yan Li. Lack of FGF21 accelerates the Th17-IL-17 axis-mediated transition from nonalcoholic steatohepatitis to hepatocellular carcinoma [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 5747.