FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC

Lei Zhang; Qing Zhang; Da Teng; Manyu Guo; Kechao Tang; Zhenglin Wang; Xiang Wei; Li Lin; Xiaomin Zhang; Xiuyun Wang; Dake Huang; Cuiping Ren; Qingsong Yang; Wenjun Zhang; Yong Gao; Wei Chen; Yongsheng Chang; Huabing Zhang

doi:10.1002/advs.202301166

FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC

Adv Sci (Weinh). 2023 Oct;10(28):e2301166. doi: 10.1002/advs.202301166. Epub 2023 Aug 11.

Authors

Lei Zhang^{1

2}, Qing Zhang¹, Da Teng³, Manyu Guo¹, Kechao Tang¹, Zhenglin Wang⁴, Xiang Wei¹, Li Lin¹, Xiaomin Zhang¹, Xiuyun Wang¹, Dake Huang⁵, Cuiping Ren⁶, Qingsong Yang³, Wenjun Zhang³, Yong Gao⁷, Wei Chen⁴, Yongsheng Chang², Huabing Zhang^{1

8}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, 230032, Hefei, China.
² Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, 300070, Tianjin, China.
³ Department of Hepatopancreatobiliary Surgery, Affifiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou), Chuzhou, 239001, China.
⁴ Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 230022, Hefei, China.
⁵ Synthetic Laboratory of School of Basic Medicine Sciences, Anhui Medical University, 230032, Hefei, China.
⁶ Department of Microbiology and Parasitology, School of Basic Medicine, Anhui Medical University, 230032, Hefei, China.
⁷ Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, 510006, Guangzhou, China.
⁸ The Affiliated Chuzhou Hospital of Anhui Medical University (The First People's Hospital of Chuzhou), Chuzhou, 239001, China.

Abstract

Most nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH-driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH-associated HCC. Furthermore, NASH-driven HCC mice models by feeding wildtype mice with high-fat/high-cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl₄ ) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH-driven HCC mice models. Hepatocyte-specific FGF9 transgenic mice (FGF9^Alb ) fed with a HFHC diet without CCl₄ treatment exhibited an increased hepatic ECM and tumor burden. However, XAV-939 treatment blocked ECM accumulation and NASH-driven HCC in FGF9^Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β-catenin dependent manner; and FGF9 exerts its effect on β-catenin stability via the ERK1/2-GSK-3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH-driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.

Keywords: FGF9; NASH; extracellular matrix; liver cancer; β-catenin.

Abstract

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