Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGF beta signalling pathway
作者全名："Gao, Qingzhu; Cheng, Bin; Chen, Chang; Lei, Chong; Lin, Xue; Nie, Dan; Li, Jingjing; Huang, Luyi; Li, Xiaosong; Wang, Kai; Huang, Ailong; Tang, Ni"
作者地址："[Gao, Qingzhu; Cheng, Bin; Lei, Chong; Lin, Xue; Li, Jingjing; Huang, Luyi; Wang, Kai; Huang, Ailong; Tang, Ni] Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ,Affiliated Hosp 2, Inst Viral Hepatitis,Dept Infect Dis, Chongqing, Peoples R China; [Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Nie, Dan] Chongqing Hosp Tradit Chinese Med, Dept Gastroenterol, Chongqing, Peoples R China; [Li, Xiaosong] Chongqing Med Univ, Affiliated Hosp 1, Clin Mol Med Testing Ctr, Chongqing, Peoples R China"
通信作者："Wang, K; Huang, AL; Tang, N (通讯作者)，Chongqing Med Univ, Key Lab Mol Biol Infect Dis, Minist Educ,Affiliated Hosp 2, Inst Viral Hepatitis,Dept Infect Dis, Chongqing, Peoples R China."
来源：CLINICAL AND TRANSLATIONAL MEDICINE
ESI学科分类：CLINICAL MEDICINE
WOS号：WOS:000842379000001
JCR分区：Q1
影响因子：10.6
年份：2022
卷号：12
期号：8
开始页：
结束页：
文献类型：Article
关键词：hepatocellular carcinoma metastasis; TGF beta/Smad signalling; UDP-GlcUA; UGDH
摘要："Background: Glucuronic acid metabolism participates in cellular detoxification, extracellular matrix remodeling and cell adhesion and migration. Here, we aimed to explore the crosstalk between dysregulated glucuronic acid metabolism and crucial metastatic signalling in glutathione S-transferase zeta 1 (GSTZ1)-deficient hepatocellular carcinoma (HCC). Methods: Transwell, HCC xenograft and Gstz1(-/-) mouse models were used to examine the role of GSTZ1 in IICC metastasis. Non-targeted and targeted metabolomics and global transcriptomic analyses were performed to screen significantly altered metabolic and signalling pathways in GSTZ1 overexpressing hepatoma cells. Further, RNA-binding protein immunoprecipitation, Biotin-RNA pull-down, mRNA decay assays and luciferase reporter assays were used to explore the interaction between RNA and RNA-binding proteins. Results: GSTZ1 was universally silenced in both human and murine HCC cells, and its deficiency contributed to HCC metastasis in vitro and in vivo. UDP-glucose 6-dehydrogenase (UGDH)-mediated UDP-glucuronic acid (UDP-GlcUA) accumulation promoted hepatoma cell migration upon GSTZ1 loss. UDP-GlcUA stabilized TGF beta R1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGF beta/Smad signalling. UGDH or TGF beta R1 blockade impaired HCC metastasis. In addition, UGDH up-regulation and UDP-GlcUA accumulation correlated with increased metastatic potential and decreased patient survival in GSTZ1-deficient HCC. Conclusions: GSTZ1 deficiency and subsequent up-regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGF beta R1 mRNA and activating TGF beta/Smad signalling. UGDH and a key metabolite, UDP-GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy."
基金机构："111 Project [D20028]; Chongqing Municipal Education Commission [HZ2021006, KJZD-M202000401, KJQN201900429]; Program for Youth Innovation in Future Medicine from Chongqing Medical University [W0036, W0101]; Open Research Fund Program of the Key Laboratory of Molecular Biology for Infectious Diseases, CQMU; 2020 Chongqing Postdoctoral Innovation Talent Support Program [274]; 68th China Postdoctoral Science Fund [2020M683637XB]; Natural Science Foundation Project of Chongqing [cstc2019jscx-dxwtBX0019, cstc2021jcyj-bsh0017]; China National Natural Science Foundation [81872270, 82072286, U20A20392]"
基金资助正文："111 Project, Grant/Award Number: D20028; Chongqing Municipal Education Commission, Grant/Award Numbers: HZ2021006, KJZD-M202000401, KJQN201900429; Program for Youth Innovation in Future Medicine from Chongqing Medical University, Grant/Award Numbers: W0036, W0101; Open Research Fund Program of the Key Laboratory of Molecular Biology for Infectious Diseases, CQMU; 2020 Chongqing Postdoctoral Innovation Talent Support Program, Grant/Award Number: 274; 68th China Postdoctoral Science Fund, Grant/Award Number: 2020M683637XB; Natural Science Foundation Project of Chongqing, Grant/Award Numbers: cstc2019jscx-dxwtBX0019, cstc2021jcyj-bsh0017; China National Natural Science Foundation, Grant/Award Numbers: 81872270, 82072286, U20A20392"
