Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFβ signalling pathway.
Dysregulated glucuronic acid metabolism exacerbates hepatocellular carcinoma progression and metastasis through the TGFβ signalling pathway.
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葡萄糖醛酸代谢失调通过 TGFβ 信号通路加剧肝细胞癌的进展和转移
DOI：
10.1002/ctm2.995
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发表时间：
2022-08
影响因子：
10.6
通讯作者：
Tang, Ni
中科院分区：
文献类型：
--
作者：
Gao, Qingzhu;Cheng, Bin;Chen, Chang;Lei, Chong;Lin, Xue;Nie, Dan;Li, Jingjing;Huang, Luyi;Li, Xiaosong;Wang, Kai;Huang, Ailong;Tang, Ni
葡萄糖醛酸代谢参与细胞解毒、细胞外基质重塑和细胞粘附和迁移。在此，我们旨在探讨谷胱甘肽S转移酶zeta 1 （GSTZ1）缺失型肝细胞癌（HCC）中葡萄糖醛酸代谢失调与关键转移信号之间的串扰。Transwell，肝癌异种移植和Gstz1 - / -小鼠模型被用来研究Gstz1在肝癌转移中的作用。在GSTZ1过表达的肝癌细胞中，进行了非靶向和靶向代谢组学和全球转录组学分析，以筛选显著改变的代谢和信号通路。此外，RNA结合蛋白免疫沉淀、生物素- RNA拉降、mRNA衰减和荧光素酶报告基因测定被用来探索RNA和RNA结合蛋白之间的相互作用。GSTZ1在人和小鼠肝癌细胞中普遍沉默，其缺失导致肝癌在体内和体外转移。UDP -葡萄糖6 -脱氢酶（UGDH）介导的UDP -葡萄糖醛酸（UDP - GlcUA）积累促进了GSTZ1缺失后肝癌细胞的迁移。UDP‐GlcUA通过增强TGFβ r1 mRNA与多嘧啶束结合蛋白3的结合来稳定TGFβ r1 mRNA，促进TGFβ/Smad信号的激活。UGDH或TGFβR1阻断可损害HCC转移。此外，UGDH上调和UDP - GlcUA积累与GSTZ1缺失型HCC的转移潜力增加和患者生存率降低相关。GSTZ1缺失和随后葡萄糖醛酸代谢途径的上调通过增加TGFβ r1 mRNA的稳定性和激活TGFβ/Smad信号传导促进HCC转移。UGDH和关键代谢物UDP - GlcUA可作为预后指标。靶向UGDH可能是一种很有前景的HCC治疗策略。1. UDP -葡萄糖6 -脱氢酶（UGDH）介导的UDP - GlcUA积累促进了GSTZ1缺失后肝癌细胞的迁移。2. UDP‐GlcUA通过增强TGFβ r1与PTBP3的结合来稳定TGFβ r1 mRNA，促进TGFβ/Smad信号的激活。3. UGDH和关键的中间代谢物UDP - GlcUA是HCC转移风险增加的有力预测因子，靶向UGDH可能是HCC治疗的一种有希望的策略。
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). Transwell, HCC xenograft and Gstz1 −/‐ mouse models were used to examine the role of GSTZ1 in HCC 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. 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 TGFβR1 mRNA by enhancing its binding to polypyrimidine tract binding protein 3, contributing to the activation of TGFβ/Smad signalling. UGDH or TGFβR1 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. GSTZ1 deficiency and subsequent up‐regulation of the glucuronic acid metabolic pathway promotes HCC metastasis by increasing the stability of TGFβR1 mRNA and activating TGFβ/Smad signalling. UGDH and a key metabolite, UDP‐GlcUA, may serve as prognostic markers. Targeting UGDH might be a promising strategy for HCC therapy. 1. UDP‐glucose 6‐dehydrogenase (UGDH)‐mediated UDP‐GlcUA accumulation promotes hepatoma cell migration upon GSTZ1 loss. 2. UDP‐GlcUA stabilized TGFβR1 mRNA by enhancing its binding to PTBP3, contributing to the activation of TGFβ/Smad signalling. 3. UGDH and a key intermediate metabolite, UDP‐GlcUA are strong predictors of an increased risk of HCC metastasis, and targeting UGDH might be a promising strategy for HCC therapy.
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