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高尔基体蛋白73促进肝细胞癌中波形蛋白的聚合。

Golgi-protein 73 facilitates vimentin polymerization in hepatocellular carcinoma.

作者信息

Hu Xinyang, Yuan Shijin, Zhou Sining, Sun Ting, Wang Chaoqun, Ying Shilong, Zhu Heping, Luo Jingfeng, Jin Hongchuan, Liu Yiming

机构信息

Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.

Cancer Center, Zhejiang University, Hangzhou 310058, China.

出版信息

Int J Biol Sci. 2023 Jul 16;19(12):3694-3708. doi: 10.7150/ijbs.85431. eCollection 2023.

DOI:10.7150/ijbs.85431
PMID:37564210
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10411459/
Abstract

Golgi-protein 73 (GP73) is highly expressed in hepatocellular carcinoma (HCC) and, as a secretory protein, it has been proposed as a serum biomarker indicating progression of HCC. The underlying mechanism by which GP73 may promote HCC metastasis is still poorly understood. In this study, we discovered that GP73 interacted with vimentin to facilitate Serine/Threonine-protein phosphatase PP1-alpha (PP1A)-mediated dephosphorylation of vimentin at S56 and facilitated vimentin polymerization, which blocked vimentin degradation via TRIM56-mediated ubiquitin/proteasome-dependent pathway. Strikingly, Clomipramine, a 5-hydroxytryptamine receptor (5-HTR) agonist approved for the treatment of depression, impaired GP73-mediated vimentin polymerization to effectively inhibit metastasis of HCC with high GP73 expression, which provided a new strategy against HCC metastasis. Lastly, it was found that serum GP73 (sGP73) correlated positively with vimentin in primary tissues of HCC, suggesting that sGP73 might serve as a potential serum biomarker for companion diagnosis of HCC with highly expressed vimentin. In summary, this study reveals the process of GP73-mediated vimentin polymerization and proves that Clomipramine serves as a potential drug targeting vimentin for metastatic HCC patients with high sGP73 level.

摘要

高尔基体蛋白73（GP73）在肝细胞癌（HCC）中高表达，作为一种分泌蛋白，它被认为是一种指示HCC进展的血清生物标志物。GP73促进HCC转移的潜在机制仍不清楚。在本研究中，我们发现GP73与波形蛋白相互作用，促进丝氨酸/苏氨酸蛋白磷酸酶PP1-α（PP1A）介导的波形蛋白在S56位点的去磷酸化，并促进波形蛋白聚合，从而通过TRIM56介导的泛素/蛋白酶体依赖性途径阻断波形蛋白降解。引人注目的是，氯米帕明是一种被批准用于治疗抑郁症的5-羟色胺受体（5-HTR）激动剂，它能损害GP73介导的波形蛋白聚合，从而有效抑制高表达GP73的HCC转移，这为抗HCC转移提供了一种新策略。最后，研究发现血清GP73（sGP73）与HCC原发组织中的波形蛋白呈正相关，提示sGP73可能作为一种潜在的血清生物标志物，用于伴发波形蛋白高表达的HCC的辅助诊断。总之，本研究揭示了GP73介导的波形蛋白聚合过程，并证明氯米帕明可作为一种潜在药物，用于治疗sGP73水平高的转移性HCC患者的波形蛋白靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/d69155c8732c/ijbsv19p3694g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/001d093e5928/ijbsv19p3694g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/8f87d52bd7c8/ijbsv19p3694g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/5baa6ee889f1/ijbsv19p3694g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/3739dcb55818/ijbsv19p3694g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/6556644e5eea/ijbsv19p3694g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/d69155c8732c/ijbsv19p3694g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/001d093e5928/ijbsv19p3694g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/8f87d52bd7c8/ijbsv19p3694g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/5baa6ee889f1/ijbsv19p3694g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/3739dcb55818/ijbsv19p3694g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/6556644e5eea/ijbsv19p3694g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b43/10411459/d69155c8732c/ijbsv19p3694g007.jpg

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Biomed Pharmacother. 2023 Apr;160:114402. doi: 10.1016/j.biopha.2023.114402. Epub 2023 Feb 13.
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Vimentin and cytokeratin: Good alone, bad together.波形蛋白和细胞角蛋白：单独很好，一起很糟。
Semin Cancer Biol. 2022 Nov;86(Pt 3):816-826. doi: 10.1016/j.semcancer.2021.12.006. Epub 2021 Dec 22.
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Sci Rep. 2024 Jun 7;14(1):13108. doi: 10.1038/s41598-024-63325-z.
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