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Int J Biol Sci 2023; 19(12):3694-3708. doi:10.7150/ijbs.85431 This issue Cite

Research Paper

Golgi-protein 73 facilitates vimentin polymerization in hepatocellular carcinoma

Xinyang Hu^1,2,*, Shijin Yuan^1,2,*, Sining Zhou^1,3,*, Ting Sun⁴, Chaoqun Wang^1,5, Shilong Ying^1,2, Heping Zhu⁶, Jingfeng Luo^1,2, Hongchuan Jin^1,2✉, Yiming Liu^1,2✉

1. Laboratory of Cancer Biology, Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
2. Cancer Center, Zhejiang University, Hangzhou 310058, China.
3. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
4. Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
5. Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang 322100, China.
6. Department of Chemistry, Zhejiang University, Hangzhou 310058, China.
^* These authors share equal contributions to this work.

✉ Corresponding authors: Yiming Liu (11618159edu.cn) and Hongchuan Jin (jinhcedu.cn).

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.

Keywords: hepatocellular carcinoma, GP73, vimentin, Clomipramine, cancer metastasis

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