Golgi-protein 73 Facilitates Vimentin Polymerization in Hepatocellular Carcinoma

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2023 Aug 11

PMID 37564210

Authors

Xinyang Hu

Shijin Yuan

Sining Zhou

Ting Sun

Chaoqun Wang

Shilong Ying

Heping Zhu

Jingfeng Luo

Hongchuan Jin

Yiming Liu

Affiliations

Soon will be listed here.

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.

Citing Articles

Golgi protein 73: the driver of inflammation in the immune and tumor microenvironment.

Feng P, Hu X, Zhou S, Liu X, Zeng L, Liu Y Front Immunol. 2025; 15():1508034.

PMID: 39845976 PMC: 11750648. DOI: 10.3389/fimmu.2024.1508034.

Oncolytic adenovirus encoding LHPP exerts potent antitumor effect in lung cancer.

Zhao Y, Liu H, Zhan Q, Jin H, Wang Y, Wang H Sci Rep. 2024; 14(1):13108.

PMID: 38849383 PMC: 11161505. DOI: 10.1038/s41598-024-63325-z.

References

Chan S, Wong V, Qin S, Chan H . Infection and Cancer: The Case of Hepatitis B. J Clin Oncol. 2015; 34(1):83-90. DOI: 10.1200/JCO.2015.61.5724. View

Ballard C, Hanney M, Theodoulou M, Douglas S, McShane R, Kossakowski K . The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009; 8(2):151-7. DOI: 10.1016/S1474-4422(08)70295-3. View

Mahammad S, Murthy S, Didonna A, Grin B, Israeli E, Perrot R . Giant axonal neuropathy-associated gigaxonin mutations impair intermediate filament protein degradation. J Clin Invest. 2013; 123(5):1964-75. PMC: 3635735. DOI: 10.1172/JCI66387. View

Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z . Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021; 39(27):3002-3011. PMC: 8445562. DOI: 10.1200/JCO.21.00163. View

Chang L, Goldman R . Intermediate filaments mediate cytoskeletal crosstalk. Nat Rev Mol Cell Biol. 2004; 5(8):601-13. DOI: 10.1038/nrm1438. View

Tian H, Lian R, Li Y, Liu C, Liang S, Li W . AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation. Nat Commun. 2020; 11(1):5127. PMC: 7550350. DOI: 10.1038/s41467-020-18929-0. View

Liu Y, Wang J, Yang R, Cheng Y, Zhou Y, Li H . GP73-mediated secretion of AFP and GP73 promotes proliferation and metastasis of hepatocellular carcinoma cells. Oncogenesis. 2021; 10(10):69. PMC: 8516944. DOI: 10.1038/s41389-021-00358-3. View

Zhao L, Zhang P, Su X, Zhang B . The ubiquitin ligase TRIM56 inhibits ovarian cancer progression by targeting vimentin. J Cell Physiol. 2017; 233(3):2420-2425. DOI: 10.1002/jcp.26114. View

Ye Q, Zhu W, Zhang J, Qin Y, Lu M, Lin G . GOLM1 Modulates EGFR/RTK Cell-Surface Recycling to Drive Hepatocellular Carcinoma Metastasis. Cancer Cell. 2016; 30(3):444-458. PMC: 5021625. DOI: 10.1016/j.ccell.2016.07.017. View

10.

Chen J, Lin Z, Liu L, Zhang R, Geng Y, Fan M . GOLM1 exacerbates CD8 T cell suppression in hepatocellular carcinoma by promoting exosomal PD-L1 transport into tumor-associated macrophages. Signal Transduct Target Ther. 2021; 6(1):397. PMC: 8602261. DOI: 10.1038/s41392-021-00784-0. View

11.

Kim H, Lv D, Zhang Y, Peng T, Ma X . Golgi phosphoprotein 2 in physiology and in diseases. Cell Biosci. 2012; 2(1):31. PMC: 3448521. DOI: 10.1186/2045-3701-2-31. View

12.

Liu Y, Hu X, Liu S, Zhou S, Chen Z, Jin H . Golgi Phosphoprotein 73: The Driver of Epithelial-Mesenchymal Transition in Cancer. Front Oncol. 2021; 11:783860. PMC: 8688837. DOI: 10.3389/fonc.2021.783860. View

13.

Wang Z, Pan B, Yao Y, Qiu J, Zhang X, Wu X . XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial-mesenchymal transition in hepatocellular carcinoma. Biomed Pharmacother. 2023; 160:114402. DOI: 10.1016/j.biopha.2023.114402. View

14.

Mao Y, Yang H, Xu H, Lu X, Sang X, Du S . Golgi protein 73 (GOLPH2) is a valuable serum marker for hepatocellular carcinoma. Gut. 2010; 59(12):1687-93. DOI: 10.1136/gut.2010.214916. View

15.

Chen H, Kuo T, Tseng C, Ma J, Yang S, Yen C . Angiopoietin-like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma. Hepatology. 2016; 64(5):1637-1651. DOI: 10.1002/hep.28773. View

16.

Liu Y, Zhang X, Zhou S, Shi J, Xu Y, He J . Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion. J Cell Mol Med. 2019; 23(4):2399-2409. PMC: 6433683. DOI: 10.1111/jcmm.14055. View

17.

Li J, Wang R, Tang D . Vimentin dephosphorylation at ser-56 is regulated by type 1 protein phosphatase in smooth muscle. Respir Res. 2016; 17(1):91. PMC: 4960799. DOI: 10.1186/s12931-016-0415-7. View

18.

Cipriani A, Furukawa T, Salanti G, Chaimani A, Atkinson L, Ogawa Y . Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018; 391(10128):1357-1366. PMC: 5889788. DOI: 10.1016/S0140-6736(17)32802-7. View

19.

Chen X, Lingala S, Khoobyari S, Nolta J, Zern M, Wu J . Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 2011; 55(4):838-45. PMC: 3177032. DOI: 10.1016/j.jhep.2010.12.043. View

20.

Chernyatina A, Nicolet S, Aebi U, Herrmann H, Strelkov S . Atomic structure of the vimentin central α-helical domain and its implications for intermediate filament assembly. Proc Natl Acad Sci U S A. 2012; 109(34):13620-5. PMC: 3427084. DOI: 10.1073/pnas.1206836109. View