Original Articles

Vol. 36 No. 4 (2025): Turkish Journal of Gastroenterology

WISP1 Inhibits Hepatocellular Carcinoma Cell Proliferation by Promoting CyclinD1 Ubiquitination and Downregulating its Expression

Main Article Content

Jinlong Yan
Jun wen Hu
Na Cheng
Nuoya Li
Anqi Xin
Zhipeng Wu
Zhengyi Wu
Jun Lei
Shouhua Zhang
Jinping Yao

Abstract

Background/Aims: Hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths, is often linked to dysregulated cell cycle proteins. This study focuses on the role of WISP1 in modulating Cyclin D1, a key cell cycle regulator, in HCC.


Materials and Methods: The study used HCCLM3 and Hep3B cells to assess the expression of Cyclin D1 and cell proliferation following the treatment of WISP1. This was achieved through Western blot, qRT-PCR, and EdU assays. Additionally, animal studies were conducted to evaluate the effects of WISP1 treatment on Cyclin D1 expression and cell proliferation.


Results: Overexpression of WISP1 in HCC cells led to a marked decrease in Cyclin D1 protein levels and reduced cell proliferation. WISP1 influences Cyclin D1 through post-translational modifications, particularly ubiquitination and proteasomal degradation.


Conclusion: The findings revealed that WISP1’s modulation of Cyclin D1 plays a critical role in inhibiting HCC cell growth, highlighting a potential therapeutic target for HCC treatment.

Cite this article as: Yan J, wen Hu J, Lei J, et al. WISP1 inhibits hepatocellular carcinoma cell proliferation by promoting CyclinD1 ubiquitination and downregulating its expression. Turk J Gastroenterol. 2025;36(4):247-254.

Article Details

References

1. Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol. 2023;20(12):864-884. [CrossRef]

2. Finn RS. Emerging targeted strategies in advanced hepatocellular carcinoma. Semin Liver Dis. 2013;33(suppl 1):S11-S19. [CrossRef]

3. Singh AK, Kumar R, Pandey AK. Hepatocellular carcinoma: causes, mechanism of progression and biomarkers. Curr Chem Genom Transl Med. 2018;12:9-26. [CrossRef]

4. Katoh M, Katoh M. Wnt signaling pathway and stem cell signaling network. Clin Cancer Res. 2007;13(14):4042-4045. [CrossRef]

5. Perbal A, Perbal B. The CCN family of proteins: a 25th anniversary picture. J Cell Commun Signal. 2016;10(3):177-190. [CrossRef]

6. Wu YL, Li HY, Zhao XP, et al. Mesenchymal stem cell-derived CCN2 promotes the proliferation, migration and invasion of human tongue squamous cell carcinoma cells. Cancer Sci. 2017;108(5):897-909. [CrossRef]

7. Wu J, Long Z, Cai H, et al. High expression of WISP1 in colon cancer is associated with apoptosis, invasion and poor prognosis. Oncotarget. 2016;7(31):49834-49847. [CrossRef]

8. Wang J, Zhang GY, Li XH. Effect of indomethacin on Bfl-1, WISP-1 and proliferating cell nuclear antigen in colon cancer cell line HCT116 cells. Chin J Dig Dis. 2006;7(4):219-224. [CrossRef]

9. Shao H, Cai L, Grichnik JM, et al. Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1. Oncogene. 2011;30(42):4316-4326. [CrossRef]

10. Soon LL, Yie TA, Shvarts A, et al. Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem. 2003;278(13):11465-11470. [CrossRef]

11. Davies SR, Watkins G, Mansel RE, et al. Differential expression and prognostic implications of the CCN family members WISP1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol. 2007;14(6):1909-1918. [CrossRef]

12. Yan J, Lei J, Chen L, et al. Human leukocyte antigen F Locus adjacent Transcript 10 overexpression disturbs WISP1 protein and mRNA expression to promote hepatocellular carcinoma progression. Hepatology. 2018;68(6):2268-2284. [CrossRef]

13. Chalermrujinanant C, Michowski W, Sittithumcharee G, et al. Cyclin D1 promotes BRCA2-Rad51 interaction by restricting cyclin A/B-dependent BRCA2 phosphorylation. Oncogene. 2016;35(22):2815-2823. [CrossRef]

14. Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 2016;94(12):1313-1326. [CrossRef]

15. Yuan C, Zhu X, Han Y, et al. Elevated HOXA1 expression correlates with accelerated tumor cell proliferation and poor prognosis in gastric cancer partly via cyclin D1. J Exp Clin Cancer Res. 2016;35:15. [CrossRef]

16. Li X, Gong X, Chen J, et al. miR-340 inhibits glioblastoma cell proliferation by suppressing CDK6, cyclin-D1 and cyclin-D2. Biochem Biophys Res Commun. 2015;460(3):670-677. [CrossRef]

17. Tu K, Liu Z, Yao B, et al. BCL-3 promotes the tumor growth of hepatocellular carcinoma by regulating cell proliferation and the cell cycle through cyclin D1. Oncol Rep. 2016;35(4):2382-2390. [CrossRef]

18. Liu J, Cui X, Qu L, et al. Overexpression of DLX2 is associated with poor prognosis and sorafenib resistance in hepatocellular carcinoma. Exp Mol Pathol. 2016;101(1):58-65. [CrossRef]

19. Qiu Y, Huang D, Sheng Y, et al. Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1. Exp Cell Res. 2021;405(1):112646. [CrossRef]

20. Zhang S, Li N, Sheng Y, et al. Hepatitis B virus induces sorafenib resistance in liver cancer via upregulation of cIAP2 expression. Infect Agent Cancer. 2021;16(1):20. [CrossRef]

21. Yang X, Feng Y, Liu Y, et al. Fuzheng Jiedu Xiaoji formulation inhibits hepatocellular carcinoma progression in patients by targeting the AKT/CyclinD1/p21/p27 pathway. Phytomedicine. 2021;87:153575. [CrossRef]

22. Brown JL, Lee DE, Rosa-Caldwell ME, et al. Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice. J Cachexia Sarcopenia Muscle. 2018;9(5):987-1002. [CrossRef]

23. Maimaiti Y, Kamali A, Yang P, et al. Hsa_circ_0008092 contributes to cell proliferation and metastasis in hepatocellular carcinoma via the miR-502-5p/CCND1 axis. Protein Pept Lett. 2022;29(7):595-604. [CrossRef]

24. Hamada T, Akahane T, Yokoyama S, et al. An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors. Sci Rep. 2022;12(1):1275. [CrossRef]

25. Ferrand N, Béreziat V, Moldes M, et al. WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity. Sci Rep. 2017;7(1):1749. [CrossRef]

Similar Articles

<< < 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 > >> 

You may also start an advanced similarity search for this article.