NOVA2 Regulates the Properties of Liver Cancer Stem Cells and Lenvatinib Resistance in Hepatocellular Carcinoma Via the Wnt Pathway

Overview

Journal J Gastrointest Oncol

Date 2024 Sep 16

PMID 39279925

Authors

Jing-Zhu Cao

Chao-Qun Wang

Zheng Shi

Jing-Yun Song

Francisco Tustumi

Tiago Biachi de Castria

Jennifer Wu

Christine Pocha

Diamantis I Tsilimigras

Zhi-Hong Wang

Tao Tao

Jin Lu

Affiliations

Soon will be listed here.

Abstract

Background: The regulation of cancer stem cells (CSCs) is influenced by RNA-binding proteins (RBPs). The present study sought to investigate the role of NOVA2 in the processes of self-renewal, carcinogenesis, and lenvatinib resistance in liver CSCs.

Methods: Neuro-oncological ventral antigen 2 (NOVA2) expression in liver CSCs was examined by real-time polymerase chain reaction (PCR). experiments were used to assess the effects of NOVA2 on liver CSC expansion and lenvatinib resistance.

Results: In our study, the expression of the RBP NOVA2 was higher in CSCs. NOVA2 also increased the capacity for self-renewal and carcinogenesis of the liver CSCs via the Wnt pathway. Further, suppressing the Wnt pathway leads to desensitization of the hepatocellular carcinoma (HCC) cells that overexpress NOVA2 to apoptosis caused by lenvatinib. Analyzing patient data confirmed reduced levels of NOVA2 and therefore we speculate that NOVA2 may serve as a potential indicator for response to lenvatinib in patients with HCC. Methyltransferase-like 3 (METTL3) and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1)-dependent N6-methyladenosine (mA) methylation were linked to upregulation of NOVA2 in HCC. Furthermore, it was shown that the expression of METTL3 was elevated in cellular models of type 2 diabetes mellitus (T2DM).

Conclusions: NOVA2 is involved in the process of liver CSC self-renewal and carcinogenesis. In addition, NOVA2 expression may help identify patients with a higher chance of benefiting from lenvatinib treatment and can be a promising therapeutic target for HCC.

Citing Articles

Integrating single cell analysis and machine learning methods reveals stem cell-related gene S100A10 as an important target for prediction of liver cancer diagnosis and immunotherapy.

Huang S, Tu T Front Immunol. 2025; 15():1534723.

PMID: 39840058 PMC: 11747724. DOI: 10.3389/fimmu.2024.1534723.

References

Rimini M, Kudo M, Tada T, Shigeo S, Kang W, Suda G . Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib. ESMO Open. 2021; 6(6):100330. PMC: 8710492. DOI: 10.1016/j.esmoop.2021.100330. View

Lai S, Gundlapalli H, Ekiz H, Jiang A, Fernandez E, Welm A . Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression. Cancer Discov. 2021; 11(12):3178-3197. PMC: 8800951. DOI: 10.1158/2159-8290.CD-20-1172. View

Meldolesi J . Alternative Splicing by NOVA Factors: From Gene Expression to Cell Physiology and Pathology. Int J Mol Sci. 2020; 21(11). PMC: 7312376. DOI: 10.3390/ijms21113941. View

Katoh M, Katoh M . WNT signaling and cancer stemness. Essays Biochem. 2022; 66(4):319-331. PMC: 9484141. DOI: 10.1042/EBC20220016. View

Dianat-Moghadam H, Sharifi M, Salehi R, Keshavarz M, Shahgolzari M, Amoozgar Z . Engaging stemness improves cancer immunotherapy. Cancer Lett. 2022; 554:216007. DOI: 10.1016/j.canlet.2022.216007. View

Najafi M, Mortezaee K, Majidpoor J . Cancer stem cell (CSC) resistance drivers. Life Sci. 2019; 234:116781. DOI: 10.1016/j.lfs.2019.116781. View

Gerstberger S, Hafner M, Tuschl T . A census of human RNA-binding proteins. Nat Rev Genet. 2014; 15(12):829-45. PMC: 11148870. DOI: 10.1038/nrg3813. View

Knupp D, Cooper D, Saito Y, Darnell R, Miura P . NOVA2 regulates neural circRNA biogenesis. Nucleic Acids Res. 2021; 49(12):6849-6862. PMC: 8266653. DOI: 10.1093/nar/gkab523. View

Xiang D, Sun W, Zhou T, Zhang C, Cheng Z, Li S . Oncofetal HLF transactivates c-Jun to promote hepatocellular carcinoma development and sorafenib resistance. Gut. 2019; 68(10):1858-1871. DOI: 10.1136/gutjnl-2018-317440. View

10.

Re A, Joshi T, Kulberkyte E, Morris Q, Workman C . RNA-protein interactions: an overview. Methods Mol Biol. 2014; 1097:491-521. DOI: 10.1007/978-1-62703-709-9_23. View

11.

Gao Y, You M, Fu J, Tian M, Zhong X, Du C . Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. J Hepatol. 2021; 76(1):148-159. DOI: 10.1016/j.jhep.2021.08.029. View

12.

Gordan J, Kennedy E, Abou-Alfa G, Beg M, Brower S, Gade T . Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020; 38(36):4317-4345. DOI: 10.1200/JCO.20.02672. View

13.

Bayik D, Lathia J . Cancer stem cell-immune cell crosstalk in tumour progression. Nat Rev Cancer. 2021; 21(8):526-536. PMC: 8740903. DOI: 10.1038/s41568-021-00366-w. View

14.

Wang J, Yu H, Dong W, Zhang C, Hu M, Ma W . N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways. Gastroenterology. 2023; 164(6):990-1005. DOI: 10.1053/j.gastro.2023.01.041. View

15.

Ganesan P, Kulik L . Hepatocellular Carcinoma: New Developments. Clin Liver Dis. 2022; 27(1):85-102. DOI: 10.1016/j.cld.2022.08.004. View

16.

Fang Z, Mei W, Qu C, Lu J, Shang L, Cao F . Role of m6A writers, erasers and readers in cancer. Exp Hematol Oncol. 2022; 11(1):45. PMC: 9361621. DOI: 10.1186/s40164-022-00298-7. View

17.

Cappuyns S, Corbett V, Yarchoan M, Finn R, Llovet J . Critical Appraisal of Guideline Recommendations on Systemic Therapies for Advanced Hepatocellular Carcinoma: A Review. JAMA Oncol. 2023; 10(3):395-404. PMC: 10837331. DOI: 10.1001/jamaoncol.2023.2677. View

18.

Corley M, Burns M, Yeo G . How RNA-Binding Proteins Interact with RNA: Molecules and Mechanisms. Mol Cell. 2020; 78(1):9-29. PMC: 7202378. DOI: 10.1016/j.molcel.2020.03.011. View

19.

Sendinc E, Shi Y . RNA m6A methylation across the transcriptome. Mol Cell. 2023; 83(3):428-441. DOI: 10.1016/j.molcel.2023.01.006. View

20.

You Q, Li R, Yao J, Zhang Y, Sui X, Xiao C . Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity. Med Oncol. 2024; 41(3):75. DOI: 10.1007/s12032-023-02295-0. View