NOVA2 regulates the properties of liver cancer stem cells and lenvatinib resistance in hepatocellular carcinoma via the Wnt pathway.

Autor:	Cao JZ; Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China., Wang CQ; Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China., Shi Z; Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China., Song JY; Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China., Tustumi F; Department of Gastroenterology, Digestive Surgery Division, University of São Paulo Medical School, Sao Paulo, Brazil., de Castria TB; Moffitt Cancer Center, Tampa, FL, USA.; Morsani College of Medicine, University of South Florida, Tampa, FL, USA., Wu J; Division of Hematology and Oncology, Perlmutter Cancer Center of NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA., Pocha C; Sanford School of Medicine, University of South Dakota, Avera Hepatology and Transplant, Sioux Falls, SD, USA., Tsilimigras DI; Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA., Wang ZH; The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China., Tao T; Department of Endocrinology and Metabolism, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China., Lu J; Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, China.
Jazyk:	angličtina
Zdroj:	Journal of gastrointestinal oncology [J Gastrointest Oncol] 2024 Aug 31; Vol. 15 (4), pp. 1674-1685. Date of Electronic Publication: 2024 Aug 01.
DOI:	10.21037/jgo-24-145
Abstrakt:	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). In vitro 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 (m 6 A) 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. Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-145/coif). T.B.d.C. received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme Corp, Astra-Zeneca, MD Health Brasil, and Remedy Health Group, support for attending meetings and travel from Ipsen and A2Bio, and payment for participation in Advisory Board from Ipsen and Moderna. The other authors have no conflicts of interest to declare. (2024 Journal of Gastrointestinal Oncology. All rights reserved.)
Databáze:	MEDLINE
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