FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer

Wei Zhu; Meiyuan Huang; Abhimanyu Thakur; Yuanliang Yan; Xiaoying Wu

doi:10.7717/peerj.14827

FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer

PeerJ. 2023 Feb 2:11:e14827. doi: 10.7717/peerj.14827. eCollection 2023.

Authors

Wei Zhu^{1

2}, Meiyuan Huang³, Abhimanyu Thakur⁴, Yuanliang Yan^{5

6}, Xiaoying Wu^{1

2

6}

Affiliations

¹ Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
² Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China.
³ Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China.
⁴ Pritzker School of Molecular Engineering, Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA.
⁵ Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China.
⁶ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Background: Chemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown.

Methods: Next-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms.

Results: In this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells.

Conclusion: FGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.

Keywords: Autophagy; Chemoresistance; FGF19; MAPK; Ovarian cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Autophagy
Cell Line, Tumor
Cisplatin
Drug Resistance, Neoplasm
Female
Fibroblast Growth Factors / genetics
Humans
In Situ Hybridization, Fluorescence
Ovarian Neoplasms* / drug therapy

Substances

Cisplatin
Antineoplastic Agents
FGF19 protein, human
Fibroblast Growth Factors

Grants and funding

This work was supported by the Hunan Provincial Natural Science Foundation of China (2019JJ40394). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.