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

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          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.

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          Most cited references36

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          Autophagy in the pathogenesis of disease.

          Beth Levine, Guido Kroemer (2008)
          Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development, and homeostasis. Autophagy principally serves an adaptive role to protect organisms against diverse pathologies, including infections, cancer, neurodegeneration, aging, and heart disease. However, in certain experimental disease settings, the self-cannibalistic or, paradoxically, even the prosurvival functions of autophagy may be deleterious. This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
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            Evolution of the Fgf and Fgfr gene families.

            Nobuyuki Itoh, David M. Ornitz (2004)
            Fibroblast growth factors (Fgfs) and Fgf receptors (Fgfrs) comprise a signaling system that is conserved throughout metazoan evolution. Twenty-two Fgfs and four Fgfrs have been identified in humans and mice. During evolution, the Fgf family appears to have expanded in two phases. In the first phase, during early metazoan evolution, Fgfs expanded from two or three to six genes by gene duplication. In the second phase, during the evolution of early vertebrates, the Fgf family expanded by two large-scale gen(om)e duplications. By contrast, the Fgfr family has expanded only in the second phase. However, the acquisition of alternative splicing by Fgfrs has increased their functional diversity. The mechanisms that regulate alternative splicing have been conserved since the divergences of echinoderms and vertebrates. The expansion of the Fgf and Fgfr gene families has enabled this signaling system to acquire functional diversity and, therefore, an almost ubiquitous involvement in developmental and physiological processes.
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              Autophagy contributes to resistance of tumor cells to ionizing radiation.

              Hassan Chaachouay, Petra A. Ohneseit, Mahmoud Toulany … (2011)
              Autophagy signaling is a novel important target to improve anticancer therapy. To study the role of autophagy on resistance of tumor cells to ionizing radiation (IR), breast cancer cell lines differing in their intrinsic radiosensitivity were used. Breast cancer cell lines MDA-MB-231 and HBL-100 were examined with respect to clonogenic cell survival and induction of autophagy after radiation exposure and pharmacological interference of the autophagic process. As marker for autophagy the appearance of LC3-I and LC3-II proteins was analyzed by SDS-PAGE and Western blotting. Formation of autophagic vacuoles was monitored by immunofluorescence staining of LC3. LC3-I and LC3-II formation differs markedly in radioresistant MDA-MB-231 versus radiosensitive HBL-100 cells. Western blot analyses of LC3-II/LC3-I ratio indicated marked induction of autophagy by IR in radioresistant MDA-MB-231 cells, but not in radiosensitive HBL-100 cells. Indirect immunofluorescence analysis of LC3-II positive vacuoles confirmed this differential effect. Pre-treatment with 3-methyladenine (3-MA) antagonized IR-induced autophagy. Likewise, pretreatment of radioresistant MDA-231 cells with autophagy inhibitors 3-MA or chloroquine (CQ) significantly reduced clonogenic survival of irradiated cells. Our data clearly indicate that radioresistant breast tumor cells show a strong post-irradiation induction of autophagy, which thus serves as a protective and pro-survival mechanism in radioresistance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Contributors
                Yuanliang Yan:
                ORCID: http://orcid.org/0000-0001-6610-3617
                Xiaoying Wu
                Journal
                Journal ID (nlm-ta): PeerJ
                Journal ID (iso-abbrev): PeerJ
                Journal ID (publisher-id): PeerJ
                Title: PeerJ
                Publisher: PeerJ Inc. (San Diego, USA )
                ISSN (Electronic): 2167-8359
                Publication date (Electronic): 2 February 2023
                Publication date Collection: 2023
                Volume: 11
                Electronic Location Identifier: e14827
                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
                Author information
                http://orcid.org/0000-0001-6610-3617
                Article
                Publisher ID: 14827
                DOI: 10.7717/peerj.14827
                PMC ID: 9899438
                SO-VID: 9692a1a5-1875-4525-82f3-e4ae02b5883b
                Copyright © © 2023 Zhu et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                History
                Date received : 13 October 2022
                Date accepted : 9 January 2023
                Funding
                Funded by: Hunan Provincial Natural Science Foundation of China
                Award ID: 2019JJ40394
                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.
                Categories
                Subject: Biochemistry
                Subject: Cell Biology
                Subject: Computational Biology
                Subject: Molecular Biology
                Subject: Oncology

                Keywords: ovarian cancer,autophagy,fgf19,mapk,chemoresistance
                Data availability:
                Keywords: ovarian cancer, autophagy, fgf19, mapk, chemoresistance

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