Yuanliang Yan

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

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.

CRABP2 reduces the sensitivity of Olaparib in ovarian cancer by downregulating Caspase-8 and decreasing the production of reactive oxygen species

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, such as Olaparib, have been pivotal in treating BRCA-deficient ovarian cancer. However, their efficacy is limited in over 40% of BRCA-deficient patients, with acquired resistance posing new clinical challenges. To address this, we employed bioinformatics methods to identify key genes impacting Olaparib sensitivity in ovarian cancer. Through comprehensive analysis of public databases including GEO, CPTAC, Kaplan Meier Plotter, and CCLE, we identified CRABP2 as significantly upregulated at both mRNA and protein levels in ovarian cancer, correlating with poor prognosis and decreased Olaparib sensitivity. Using colony formation and CCK-8 assays, we confirmed that CRABP2 knockdown in OVCAR3 and TOV112D cells enhanced sensitivity to Olaparib. Additionally, 4D label-free quantitative proteomics analysis, GSEA, and GO/KEGG analysis revealed CRABP2's involvement in regulating oxidation signals. Flow cytometry, colony formation assays, and western blotting demonstrated that CRABP2 knockdown promoted ROS production by activating Caspase-8, thereby augmenting Olaparib sensitivity and inhibiting ovarian cancer cell proliferation. Moreover, in xenograft models, CRABP2 knockdown significantly suppressed tumorigenesis and enhanced Olaparib sensitivity, with the effect being reversed upon Caspase-8 knockdown. These findings suggest that CRABP2 may modulate Olaparib sensitivity in ovarian cancer through the Caspase-8/ROS axis, highlighting its potential as a target for Olaparib sensitization.