成纤维细胞生长因子 19 通过激活 MAPK 信号通路促进卵巢癌细胞自噬和顺铂耐药性。
FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer.
机构信息
Department of Pathology, Xiangya Hospital, Central South University, Changsha, China.
Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China.
出版信息
PeerJ. 2023 Feb 2;11:e14827. doi: 10.7717/peerj.14827. eCollection 2023.
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 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.
背景
化疗是卵巢癌患者的主要治疗方法之一。自噬与肿瘤细胞的化疗耐药性有关。最近的研究表明，成纤维细胞生长因子 19（FGF19）可能参与恶性肿瘤的发生和发展。然而，FGF19 与卵巢癌中的自噬之间的关系尚不清楚。
方法
对 62 例高级别浆液性卵巢癌（HGSOC）进行下一代测序（NGS）分析基因突变谱。荧光原位杂交（FISH）验证 HGSOC 组织中 FGF19 的扩增。实时定量 PCR（qPCR）和免疫组织化学（IHC）用于分析 FGF19 在 mRNA 和蛋白表达上的差异。同时，采用生物信息学技术分析 FGF19 的表达谱及其与预后的相关性。此外，免疫荧光、透射电子显微镜和细胞计数试剂盒 8（CCK-8）用于研究潜在机制。
结果
在这项研究中，我们发现 FGF19 通过诱导自噬促进卵巢癌细胞对顺铂的耐药性。对 62 例 HGSOC 病例的 NGS 分析发现了一个显著扩增的基因，FGF19。此外，卵巢癌样本中的 FGF19 表达水平高于正常样本。FISH 结果显示 FGF19 扩增与表达呈正相关。FGF19 敲低通过降低 LC3 和 Beclin 1 的表达，增加 SQSTM1/p62 的表达，抑制细胞自噬。此外，我们观察到 FGF19 敲低后 p38 MAPK 磷酸化下调。干扰素-γ（IFN-γ），一种潜在的 p38 MAPK 激活剂，可拮抗 FGF19 敲低对卵巢癌细胞自噬和顺铂抗增殖作用的抑制作用。
结论
FGF19 通过激活 p38 MAPK 通路增加卵巢癌中的自噬和化疗耐药性。这些结果表明 FGF19 可能成为卵巢癌的潜在治疗靶点。
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