Overexpression of HNF4G can Increase the Resistance of Ovarian Cancer Cells to Olaparib

Introduction: Ovarian cancer (OV) is one of the most malignant gynecological cancers. Poly(ADP-ribose) polymerase inhibitors (PARPi) represent the first-line maintenance therapy, effectively prolonging patient survival; however, the development of PARPi re-sistance poses a significant challenge for OV maintenance therapy. Previous studies have in-dicated that HNF4G functions as an oncogene in various tumors, but its role in OV develop-ment and Olaparib resistance remains unexplored. Methods: We established an Olaparib-resistant OV cell line, SKOV3-PARPi, from the paren-tal SKOV3 cell line. The impact of HNF4G on SKOV3 cell resistance to Olaparib was inves-tigated using qRT-PCR, CCK-8 assay, Transwell assay, colony formation assay, scratch assay, Western blot, flow cytometry, as well as a nude mouse xenograft tumor model and immuno-histochemistry. The function of HNF4G in SKOV3-Olaparib resistant cells was elucidated and subsequently validated through the animal tumor model. Result: Prolonged Olaparib exposure induced acquired resistance in SKOV3 cells. Compared to parental OV cells, HNF4G expression was upregulated in Olaparib-resistant cells. Overex-pression of HNF4G enhanced Olaparib resistance in OV cells, whereas HNF4G knockdown diminished it. Furthermore, increased protein levels of components within the PI3K-AKT sig-naling pathway were observed in Olaparib-resistant cells. Knocking down HNF4G expression in resistant cells significantly slowed tumor growth under Olaparib treatment. Changes in the protein levels of HNF4G and PI3K-AKT pathway components in the in vivo xenograft tumor tissues were consistent with the cellular observations. Conclusion: Overexpression of HNF4G plays a crucial role in conferring Olaparib resistance in OV by activating the PI3K-AKT signaling pathway. HNF4G may serve as a potential ther-apeutic target for patients with Olaparib-resistant OV.