{"title":"Overexpression of HNF4G can Increase the Resistance of Ovarian Cancer Cells to Olaparib.","authors":"Ying Dong, Yue Deng, Huilin Yang, Youfang Hou, Qin Zhang, Lihua Yang","doi":"10.2174/0115680096410121250926110350","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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 resistance poses a significant challenge for OV maintenance therapy. Previous studies have indicated that HNF4G functions as an oncogene in various tumors, but its role in OV development and Olaparib resistance remains unexplored.</p><p><strong>Methods: </strong>We established an Olaparib-resistant OV cell line, SKOV3-PARPi, from the parental SKOV3 cell line. The impact of HNF4G on SKOV3 cell resistance to Olaparib was investigated 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.</p><p><strong>Results: </strong>Prolonged Olaparib exposure induced acquired resistance in SKOV3 cells. Compared to parental OV cells, HNF4G expression was upregulated in Olaparib-resistant cells. Overexpression of HNF4G enhanced Olaparib resistance in OV cells, whereas HNF4G knockdown diminished it. Furthermore, increased protein levels of components within the PI3K-AKT signaling 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.</p><p><strong>Conclusion: </strong>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 therapeutic target for patients with Olaparib-resistant OV.</p>","PeriodicalId":10816,"journal":{"name":"Current cancer drug targets","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current cancer drug targets","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/0115680096410121250926110350","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 resistance poses a significant challenge for OV maintenance therapy. Previous studies have indicated that HNF4G functions as an oncogene in various tumors, but its role in OV development and Olaparib resistance remains unexplored.
Methods: We established an Olaparib-resistant OV cell line, SKOV3-PARPi, from the parental SKOV3 cell line. The impact of HNF4G on SKOV3 cell resistance to Olaparib was investigated 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.
Results: Prolonged Olaparib exposure induced acquired resistance in SKOV3 cells. Compared to parental OV cells, HNF4G expression was upregulated in Olaparib-resistant cells. Overexpression of HNF4G enhanced Olaparib resistance in OV cells, whereas HNF4G knockdown diminished it. Furthermore, increased protein levels of components within the PI3K-AKT signaling 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 therapeutic target for patients with Olaparib-resistant OV.
期刊介绍：
Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes and genes.
Current Cancer Drug Targets publishes original research articles, letters, reviews / mini-reviews, drug clinical trial studies and guest edited thematic issues written by leaders in the field covering a range of current topics on drug targets involved in cancer.
As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.
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