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Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic
Fu Jun1,2, Zheng Peng3,4, Yi Zhang3,4
1Department of Oncology, Xiangya Hospital, Central South University, Changsha, China.
Abstract:
The development of drug resistance remains one of the major challenges to current chemotherapeutic regimens in gestational trophoblastic neoplasia (GTN). Further understanding on the mechanisms of drug resistance would help to develop more effective therapy to treat GTN. Herein, tandem mass tag-based (TMT) quantitative proteomic technique was used to establish drug resistance-related proteomic profiles in chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu). In total, we identified 5,704 protein groups, among which 4,997 proteins were quantified in JEG3 and its chemoresistant sublines. Bioinformatics analysis revealed that multiple biological processes/molecular pathways/signaling networks were involved in the regulation of drug resistance in chemoresistant JEG3 sublines. SOX8 was upregulated in all the three chemoresistant sublines, and its function was further investigated. Knockdown of SOX8 significantly reduced cell viability, impaired soft agar clonogenesis, and increased caspase-3 activities after drug treatment in JEG3 chemoresistant sublines. In addition, over-expression of SOX8 promoted cell survival, enhanced soft agar clonogenesis, and attenuated caspase-3 activities after drug treatment in GTN cells. Importantly, SOX8 might be a potential regulator of reactive oxygen species (ROS) homeostasis, as SOX8 regulated the expression of antioxidant enzymes (GPX1, HMOX1) and reduced drug-induced ROS accumulation in GTN cell models. Collectively, SOX8 might promote drug resistance through attenuating the accumulation of ROS induced by chemotherapeutic drugs in GTN cells. Targeting SOX8 might be useful to sensitize GTN cells to chemotherapy.
Insights
Drug resistance in gestational trophoblastic neoplasia (GTN) is a major challenge. Understanding SOX8
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Drug resistance is a significant obstacle in treating gestational trophoblastic neoplasia (GTN).
- Understanding the molecular mechanisms underlying chemoresistance is crucial for developing effective therapies.
Purpose of the Study:
- To investigate proteomic profiles associated with drug resistance in GTN.
- To identify key regulatory factors involved in chemoresistance.
- To explore the functional role of SOX8 in GTN drug resistance.
Main Methods:
- Tandem mass tag (TMT)-based quantitative proteomics was employed.
- Chemoresistant GTN cell models (JEG3/MTX, JEG3/VP16, JEG3/5-Fu) were established.
- Bioinformatics analysis, gene knockdown, and overexpression studies were performed.
Main Results:
- Proteomic analysis identified 5,704 protein groups, revealing pathways involved in drug resistance.
- SOX8 was consistently upregulated in chemoresistant GTN cell lines.
- SOX8 knockdown decreased viability and increased apoptosis, while SOX8 overexpression promoted survival and reduced drug-induced reactive oxygen species (ROS).
Conclusions:
- SOX8 plays a critical role in promoting chemoresistance in GTN.
- SOX8 may confer drug resistance by regulating reactive oxygen species (ROS) homeostasis.
- Targeting SOX8 presents a potential strategy to sensitize GTN cells to chemotherapy.
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