Quantitative Proteomic Profiling Identifies SOX8 as Novel Regulator of Drug Resistance in Gestational Trophoblastic Neoplasia

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.

SOX8 Affects Tumoral SPARC Expression by Regulating EZH2 to Attenuate Effectiveness of albumin-bound paclitaxel in PDAC

“…It has been reported to be overexpressed and acts as an oncogene in liver cancer 16 and breast cancer 9 . Notably, SOX8 plays an important role in chemotherapy resistance of gestational trophoblastoma, and it participates in multiple drug-resistant pathways 17 . In the present study, we found that PDAC patients with high SOX8 expression exhibited poor response to albumin-bound paclitaxel chemotherapy through cohort study and validation of our hospital PDAC cancer tissue.…”

SLAMF1 Promotes Methotrexate Resistance via Activating Autophagy in Choriocarcinoma Cells

“…Soft agar clonogenesis assay was used to examine the clonogenesis potential of choriocarcinoma cells as we described previously. 21 After incubation with or without MTX for 10~12 days, the colonies (>50 cells) were counted.…”