Down-regulation of UTP23 promotes paclitaxel resistance and predicts poorer prognosis in ovarian cancer

Objective: Frequent resistance to paclitaxel and carboplatin based chemotherapy remains a therapeutic challenge in ovarian cancer. UTP23, a small sub-unit processome component, is down-regulated in a paclitaxel-resistant cell line SKOV3-TR30 compared with its parental SKOV3 cells based on our previous study. However, the specific mechanism of UTP23 in regulating ovarian cancer chemotherapy resistance remains largely unknown.

Methods: Immunohistochemical (IHC) staining was used to measure UTP23 expression in 133 ovarian cancer tissues. Then we used short hairpin RNA (shRNA), over-expression plasmid and cell counting kit-8 (CCK-8) assay to evaluate the function of UTP23 on modulating paclitaxel resistance in ovarian cancer. RNA-sequencing (RNA-seq) was used to find targeted downstream molecular of UTP23. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were utilized to detect related genes expression.

Results: We confirmed that UTP23 was down-regulated in both SKOV3-TR30 and A2780-TR cells compared with their parental cells. Decreased UTP23 expression was observed in ovarian cancer tissues with paclitaxel resistance. Moreover, lower expression of UTP23 was tightly correlated with patients of worse prognosis. Further UTP23 silence by shRNA increased paclitaxel resistance in SKOV3 and A2780 cells. And UTP23 over-expression by plasmid decreased paclitaxel resistance in SKOV3-TR30 and A2780-TR cells. Additionally, RNA-seq and qRT-PCR validation revealed that growth differentiation factor 15 (GDF15) was probably a downstream target for UTP23. GDF15 was notably up-regulated upon the depletion of UTP23 in both SKOV3 and A2780 cells.

Conclusion: Our findings elucidated a previously unknown function for UTP23 in regulating paclitaxel sensitivity and UTP23 could serve as a potential prognostic predictor for ovarian cancer.