DTX3L promotes ovarian cancer progression and cisplatin resistance by activating JAK1/STAT1/OAS3 pathway.

Ovarian cancer is the third most prevalent malignancy of the female reproductive system. Due to its insidious early symptoms, most patients are diagnosed at an advanced stage and have a poor prognosis, highlighting an urgent need for more effective therapeutic strategies. Deltex E3 ubiquitin ligase 3 L (DTX3L), also known as B-lymphoma and BAL-associated protein (BBAP), is an E3 ubiquitin ligase reported to be critical in the progression of various tumors. However, the specific mechanisms underlying the role of DTX3L in ovarian cancer tumorigenesis and progression remain poorly understood. Bioinformatics tools, including GEPIA, GEO, TCGA, Kaplan-Meier Plotter, JASPAR, and STRING, were employed to analyze the expression profiles of DTX3L and 2’-5’-oligoadenylate synthetase 3 (OAS3) in ovarian cancer tissues and normal ovarian tissues, as well as to predict correlations between DTX3L and the JAK1/STAT1/OAS3 signaling axis. At the tissue level, immunohistochemistry (IHC), polymerase chain reaction (PCR), and Western blotting (WB) were conducted to detect the expression of DTX3L and OAS3 in normal ovarian tissues, benign ovarian tumors, borderline ovarian tumors, and ovarian cancer tissues. At the cellular level, ovarian cancer cell lines (A2780, SKOV3, and OVCAR3)assays, CCK-8 assays, wound healing assays, Transwell assays, TUNEL assays, and flow cytometry were performed to assess the effects of altered DTX3L expression on ovarian cancer cell proliferation, migration, invasion, and chemoresistance. Immunofluorescence (IF), PCR, and WB were employed to examine the regulatory effects of DTX3L knockdown or overexpression on OAS3 expression. Additionally, WB was used to evaluate the activation status of the JAK1/STAT1 pathway following manipulation of DTX3L expression. A rescue experiment was conducted to investigate changes in OAS3 expression and the biological behaviors of ovarian cancer cells after simultaneous DTX3L overexpression and inhibition of JAK1 activation. In vivo, nude mouse xenograft models of ovarian cancer with stable DTX3L knockdown or overexpression were established. Tumor growth curves were plotted, and IHC, PCR, and WB were performed to measure DTX3L and OAS3 expression levels in xenograft tumors from each group. DTX3L and OAS3 were highly expressed in ovarian cancer tissues and cell lines. High DTX3L expression promoted proliferation, migration, and invasion of ovarian cancer cells, enhanced resistance to cisplatin, and inhibited apoptosis. Mechanistically, DTX3L upregulated OAS3 expression by activating the JAK1/STAT1 signaling pathway. Inhibition of JAK1/STAT1 signaling partially reversed the oncogenic effects induced by DTX3L overexpression. In vivo experiments showed that DTX3L knockdown suppressed ovarian cancer growth and decreased OAS3 expression in xenograft tumors. DTX3L acts as a potential oncogene in ovarian cancer by inducing OAS3 overexpression via activation of the JAK1/STAT1 signaling pathway, thereby promoting ovarian cancer progression and cisplatin resistance. Collectively, DTX3L holds promise as a biomarker for ovarian cancer diagnosis and prognosis, and represents a novel therapeutic target for ovarian cancer treatment.