Department of Gynecology II, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, P. R. China.
Cancer Biol Ther. 2024 Dec 31;25(1):2427415. doi: 10.1080/15384047.2024.2427415. Epub 2024 Nov 12.
Ovarian cancer (OC) is recognized as the most lethal type of gynecological malignancy, making treatment options challenging. Discovering novel therapeutic targets will benefit OC patients. This study aimed to reveal the mechanism by which SRSF9 regulates OC progression. Cell proliferation was determined via CCK-8 assays, whereas cell migration and invasion were monitored via Transwell assays. Western blotting and qPCR assays were used to detect protein and mRNA alterations. RNA pull-down, RNA immunoprecipitation (RIP), and actinomycin D experiments were performed to investigate the relationships between SRSF9 and USP22. Co-IP was used to validate the interaction between USP22 and ZEB1. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were used to verify the regulatory effect of ZEB1 on the transcription of SRSF9. Subcutaneous xenograft models were established to evaluate the impact of SRSF9 on tumor development. Knockdown of SRSF9 significantly suppressed the proliferation, invasion, migration, tumorigenicity, and epithelial‒mesenchymal transition (EMT) of OC cells. SRSF9 can bind to USP22 mRNA, increasing its stability. Moreover, the overexpression of USP22 reversed the impact of SRSF9 silencing on malignant phenotypes. USP22 can mediate the deubiquitination of ZEB1, thereby enhancing the progression of OC. Furthermore, ZEB1 upregulated SRSF9 expression through transcriptional activation, thus establishing a positive feedback loop. SRSF9 enhanced the malignant characteristics of OC through a positive feedback loop of SRSF9/USP22/ZEB1. This functional circuit may help in the development of novel therapeutic approaches for treating OC.
卵巢癌 (OC) 是一种致命的妇科恶性肿瘤，其治疗选择具有挑战性。寻找新的治疗靶点将使 OC 患者受益。本研究旨在揭示 SRSF9 调节 OC 进展的机制。通过 CCK-8 测定法测定细胞增殖，通过 Transwell 测定法监测细胞迁移和侵袭。使用 Western blot 和 qPCR 测定法检测蛋白和 mRNA 变化。进行 RNA 下拉、RNA 免疫沉淀 (RIP) 和放线菌素 D 实验以研究 SRSF9 和 USP22 之间的关系。使用 Co-IP 验证 USP22 和 ZEB1 之间的相互作用。进行染色质免疫沉淀 (ChIP) 和双荧光素酶报告基因测定以验证 ZEB1 对 SRSF9 转录的调节作用。建立皮下异种移植模型以评估 SRSF9 对肿瘤发展的影响。SRSF9 的敲低显著抑制 OC 细胞的增殖、侵袭、迁移、致瘤性和上皮-间充质转化 (EMT)。SRSF9 可以与 USP22 mRNA 结合，增加其稳定性。此外，USP22 的过表达逆转了 SRSF9 沉默对恶性表型的影响。USP22 可以介导 ZEB1 的去泛素化，从而促进 OC 的进展。此外，ZEB1 通过转录激活上调 SRSF9 的表达，从而建立正反馈环。SRSF9 通过 SRSF9/USP22/ZEB1 的正反馈环增强 OC 的恶性特征。该功能回路可能有助于开发治疗 OC 的新治疗方法。
