Table_4_Splicing Factor DDX23, Transcriptionally Activated by E2F1, Promotes Ovarian Cancer Progression by Regulating FOXM1.xlsx

Ovarian carcinoma remains the most lethal gynecological carcinoma. Abnormal expression of splicing factors is closely related to the occurrence and development of tumors. The DEAD-box RNA helicases are important members of the splicing factor family. However, their role in the occurrence and progression of ovarian cancer is still unclear. In this study, we identified DEAD-box helicase 23 (DDX23) as a key DEAD-box RNA helicase in ovarian cancer using bioinformatics methods. We determined that DDX23 was upregulated in ovarian cancer and its high expression predicted poor prognosis. Functional assays indicated that DDX23 silencing significantly impeded cell proliferation/invasion in vitro and tumor growth in vivo. Mechanistically, transcriptomic analysis showed that DDX23 was involved in mRNA processing in ovarian cancer cells. Specifically, DDX23 regulated the mRNA processing of FOXM1. DDX23 silencing reduced the production of FOXM1C, the major oncogenic transcript of FOXM1 in ovarian cancer, thereby decreasing the FOXM1 protein expression and attenuating the malignant progression of ovarian cancer. Rescue assays indicated that FOXM1 was a key executor in DDX23-induced malignant phenotype of ovarian cancer. Furthermore, we confirmed that DDX23 was transcriptionally activated by the transcription factor (TF) E2F1 in ovarian cancer using luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. In conclusion, our study demonstrates that high DDX23 expression is involved in malignant behavior of ovarian cancer and DDX23 may become a potential target for precision therapy of ovarian cancer.

卵巢癌（Ovarian carcinoma）仍是致死率最高的妇科恶性肿瘤。剪接因子（splicing factor）的异常表达与肿瘤的发生发展密切相关。DEAD-box RNA解旋酶（DEAD-box RNA helicases）是剪接因子家族的重要成员，但其在卵巢癌发生发展中的作用仍未明确。本研究通过生物信息学方法，将DEAD-box解旋酶23（DDX23）鉴定为卵巢癌中关键的DEAD-box RNA解旋酶。研究证实，DDX23在卵巢癌组织中呈高表达，且其高表达预示患者预后不良。功能实验结果显示，沉默DDX23可显著抑制卵巢癌细胞的体外增殖与侵袭能力，并阻滞体内肿瘤生长。机制研究表明，转录组学分析显示DDX23参与卵巢癌细胞的mRNA加工过程，具体而言，DDX23可调控FOXM1的mRNA加工：沉默DDX23可减少FOXM1C——FOXM1在卵巢癌中主要的致癌转录本——的生成，进而降低FOXM1蛋白的表达水平，削弱卵巢癌的恶性进展。挽救实验结果证实，FOXM1是DDX23诱导卵巢癌恶性表型的关键效应分子。此外，本研究通过荧光素酶报告基因实验与染色质免疫共沉淀（chromatin immunoprecipitation，ChIP）实验，证实转录因子（transcription factor，TF）E2F1可在卵巢癌中转录激活DDX23的表达。综上，本研究证实DDX23高表达参与卵巢癌的恶性生物学行为，DDX23有望成为卵巢癌精准治疗的潜在靶点。