Li Yingwei, Chen Zhongshao, Gao Yuehan, Liu Yanling, Gao Qianqian, Pu Yingying, Xiao Huimin, Diao Yuchao, Guo Li, Yuan Cunzhong, Yan Shi, Yang Ning, Kong Beihua
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Ji'nan, Shandong Province, China.
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Ji'nan, Shandong Province, China.
Oncogene. 2025 Apr 11. doi: 10.1038/s41388-025-03386-0.
Dysfunction or aberrant expression of DEAD-box RNA helicases might play a role in the initiation and progression of human cancers. Nevertheless, the key regulator and underlying molecular mechanism have yet to be fully elucidated in ovarian cancer. This study identified DDX39A as one of the prominently upregulated genes in ovarian cancer through a systematic analysis of RNA helicase expression profiles using the CPTAC and TCGA ovarian cancer datasets. High expression of DDX39A was confirmed in paraffin-embedded ovarian cancer samples. Specifically, elevated DDX39A expression was found to be associated with poor overall survival in ovarian cancer patients. Antisense oligonucleotide-mediated DDX39A silencing led to a decrease in the proliferation capacity of a CDX model and a PDX model. Furthermore, DDX39A expression is regulated by the splicing factor SNRPB. SNRPB depletion or DDX39A knockdown induced the retention of DDX39A introns 6 and 8 to generate the noncoding transcript DDX39A-209, which yielded premature termination codons and resulted in nonsense-mediated RNA decay and decreased expression of the DDX39A protein. DDX39A silencing reduced the proliferative and metastatic capacities of SNRPB-overexpressing cells, indicating that DDX39A mediates the oncogenic function of SNRPB in ovarian cancer cells. In addition, RNA-Seq data analysis revealed that DDX39A promotes the proliferation and metastasis of ovarian cancer cells through the regulation of exon skipping of ITGA6 to produce the oncogenic ITGA6A transcript. These findings suggest that the SNRPB/DDX39A/ITGA6 axis plays critically important role in the progression of ovarian cancer, which increases our understanding of the role of DEAD-box RNA helicases and provides a viable therapeutic target for ovarian cancer.
DEAD盒RNA解旋酶功能异常或表达异常可能在人类癌症的发生和发展中起作用。然而，在卵巢癌中，关键调节因子和潜在分子机制尚未完全阐明。本研究通过使用CPTAC和TCGA卵巢癌数据集对RNA解旋酶表达谱进行系统分析，确定DDX39A是卵巢癌中显著上调的基因之一。在石蜡包埋的卵巢癌样本中证实了DDX39A的高表达。具体而言，发现DDX39A表达升高与卵巢癌患者的总生存期较差有关。反义寡核苷酸介导的DDX39A沉默导致CDX模型和PDX模型的增殖能力下降。此外，DDX39A的表达受剪接因子SNRPB的调节。SNRPB缺失或DDX39A敲低诱导DDX39A内含子6和8保留，产生非编码转录本DDX39A-209，其产生过早终止密码子，导致无义介导的RNA降解和DDX39A蛋白表达降低。DDX39A沉默降低了SNRPB过表达细胞的增殖和转移能力，表明DDX39A介导SNRPB在卵巢癌细胞中的致癌功能。此外，RNA-Seq数据分析显示，DDX39A通过调节ITGA6外显子跳跃以产生致癌性ITGA6A转录本，促进卵巢癌细胞的增殖和转移。这些发现表明，SNRPB/DDX39A/ITGA6轴在卵巢癌进展中起至关重要的作用，这增加了我们对DEAD盒RNA解旋酶作用的理解，并为卵巢癌提供了一个可行的治疗靶点。
