TRAF4 promotes the malignancy of ovarian high-grade serous carcinoma by activating YAP pathway

Ovarian high-grade serous carcinoma (HGSC) accounts for the majority of deaths caused by epithelial ovarian cancer. The precise molecular changes attributable for the pathogenesis of HGSC are still largely unknown. TRAF4 has been identified to be up-regulated in some cancers. However, the association between TRAF4 and the malignancy of HGSC has not been elucidated before. In this study, we aim to explore the prognostic value and function of TRAF4 in HGSC. The results of immunohistochemistry in 174 cases of HGSC showed that high expression of TRAF4 was significantly associated with a shorter overall survival (p=0.005) and recurrence-free survival (p=0.003) in HGSC. Knock-down of TRAF4 inhibited the malignancy of ovarian cancer cells, and over-expression of TRAF4 increased cell malignancy both in vitro and in vivo. Moreover, mechanism studies demonstrated that TRAF4 promoted cell malignancy by activating YAP pathway in HGSC. In conclusion, TRAF4 could be a prognostic biomarker for HGSC and increase HGSC cell malignancy by activating YAP pathway, which may serve as a potential therapeutic target for HGSC. Comparative gene expression profiling analysis of RNA-seq data for ovarian cancer cells and its knockdown derivatives (siTRAF4).

卵巢高级别浆液性癌（HGSC）是上皮性卵巢癌致死的主要病因。目前学界对其发病机制相关的精准分子改变仍知之甚少。肿瘤坏死因子受体相关因子4（TRAF4）已被证实于多种癌症中呈高表达，但此前尚未明确TRAF4与卵巢高级别浆液性癌恶性表型之间的关联。本研究旨在探究TRAF4在卵巢高级别浆液性癌中的预后价值与生物学功能。对174例卵巢高级别浆液性癌组织的免疫组化结果显示，TRAF4高表达与患者更短的总生存期（p=0.005）及无复发生存期（p=0.003）显著相关。敲低TRAF4可抑制卵巢癌细胞的恶性表型，而过表达TRAF4则在体外及体内实验中均增强了癌细胞的恶性程度。进一步的机制研究证实，TRAF4可通过激活YAP信号通路促进卵巢高级别浆液性癌细胞的恶性表型。综上，TRAF4可作为卵巢高级别浆液性癌的预后生物标志物，并通过激活YAP信号通路增强癌细胞恶性表型，有望成为该疾病潜在的治疗靶点。本数据集涵盖针对卵巢癌细胞及其TRAF4敲低衍生物（siTRAF4）的RNA测序（RNA-seq）数据所开展的比较基因表达谱分析。