Dai Lan, Wang Wenjing, Liu Yixuan, Song Keqi, Di Wen
Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Ann Transl Med. 2021 Apr;9(8):645. doi: 10.21037/atm-20-6742.
Epithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to evaluate further the expression characteristics and clinical significance of SphK2 in EOC and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival.
The expression of SphK2 was examined by immunohistochemistry (IHC) and Western blot, and its clinical implications and prognostic significance were analyzed. We performed a cellular proliferation assay, and a mouse xenograft model was established to confirm the roles of SphK2 and . Cell cycle analysis, apoptosis assay, and Western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA), and Western blot were used to investigate the downstream signaling pathways related to SphK2 function.
The expression level of SphK2 was shown to be associated with stage, histological grade, lymph node metastasis, and ascites status. More importantly, a high SphK2 expression level was a prognostic indicator of overall survival (OS) and relapse-free survival (RFS). Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited EOC cell proliferation both in vitro and in vivo. Furthermore, ERK/c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells.
Our findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating the ERK/c-Myc pathway. This indicated that SphK2 might serve as a prognostic marker and potential therapeutic target in EOC.
上皮性卵巢癌（EOC）是女性癌症死亡的主要原因。在我们之前的研究中，鞘氨醇激酶2（SphK2）抑制剂显示出抗EOC活性。本研究的目的是进一步评估SphK2在EOC中的表达特征和临床意义，并探讨SphK2在EOC细胞存活中的作用及潜在机制。
通过免疫组织化学（IHC）和蛋白质印迹法检测SphK2的表达，并分析其临床意义和预后意义。我们进行了细胞增殖试验，并建立了小鼠异种移植模型以证实SphK2的作用。进行细胞周期分析、凋亡检测和蛋白质印迹法以检测细胞周期进程和凋亡率。基因集富集分析（GSEA）和蛋白质印迹法用于研究与SphK2功能相关的下游信号通路。
SphK2的表达水平与分期、组织学分级、淋巴结转移和腹水状态相关。更重要的是，高SphK2表达水平是总生存期（OS）和无复发生存期（RFS）的预后指标。此外，敲低SphK2可在体外和体内阻止细胞周期进程并抑制EOC细胞增殖。此外，ERK/c-Myc是EOC进展中的关键通路，对SphK2介导的EOC细胞促有丝分裂作用很重要。
我们的研究结果首次证明SphK2通过调节ERK/c-Myc通路在EOC增殖中起关键作用。这表明SphK2可能作为EOC的预后标志物和潜在治疗靶点。
