Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial–mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC.

中文翻译：

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IL-6 和缺氧通过 IL-6/STAT3/HIF-1α 反馈回路协同促进 EMT 介导的上皮性卵巢癌侵袭

广泛的腹膜扩散和远处转移的能力是上皮性卵巢癌 (EOC) 死亡率的主要原因。越来越多的证据表明白细胞介素 6 (IL-6) 促进 EOC 中的肿瘤侵袭和迁移，尽管其分子机制仍有待完全阐明。同时，低氧微环境已被认为可通过触发几种癌症的上皮-间质转化 (EMT) 来引起转移。在这里，我们研究了 IL-6 和缺氧在两种 EOC 细胞系 A2780 细胞和 SKOV3 细胞中诱导 EMT 之间的协同作用。IL-6 的外源重组和质粒调节的 IL-6 自分泌产生均在 EOC 细胞中诱导 EMT 表型，其特征是 E-钙粘蛋白下调以及波形蛋白和 EMT 相关转录因子的表达上调。IL-6 和缺氧的联合作用比任何一种治疗对 EMT 的影响更显着。抑制缺氧诱导因子-1IL-6处理前的α（HIF-1 α）抑制了EOC细胞的EMT表型和侵袭能力，表明HIF-1 α在与IL-6相关的EMT调控通路中占据关键位置。在来自癌症基因组图谱数据集的 489 个卵巢样本中，发现 EMT 评分分别与 IL-6、信号转导和转录激活因子 3 (STAT3) 以及 HIF-1 α的 mRNA 水平呈正相关。接下来，化学抑制剂对上述分子的阻断逆转了由外源性或内源性 IL-6 诱导的 EMT 标志物蛋白质水平的改变。这些发现表明 IL-6 和 HIF-1 α之间存在正反馈回路，并通过 STAT3 信号诱导和维持 EMT 表型，这可能为 EOC 的预后预测和治疗靶点提供新的理论基础。