Background/Objective:Ovarian cancer (OC) is one of the most lethal gynecological cancers, having a worldwide mortality rate of 66% in 2020. The overall 5-year relative survival rate is only 21% for distant stages, due to the lack of early diagnosis. Epithelial OC, the most common high-grade serous carcinoma, carries p53 mutations in most cases. However, we found that the immediate early response 5 gene (IER5), a p53 target gene, is overexpressed in ovarian cancer cells. The molecular mechanism underlying the role of IER5 in OC has not been well studied. We previously reported that IER5 promotes the dephosphorylation and activation of heat shock factor-1 (HSF1), the master regulator of proteostasis, which induces heat shock protein (HSP) expression.Methods/Results:Here we show thatIer5mRNA expression is higher in ovarian cancer cells (MOV, ID8G, and HM-1) compared to normal ovarian cells. We also show that OC cells floating in the ascites have higherIer5expression than the parental strain. Knockdown ofIer5suppressed HSP upregulation and proliferation of OC, while overexpression of IER5 promoted HSP upregulation. Knockdown ofHsf1showed results similar toIer5knockdown.Conclusions: These results indicate that the IER5-HSF1 pathway contributes to the proliferation and peritoneal dissemination of OC cells. We also found that higher expression ofIER5family genes is related to poorer prognosis of OC patients, suggesting the potential of the IER5 gene family as diagnostic markers for OC, as well as potential therapeutic targets.
背景/目的：卵巢癌是最致命的妇科恶性肿瘤之一，2020年全球死亡率达66%。由于缺乏早期诊断手段，远端转移期患者的5年相对生存率仅为21%。上皮性卵巢癌中最常见的高级别浆液性癌大多携带p53基因突变。然而我们发现p53靶基因——即刻早期反应5基因在卵巢癌细胞中呈现过表达现象。IER5在卵巢癌中的作用机制尚未明确。我们前期研究发现IER5能促进蛋白质稳态主调控因子热休克因子1的去磷酸化激活，进而诱导热休克蛋白表达。 方法/结果：本研究发现卵巢癌细胞系（MOV、ID8G、HM-1）中Ier5 mRNA表达水平显著高于正常卵巢细胞。腹水悬浮的卵巢癌细胞较亲本株系呈现更高的Ier5表达。敲低Ier5可抑制热休克蛋白上调及卵巢癌细胞增殖，而过表达IER5则促进热休克蛋白表达。Hsf1基因敲低实验呈现与Ier5敲低相似的表型。 结论：IER5-HSF1信号通路促进卵巢癌细胞增殖及腹膜播散。IER5家族基因高表达与卵巢癌患者不良预后显著相关，提示该基因家族具有作为卵巢癌诊断标志物及潜在治疗靶点的价值。
IER5 Promotes Ovarian Cancer Cell Proliferation and Peritoneal Dissemination
肿瘤(癌症)患者之家