Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109-2800, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2800, USA.
Theranostics. 2019 Jul 28;9(19):5478-5496. doi: 10.7150/thno.33444. eCollection 2019.
Inhibiting STAT3 signaling reduces tumor progression, metastasis and chemoresistance, however the precise molecular mechanism has not been fully delineated in ovarian cancer.
In this study, we generated knockout (KO) ovarian cancer cell lines. Effects of KO on cell proliferation, migration and spheroid formation were assessed and effects on tumor growth were tested using several tumor xenograft models. We used multi-omic genome-wide profiling to identify multi-level (Bru-Seq, RNA-Seq, and MS Proteomic) expression signatures of KO ovarian cancer cells.
We observed that deletion of blocked cell proliferation and migration and suppressed tumor growth in mice. Deletion of transcriptionally suppressed key genes involved in EMT, cell cycle progression, E2F signaling, and altered stemness markers. Notably, KO of resulted in modulation of the expression of other STAT family members.
Our study presents a rich, multi-faceted summary of the molecular mechanisms impacted by deletion and provides new insight for 's potential as a therapeutic target in ovarian cancer.
抑制 STAT3 信号通路可降低肿瘤的进展、转移和化疗耐药性，但在卵巢癌中，其确切的分子机制尚未完全阐明。
在本研究中，我们生成了 STAT3 缺失（KO）卵巢癌细胞系。通过检测细胞增殖、迁移和球体形成，评估了 STAT3 KO 对细胞的影响，并通过多种肿瘤异种移植模型检测了 STAT3 KO 对肿瘤生长的影响。我们使用多组学全基因组谱分析来鉴定 STAT3 KO 卵巢癌细胞的多层次（Bru-Seq、RNA-Seq 和 MS 蛋白质组学）表达特征。
我们发现，STAT3 的缺失阻断了细胞的增殖和迁移，并抑制了小鼠体内的肿瘤生长。STAT3 的缺失转录抑制了 EMT、细胞周期进程、E2F 信号和改变的干性标志物中涉及的关键基因。值得注意的是，STAT3 的缺失导致其他 STAT 家族成员的表达发生变化。
我们的研究全面、多方面地总结了 STAT3 缺失所影响的分子机制，并为 STAT3 作为卵巢癌治疗靶点的潜力提供了新的见解。
