Siraj Abdul K, Pratheeshkumar Poyil, Divya Sasidharan Padmaja, Parvathareddy Sandeep Kumar, Alobaisi Khadija A, Thangavel Saravanan, Siraj Sarah, Al-Badawi Ismail A, Al-Dayel Fouad, Al-Kuraya Khawla S
Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Front Pharmacol. 2020 Dec 3;11:598880. doi: 10.3389/fphar.2020.598880. eCollection 2020.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. Krupple-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in a variety of cancer types. However, its role and expression in EOC is not fully illustrated. Immunohistochemical analysis was performed to assess KLF5 protein expression in 425 primary EOC samples using tissue microarray. We also addressed the function of KLF5 in EOC and its interaction with signal transducer and activator of transcription 3 (STAT3) signaling pathway. We found that KLF5 overexpressed in 53% (229/425) of EOC samples, and is associated with aggressive markers. Forced expression of KLF5 enhanced cell growth in low expressing EOC cell line, MDAH2774. Conversely, knockdown of KLF5 reduced cell growth, migration, invasion and progression of epithelial to mesenchymal transition in KLF5 expressing cell lines, OVISE and OVSAHO. Importantly, silencing of KLF5 decreased the self-renewal ability of spheroids generated from OVISE and OVSAHO cell lines. In addition, downregulation of KLF5 potentiated the effect of cisplatin to induce apoptosis in these cell lines. These data reveals the pro-tumorigenic role of KLF5 in EOC and uncover its role in activation of STAT3 signaling pathway, suggesting the importance of KLF5 as a potential therapeutic target for EOC therapy.
上皮性卵巢癌（EOC）是最致命的妇科恶性肿瘤。尽管有目前的治疗和手术选择，但晚期EOC的预后仍然很差。在EOC的治疗中，迫切需要确定新的分子治疗靶点。Krupple样因子5（KLF5）是一种锌指转录因子，在多种癌症类型中高表达。然而，其在EOC中的作用和表达尚未完全阐明。本研究采用组织芯片对425例原发性EOC样本进行免疫组化分析，以评估KLF5蛋白的表达情况。我们还探讨了KLF5在EOC中的功能及其与信号转导和转录激活因子3（STAT3）信号通路的相互作用。我们发现，53%（229/425）的EOC样本中KLF5过表达，且与侵袭性标志物相关。在低表达的EOC细胞系MDAH2774中，强制表达KLF5可促进细胞生长。相反，在表达KLF5的细胞系OVISE和OVSAHO中，敲低KLF5可降低细胞生长、迁移、侵袭以及上皮-间质转化进程。重要的是，沉默KLF5可降低由OVISE和OVSAHO细胞系生成的球体的自我更新能力。此外，下调KLF5可增强顺铂在这些细胞系中诱导凋亡的作用。这些数据揭示了KLF5在EOC中的促肿瘤作用，并揭示了其在激活STAT3信号通路中的作用，表明KLF5作为EOC治疗潜在靶点的重要性。
