Department of Pathology, University of Hong Kong, Queen Mary Hospital, Special Administrative Region of China, Hong Kong, China.
Oncogene. 2013 Jul 25;32(30):3500-9. doi: 10.1038/onc.2012.363. Epub 2012 Sep 3.
Ovarian cancer is the most lethal of all gynecological malignancies, and the identification of novel prognostic and therapeutic targets for ovarian cancer is crucial. It is believed that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. NANOG is one of the key transcription factors essential for maintaining self-renewal and pluripotency in stem cells. This study investigated the role of NANOG in ovarian carcinogenesis and showed overexpression of NANOG mRNA and protein in the nucleus of ovarian cancers compared with benign ovarian lesions. Increased nuclear NANOG expression was significantly associated with high-grade cancers, serous histological subtypes, reduced chemosensitivity, and poor overall and disease-free survival. Further analysis showed NANOG is an independent prognostic factor for overall and disease-free survival. Moreover, NANOG was highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Stable knockdown of NANOG impeded ovarian cancer cell proliferation, migration and invasion, which was accompanied by an increase in mRNA expression of E-cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1. Conversely, ectopic NANOG overexpression enhanced ovarian cancer cell migration and invasion along with decreased E-cadherin, caveolin-1, FOXO1, FOXO3a, FOXJ1 and FOXB1 mRNA expression. Importantly, we found Nanog-mediated cell migration and invasion involved its regulation of E-cadherin and FOXJ1. This is the first report revealing the association between NANOG expression and clinical outcome of patients with ovarian cancers, suggesting NANOG to be a potential prognostic marker and therapeutic molecular target in ovarian cancer.
卵巢癌是所有妇科恶性肿瘤中致死率最高的，因此寻找新的卵巢癌预后和治疗靶点至关重要。目前认为只有一小部分癌细胞具有干细胞特性，这些特性与肿瘤生长、转移进展和复发有关。NANOG 是维持干细胞自我更新和多能性的关键转录因子之一。本研究探讨了 NANOG 在卵巢癌发生中的作用，结果显示与良性卵巢病变相比，卵巢癌组织中 NANOG mRNA 和蛋白在细胞核中的表达上调。核内 NANOG 表达增加与高级别癌症、浆液性组织学亚型、化疗敏感性降低以及总生存期和无病生存期不良显著相关。进一步分析表明，NANOG 是总生存期和无病生存期的独立预后因素。此外，具有转移相关特性的卵巢癌细胞系和转移性病灶的临床样本中 NANOG 高表达。NANOG 稳定敲低可抑制卵巢癌细胞增殖、迁移和侵袭，同时 E-钙黏蛋白、小窝蛋白-1、FOXO1、FOXO3a、FOXJ1 和 FOXB1 的 mRNA 表达增加。相反，过表达 NANOG 可增强卵巢癌细胞的迁移和侵袭能力，同时降低 E-钙黏蛋白、小窝蛋白-1、FOXO1、FOXO3a、FOXJ1 和 FOXB1 的 mRNA 表达。重要的是，我们发现 Nanog 介导的细胞迁移和侵袭涉及它对 E-钙黏蛋白和 FOXJ1 的调节。这是首次报道 NANOG 表达与卵巢癌患者临床结局的相关性，表明 NANOG 可能成为卵巢癌潜在的预后标志物和治疗靶点。
