NFATc3 plays an oncogenic role in oral/oropharyngeal squamous cell carcinomas by promoting cancer stemness via expression of OCT4.
NFATc3 plays an oncogenic role in oral/oropharyngeal squamous cell carcinomas by promoting cancer stemness via expression of OCT4.
复制标题
DOI：
10.18632/oncotarget.26774
复制
发表时间：
2019-03-19
期刊：
影响因子：
--
通讯作者：
Shin, Ki-Hyuk
中科院分区：
文献类型：
--
作者：
Lee, Sung Hee;Kieu, Calvin;Shin, Ki-Hyuk
活化T细胞核因子（NFATc 1-c4）是一个转录因子家族，通过调节下游靶基因参与多种生物学过程。然而，它们在癌症进展中的作用仍然存在争议。我们在这里报告，NFATc 3是NFAT在人类口腔上皮细胞中的主要亚型，其表达在口腔/口咽鳞状细胞癌（OSCC）的进展过程中逐步增加。更重要的是，NFATc 3高度富集在OSCC的自我更新癌症干细胞样细胞（CSC）中。NFATc 3的表达增加是CSC自我更新的维持所必需的，因为NFATc 3抑制抑制了OSCC细胞中肿瘤球的形成。相反，在非致瘤性永生化口腔上皮细胞中异位表达NFATc 3导致获得自我更新和CSC表型增加，例如增强的ALDH 1HIGH细胞群体、移动性和耐药性，表明NFATc 3在CSC表型维持中的功能作用。NFATc 3表达也将非致瘤性口腔上皮细胞转化为恶性表型。机制研究进一步揭示，NFATc 3结合到OCT 4的启动子上，OCT 4是一种干性转录因子，用于其激活，从而促进CSC表型。此外，在具有异位NFATc 3过表达和OSCC的细胞中抑制OCT 4废除CSC表型，并且异位OCT 4表达充分诱导CSC表型。我们的研究表明，NFATc 3通过新的NFATc 3-OCT 4轴在维持癌症干细胞性和OSCC进展中起重要作用，这表明该轴可能是OSCC CSC的潜在治疗靶点。
Nuclear factor of activated T cells (NFATc1-c4), a family of transcription factors, is involved in many biological processes by regulating various downstream target genes. However, their role in cancer progression remains controversial. We here report that NFATc3 is the dominant isoform of NFAT in human oral epithelial cells, and its expression was increased in a stepwise manner during the progression of oral/oropharyngeal squamous cell carcinoma (OSCC). More importantly, NFATc3 was highly enriched in self-renewing cancer stem-like cells (CSCs) of OSCC. Increased expression of NFATc3 was required for the maintenance of CSC self-renewal, as NFATc3 inhibition suppressed tumor sphere formation in OSCC cells. Conversely, ectopic NFATc3 expression in non-tumorigenic immortalized oral epithelial cells resulted in the acquisition of self-renewal and increase in CSC phenotype, such as enhanced ALDH1HIGH cell population, mobility and drug resistance, indicating the functional role of NFATc3 in the maintenance of CSC phenotype. NFATc3 expression also converted the non-tumorigenic oral epithelial cells to malignant phenotypes. Mechanistic investigations further reveal that NFATc3 binds to the promoter of OCT4, a stemness transcription factor, for its activation, thereby promoting CSC phenotype. Moreover, suppression of OCT4 abrogated CSC phenotype in the cell with ectopic NFATc3 overexpression and OSCC, and ectopic OCT4 expression sufficiently induced CSC phenotype. Our study indicates that NFATc3 plays an important role in the maintenance of cancer stemness and OSCC progression via novel NFATc3-OCT4 axis, suggesting that this axis may be a potential therapeutic target for OSCC CSCs.