a Department of Otolaryngology Head and Neck Surgery , The First Affiliated Hospital of Zhengzhou University , Zhengzhou , Henan , China.
b Department of Head and Neck Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine , Central South University , Changsha , Hunan , China.
Cell Cycle. 2018;17(18):2284-2295. doi: 10.1080/15384101.2018.1526601. Epub 2018 Oct 9.
A different expression signature of miRNA in oral squamous cell carcinoma (OSCC) has been validated. MicroRNA-16 (miR-16) as one of the distinctly dysregulated miRNAs in OSCC, its functional role in progression of OSCC remains not fully clear. Herein, miR-16 expression was significantly lower in OSCC tissues compared to that in adjacent normal tissues (n = 131). A lower level of miR-16 was found to be associated with poor prognosis on a cohort of 131 patients with OSCC, and on an extensive public data (457) from TCGA database. Additionally, expression of TLK1 was significantly higher in OSCC tissues compared to that in adjacent normal tissues, which is negatively correlated with miR-16 expression in OSCC. Bioinformatics analyses exhibited that TLK1 is a potential downstream effector of miR-16 by directly targeting the 3'-untranslated regions (3'-UTR) of mRNA. Forced expression of miR-16 in OSCC cell lines inhibits cell proliferation in vitro, and tumor growth in vivo by inhibition of TLK1. Mechanistically, downregulation of TLK1 by miR-16 enhances higher level of DNA damage leading to a significant increase of G/M arrest in SCC9 cells. And, overexpression of TLK1 substantially reduces DNA damage and G/M arrest by activation of TLK1-dependent cell cycle checkpoint response. To conclude, miR-16 is downregulated in OSCC and serves as tumor suppressor in OSCC progression by targeting TLK1, which has potential to be the novel therapeutic targets and diagnostic biomarkers for OSCC.
在口腔鳞状细胞癌（OSCC）中已经验证了 miRNA 的不同表达特征。miR-16 作为 OSCC 中明显失调的 miRNA 之一，其在 OSCC 进展中的功能作用尚不完全清楚。在此，与相邻正常组织（n=131）相比，OSCC 组织中 miR-16 的表达显著降低。在 131 例 OSCC 患者的队列中，较低的 miR-16 水平与不良预后相关，在 TCGA 数据库的广泛公共数据（457）中也是如此。此外，与相邻正常组织相比，OSCC 组织中 TLK1 的表达明显更高，并且与 OSCC 中的 miR-16 表达呈负相关。生物信息学分析表明，TLK1 是 miR-16 的潜在下游效应子，通过直接靶向 mRNA 的 3'-非翻译区（3'-UTR）。在 OSCC 细胞系中强制表达 miR-16 可通过抑制 TLK1 来抑制体外细胞增殖和体内肿瘤生长。从机制上讲，miR-16 通过下调 TLK1 可导致 SCC9 细胞中 G/M 期阻滞显著增加，从而导致更高水平的 DNA 损伤。并且，TLK1 的过表达通过激活 TLK1 依赖性细胞周期检查点反应可大大减少 DNA 损伤和 G/M 期阻滞。总之，miR-16 在 OSCC 中下调，通过靶向 TLK1 作为 OSCC 进展中的肿瘤抑制因子，具有成为 OSCC 新型治疗靶点和诊断生物标志物的潜力。
