Yang Wei, Dou Changwei, Wang Yufeng, Jia Yuli, Li Chao, Zheng Xin, Tu Kangsheng
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Rep. 2015 Nov;34(5):2576-84. doi: 10.3892/or.2015.4210. Epub 2015 Aug 19.
Deregulation of microRNA-92a (miR-92a) has been reported in several human cancers and is associated with prognosis of patients. However, the clinical significance of miR-92a and the underlying mechanisms involved in hepatocarcinogenesis remain to be determined. The aim of the present study was to determine the role of miR-92a in hepatocellular carcinoma (HCC). The results showed that the expression of miR-92a was upregulated in HCC tissues as compared with matched tumor-adjacent tissues. A high expression of miR-92a was observed in HCC cell lines as compared with a non-transformed hepatic cell line. The gain- and loss-of-function studies revealed that miR-92a significantly promoted proliferation and cell cycle transition from G1 to S phase, and inhibited apoptosis of HCC cell in vitro. In tumor‑bearing nude mice, the downregulation of miR-92a suppressed tumor growth of HCC in vivo. miR-92a was inversely correlated with F-box and WD repeat domain-containing 7 (FBXW7) expression in HCC tissues. Furthermore, miR-92a negatively regulated FBXW7 abundance in HCC cells. In the present study, FBXW7 was identified as a direct target of miR-92a. Notably, alterations of FBXW7 expression abrogated the effects of miR-92a on HCC cell proliferation, cell cycle and apoptosis. Clinical association analysis revealed that a high expression of miR-92a was correlated with poor prognostic characteristics of HCC. Notably, the high expression of miR-92a conferred a reduced 5-year overall survival (OS) and recurrence-free survival (RFS) of HCC patients. The multivariate Cox regression analysis demonstrated that miR-92a expression was an independent prognostic marker for predicting survival of HCC patients. In conclusion, the results of the present study suggested that miR-92a promotes the tumor growth of HCC by targeting FBXW7 and may serve as a novel prognostic biomarker and therapeutic target for HCC.
已有报道称，几种人类癌症中存在微小RNA-92a（miR-92a）失调的情况，且其与患者的预后相关。然而，miR-92a的临床意义以及肝癌发生过程中的潜在机制仍有待确定。本研究的目的是确定miR-92a在肝细胞癌（HCC）中的作用。结果显示，与配对的癌旁组织相比，miR-92a在HCC组织中的表达上调。与未转化的肝细胞系相比，在HCC细胞系中观察到miR-92a的高表达。功能获得和功能缺失研究表明，miR-92a在体外显著促进HCC细胞增殖和从G1期到S期的细胞周期转变，并抑制HCC细胞凋亡。在荷瘤裸鼠中，miR-92a的下调抑制了体内HCC的肿瘤生长。miR-92a与HCC组织中含F盒和WD重复结构域7（FBXW7）的表达呈负相关。此外，miR-92a在HCC细胞中负向调节FBXW7的丰度。在本研究中，FBXW7被确定为miR-92a的直接靶点。值得注意的是，FBXW7表达的改变消除了miR-92a对HCC细胞增殖、细胞周期和凋亡的影响。临床关联分析显示，miR-92a的高表达与HCC的不良预后特征相关。值得注意的是，miR-92a的高表达导致HCC患者的5年总生存率（OS）和无复发生存率（RFS）降低。多变量Cox回归分析表明，miR-92a表达是预测HCC患者生存的独立预后标志物。总之，本研究结果表明，miR-92a通过靶向FBXW7促进HCC的肿瘤生长，可能作为HCC的一种新型预后生物标志物和治疗靶点。
