MicroRNA-99a Inhibits Hepatocellular Carcinoma Growth and Correlates with Prognosis of Patients with Hepatocellular Carcinoma
MicroRNA-99a Inhibits Hepatocellular Carcinoma Growth and Correlates with Prognosis of Patients with Hepatocellular Carcinoma
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DOI：
10.1074/jbc.m111.270561
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发表时间：
2011-10-21
影响因子：
4.8
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Li, Dong;Liu, Xingguang;Cao, Xuetao
在我们通过Illumina Solexa大规模平行特征测序进行的深入分析中，我们发现microRNA-99a （miR-99a）是正常人类肝脏miR-Nome中第6个丰富的microRNA，但在肝细胞癌（HCC）中明显下调。令人信服的证据表明，microrna在HCC的发展中起着重要作用。然而，miR-99a失调在HCC中的生物学功能尚不清楚。在本研究中，我们发现miR-99a在HCC组织和细胞系中显著降低。重要的是，HCC组织中较低的miR-99a表达与HCC患者较短的生存期显著相关，miR-99a被认为是HCC患者预后的独立预测因子。此外，miR-99a的恢复通过诱导G(1)期细胞周期阻滞显著抑制HCC细胞的体外生长。瘤内注射胆固醇偶联的miR-99a模拟物显著抑制肝癌裸鼠肿瘤生长，降低甲胎蛋白水平。胰岛素样生长因子1受体（IGF-1R）和哺乳动物雷帕霉素靶点（mTOR）被进一步表征为miR-99a的直接靶点。此外，在HCC组织中发现IGF-1R和mTOR蛋白水平与miR-99a表达呈负相关。miR-99a模拟物抑制IGF-1R和mTOR通路，随后抑制HCC细胞中细胞周期相关蛋白的表达，包括细胞周期蛋白D1。总之，miR-99a在HCC组织中经常下调表达，并与HCC患者的预后相关，因此提出miR-99a可作为HCC的前瞻性预后预测因子。miR-99a通过诱导细胞周期阻滞抑制HCC生长，提示miR-99a是HCC治疗的潜在肿瘤抑制因子。
In our in-depth analysis carried out by the Illumina Solexa massive parallel signature sequencing, microRNA-99a (miR-99a) was found to be the sixth abundant microRNA in the miR-Nome of normal human liver but was markedly down-regulated in hepatocellular carcinoma (HCC). Compelling evidence has suggested the important roles of microRNAs in HCC development. However, the biological function of miR-99a deregulation in HCC remains unknown. In this study, we found that miR-99a was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-99a expression in HCC tissues significantly correlated with shorter survival of HCC patients, and miR-99a was identified to be an independent predictor for the prognosis of HCC patients. Furthermore, restoration of miR-99a dramatically suppressed HCC cell growth in vitro by inducing the G(1) phase cell cycle arrest. Intratumoral injection of cholesterol-conjugated miR-99a mimics significantly inhibited tumor growth and reduced the alpha-fetoprotein level in HCC-bearing nude mice. Insulin-like growth factor 1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) were further characterized as the direct targets of miR-99a. Furthermore, protein levels of IGF-1R and mTOR were found to be inversely correlated with miR-99a expression in HCC tissues. miR-99a mimics inhibited IGF-1R and mTOR pathways and subsequently sup-pressed expression of cell cycle-related proteins, including cyclin D1 in HCC cells. Conclusively, miR-99a expression was frequently down-regulated in HCC tissues and correlates with the prognosis of HCC patients, thus proposing miR-99a as a prospective prognosis predictor of HCC. miR-99a suppresses HCC growth by inducing cell cycle arrest, suggesting miR-99a as potential tumor suppressor for HCC therapeutics.