Upregulation of miR-362-3p Modulates Proliferation and Anchorage-Independent Growth by Directly Targeting Tob2 in Hepatocellular Carcinoma
Upregulation of miR-362-3p Modulates Proliferation and Anchorage-Independent Growth by Directly Targeting Tob2 in Hepatocellular Carcinoma
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DOI：
10.1002/jcb.25110
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发表时间：
2015-08-01
影响因子：
4
通讯作者：
Li, Youjun
中科院分区：
文献类型：
--
作者：
Shen, Hongxing;Li, Wenjuan;Li, Youjun
microRNA（miRNAs）的异常调节有助于人类恶性肿瘤的发病机制，并且miRNAs的表达可以受到遗传和表观遗传变化的影响，例如其启动子的CpG岛的甲基化。为了鉴定由DNA甲基化调控的miRNA，在两个肝细胞癌（HCC）细胞系和两个正常永生化细胞系中分析了总体miRNA表达谱，所述细胞系用5-氮杂-2-脱氧胞苷（DAC，DNA甲基化抑制剂）加TSA（曲古抑菌素A，组蛋白去乙酰化酶抑制剂）处理。结果显示，这些表观遗传药物对miRNA表达的影响是依赖于或不依赖于细胞类型的，特别是miR-362- 3 p。与正常细胞和癌旁组织相比，miR-362- 3 p在人肝癌细胞和组织中表达增加，而其启动子甲基化水平显著降低。miR-362- 3 p的异位表达增加了增殖和锚定非依赖性软琼脂生长，其表达抑制具有相反的作用，与其在HCC细胞中的直接靶点Tob 2的调节相关。Tob 2的抑制再现了miR-362- 3 p过表达的作用，而Tob 2的增强表达逆转了miR-362- 3 p的促进作用。Tob 2在人原发性肝癌中的表达与邻近的非癌组织相比是减少的。我们的研究结果表明，miR-362- 3 p和Tob 2的失调可能有助于HCC恶性。J.细胞。116：1563-1573，2015. (c)2015 Wiley Periodicals，Inc.
The dysregulation of microRNAs (miRNAs) contributes to the pathogenesis of human malignancies, and miRNA expression can be affected by genetic and epigenetic changes, such as methylation of the CpG islands of their promoters. To identify miRNAs regulated by DNA methylation, the global miRNA expression profile was analyzed in two hepatocellular carcinoma (HCC) cell lines and two normal immortalized cell lines treated with 5-Aza-2-deoxycytidine (DAC, an inhibitor of DNA methylation) plus TSA (Trichostatin A, histone deacetylase inhibitor). Results revealed that these epigenetic drugs differentially affect miRNA expression that is dependent or independent of cell type, especially miR-362-3p. miR-362-3p expression increased while methylation of its promoter significantly decreased in human HCC cells and tissues compared with normal cells and adjacent noncancerous tissues. Ectopic expression of miR-362-3p increased proliferation and anchorage-independent soft agar growth and its expression inhibition had opposing effects that were associated with regulation of its direct targetTob2 in HCC cells. Inhibition of Tob2 recapitulated the effects of miR-362-3p overexpression, whereas enforced Tob2 expression reversed the promoting effects of miR-362-3p. Tob2 expression was reduced in human primary HCCs compared to adjacent noncancerous tissues. Our findings suggest that dysregulation of miR-362-3p and Tob2 may contribute to HCC malignancy. J. Cell. Biochem. 116: 1563-1573, 2015. (c) 2015 Wiley Periodicals, Inc.