Identification of miRNomes in human stomach and gastric carcinoma reveals miR-133b/a-3p as therapeutic target for gastric cancer
Identification of miRNomes in human stomach and gastric carcinoma reveals miR-133b/a-3p as therapeutic target for gastric cancer
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人胃和胃癌中 miRNome 的鉴定揭示了 miR-133b/a-3p 作为胃癌的治疗靶点。
DOI：
10.1016/j.canlet.2015.06.028
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发表时间：
2015-12-01
期刊：
影响因子：
9.7
通讯作者：
Cai, Qingping
中科院分区：
文献类型：
--
作者：
Liu, Yanfang;Zhang, Xin;Cai, Qingping
胃癌（GC）是世界范围内第四常见的恶性肿瘤和第二大癌症死亡原因，但这种临床异质性疾病的分子机制是复杂的，并且仍然远未完全理解。越来越多的证据表明microRNA（miRNA）的异常表达与肿瘤的发生有关。然而，它们在GC中的准确表达模式、功能和机制仍不清楚。在此，跨TCGA数据集进行miRNome的热图分析，发现miR-133家族的表达在GC中一致下调。这一结果在2个胃癌细胞系和20对原发性胃癌组织中得到证实，进一步研究表明miR-133的下调主要是通过其启动子区域的组蛋白修饰介导的。重要的是，恢复miR-133b/a-3p表达可通过靶向抗凋亡分子Mc-1和Bcl-xL抑制胃癌细胞增殖并促进细胞凋亡。与体外结果一致，重新引入miR-133 b/a-3p表达显著延迟了异种移植裸鼠中GC细胞的肿瘤形成并减小了肿瘤大小。并在异种移植小鼠中验证了miR-133b/a-3p与其靶点之间的负相关性。综上所述，我们的研究结果表明，miR-133b/a-3p通过直接靶向Mcl-1和Bcl-xL在GC中起肿瘤抑制剂的作用。揭示通过miRNA介导的途径抑制癌基因的新机制为GC治疗提供了新途径。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Gastric cancer (GC) is the fourth most frequent malignant disease and the second leading cause of cancer mortality worldwide, but the molecular mechanisms underlying this clinically heterogeneous disease are complex and remain far from completely understood. Accumulating evidence suggests that abnormal microRNA (miRNA) expression is involved in tumorigenesis. However, their accurate expression pattern, function, and mechanism in GC remain unclear. Here, a heatmap analysis of the miRNomes was performed across TCGA datasets and the expression of miR-133 family was found to be consistently downregulated in GC. This result was confirmed in two GC cell lines and 20 pairs of primary GC tissues, and further study demonstrated that the downregulation of miR-133 was mainly mediated by histone modification within its promoter region. Importantly, restoration of miR-133b/a-3p expression could suppress GC cell proliferation and promote cell apoptosis by targeting anti-apoptotic molecules Mc-1 and Bcl-xL. Consistent with in vitro results, reintroducing of miR-133b/a-3p expression significantly delayed tumor formation and reduced tumor size of GC cells in xenograft nude mice. And the inverse relationship between miR-133b/a-3p and its targets was verified in xenograft mice. Taken together, our findings suggest that miR-133b/a-3p acts as a tumor suppressor in GC by directly targeting Mcl-1 and Bcl-xL. Revealing novel mechanism for oncogene inhibition by miRNA-mediated pathways offers new avenues for GC treatment. (C) 2015 Elsevier Ireland Ltd. All rights reserved.