The miR-573/apoM/Bcl2A1-dependent signal transduction pathway is essential for hepatocyte apoptosis and hepatocarcinogenesis
The miR-573/apoM/Bcl2A1-dependent signal transduction pathway is essential for hepatocyte apoptosis and hepatocarcinogenesis
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miR-573/apoM/Bcl2A1依赖性信号转导通路对于肝细胞凋亡和肝癌发生至关重要
DOI：
10.1007/s10495-015-1153-x
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发表时间：
2015-10-01
期刊：
影响因子：
7.2
通讯作者：
Wang, Qian
中科院分区：
文献类型：
--
作者：
Hu, Yan-Wei;Chen, Zhi-Ping;Wang, Qian
肝细胞癌（Hepatocellular carcinoma，HCC）是最常见的恶性肿瘤之一，在世界范围内发病率呈上升趋势。载脂蛋白M（apoM）是一种新的载脂蛋白，主要在肝、肾组织中表达。然而，apoM的抗肿瘤特性在很大程度上仍然未知。我们在体内和体外研究apoM在HCC中的抗肿瘤活性和机制。生物信息学分析和荧光素酶报告基因检测结果表明apoM是hsa-miR-573的潜在靶点，转染hsa-miR-573模拟物后apoM表达下调。apoM过表达抑制肝癌细胞的迁移、侵袭和增殖。hsa-miR-573在肝癌细胞中的过表达降低apoM的表达，导致促进肝癌细胞的体外侵袭、迁移和增殖。此外，hsa-miR-573显著促进裸鼠中异种移植肿瘤的生长，伴随着细胞凋亡的减少。ApoM能明显抑制裸鼠移植瘤的生长，并促进细胞凋亡。apoM过表达可抑制Bcl 2A 1 mRNA和蛋白水平的表达，apoM引起的凋亡率增加可被Bcl 2A 1过表达所补偿。这些结果提供了证据表明hsa-miR-573通过抑制肝细胞凋亡促进肿瘤生长，并且这种促肿瘤作用可能以apoM依赖性方式通过Bcl 2A 1介导。因此，我们的研究结果可能有助于提高对hsa-miR-573和apoM在HCC发病机制中的关键作用的理解。
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with an increasing incidence worldwide. Apolipoprotein M (apoM) is a novel apolipoprotein that is mainly expressed in liver and kidney tissues. However, the anti-tumor properties of apoM remain largely unknown. We evaluated the anti-tumor activities and mechanisms of apoM in HCC both in vivo and in vitro. Bioinformatic analysis and luciferase reporter assay results showed that apoM was a potential target of hsa-miR-573 and was downregulated after transfection with hsa-miR-573 mimics. Overexpression of apoM suppressed migration, invasion, and proliferation of hepatoma cells in vitro. Overexpression of hsa-miR-573 in hepatoma cells reduced apoM expression, leading to promotion of the invasion, migration, and proliferation of hepatoma cells in vitro. In addition, hsa-miR-573 markedly promoted growth of xenograft tumors in nude mice with an accompanying reduction in cell apoptosis. ApoM markedly inhibited growth of xenograft tumors in nude mice and promoted cell apoptosis. Moreover, Bcl2A1 mRNA and protein levels were inhibited by apoM overexpression and an increase in apoptosis rate by apoM was markedly compensated by Bcl2A1 overexpression in HepG2 cells. These results provide evidence that hsa-miR-573 promoted tumor growth by inhibition of hepatocyte apoptosis and this pro-tumor effect might be mediated through Bcl2A1 in an apoM-dependent manner. Therefore, our findings may be useful to improve understanding of the critical effects of hsa-miR-573 and apoM in HCC pathogenesis.