miR-15b-5p induces endoplasmic reticulum stress and apoptosis in human hepatocellular carcinoma, both in vitro and in vivo, by suppressing Rab1A.
miR-15b-5p induces endoplasmic reticulum stress and apoptosis in human hepatocellular carcinoma, both in vitro and in vivo, by suppressing Rab1A.
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DOI：
10.18632/oncotarget.3970
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发表时间：
2015-06-30
期刊：
影响因子：
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通讯作者：
Huang C
中科院分区：
文献类型：
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作者：
Yang Y;Hou N;Wang X;Wang L;Chang S;He K;Zhao Z;Zhao X;Song T;Huang C
在人肝细胞癌（HCC）中，miRNAs的异常表达与肿瘤细胞的增殖、凋亡、侵袭和靶向下游蛋白的迁移相关。据报道，HCC组织中miR-15b水平升高；然而，它们与HCC复发呈负相关。我们的目的是了解这种现象的原因。我们使用逆转录聚合酶链反应（RT-PCR）检测miR-15b-5p在HCC组织和HCC细胞系中的表达。我们的结果与报告一致。利用生物信息学和荧光素酶报告基因检测，我们发现Rab1A是miR-15b-5p的一个新的直接靶点。用shRab1A抑制Rab1A的功能还可以抑制HCC细胞的生长，诱导内质网应激（ERS）和细胞凋亡。同样，通过过表达miR-15b-5p抑制Rab1A也能抑制细胞生长，诱导ERS和凋亡。此外，Rab1A的重新表达挽救了miR-15b-5p诱导的肝癌细胞ERS、细胞凋亡和生长抑制。进一步进行体内测定来证实它们。综上所述，我们的数据表明，miR-15b-5p通过靶向和抑制Rab1A来诱导ERS、细胞凋亡和生长抑制，Rab1A在HCC中作为肿瘤抑制基因。这一发现表明Rabs、mirna和细胞凋亡之间存在一种新的关系。
In human hepatocellular carcinoma (HCC), aberrant expression of miRNAs correlates with tumor cell proliferation, apoptosis, invasion, and migration by targeting downstream proteins. miR-15b levels are reported increased in HCC tissues; however, they negatively correlate to HCC recurrence. Our aim was to understand the reason for this phenomenon. We used the reverse transcription-polymerase chain reaction (RT-PCR) to measure miR-15b-5p expression in both HCC tissues and HCC cell lines. Our results were consistent with the report. Using bioinformatics and luciferase reporter assays, we identified Rab1A as a novel and direct target of miR-15b-5p. Inhibiting the function of Rab1A with shRab1A also inhibited the growth of HCC cells and induced endoplasmic reticulum stress (ERS) and apoptosis. Similarly, suppressing Rab1A by overexpression of miR-15b-5p also inhibited cell growth and induced ERS and apoptosis. Moreover, re-expression of Rab1A rescued the miR-15b-5p -induced ERS, apoptosis, and growth inhibition in HCC cells. In vivo assays were further performed to testify them. Taken together, our data suggest that miR-15b-5p induces ERS, apoptosis, and growth inhibition by targeting and suppressing Rab1A, acting as a tumor suppressor gene in HCC. This finding suggests a novel relation among Rabs, miRNAs, and apoptosis.