miR-663 overexpression induced by endoplasmic reticulum stress modulates hepatocellular carcinoma cell apoptosis via transforming growth factor beta 1.
miR-663 overexpression induced by endoplasmic reticulum stress modulates hepatocellular carcinoma cell apoptosis via transforming growth factor beta 1.
复制标题
内质网应激诱导的miR-663过表达通过转化生长因子β1调节肝癌细胞凋亡
DOI：
10.2147/ott.s96902
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发表时间：
2016
影响因子：
4
通讯作者：
Sun G
中科院分区：
文献类型：
--
作者：
Huang Y;Liu J;Fan L;Wang F;Yu H;Wei W;Sun G
microRNA通常在许多人类癌症（例如肝细胞癌（HCC））中失调，但失调的确切机制尚未被广泛研究。尽管先前的研究表明肝癌细胞对内质网（ER）应激诱导的凋亡具有抵抗性，但关于microRNA与ER应激介导的凋亡抵抗之间的关系知之甚少。在这项研究中，我们已经证明了第一次，miR-663的表达水平显着上调与衣霉素，ER应激诱导剂共孵育的HCC细胞，通过microRNA染色质免疫沉淀微阵列和定量实时聚合酶链反应，然而，miR-663对HCC细胞凋亡的影响仍然未知。为了研究miR-663在HCC中的潜在参与，用miR-663的模拟物或抑制剂转染HepG 2细胞。因此，我们确定下调miR-663抑制HCC细胞增殖，并促进ER应激下的凋亡。靶基因分析进一步预测miR-663对HCC细胞的作用是通过直接靶向转化生长因子β 1（TGF β 1）介导的。有趣的是，在HepG 2细胞中，通过miR-663的抑制剂或模拟物下调或上调miR-663后，TGFB 1的表达水平呈相反变化。此外，TGFB 1敲低抑制HepG 2细胞的凋亡。总之，我们的研究确定了miR-663通过TGFB 1在HCC细胞中作为ER应激介导的凋亡抗性的关键调节因子的作用。因此，针对miR-663/TGFB 1轴的治疗可能代表了克服HCC中细胞凋亡抵抗的有希望的策略。
microRNAs are commonly dysregulated in a number of human cancers, for example, hepatocellular carcinoma (HCC), but the precise mechanism of dysregulation has not been extensively studied. Although previous studies have indicated that HCC cells are resistant to endoplasmic reticulum (ER) stress-induced apoptosis, little is known about the relationship between microRNAs and ER stress-mediated apoptosis resistance. In this study, we have demonstrated for the first time that the expression level of miR-663 was significantly upregulated in HCC cells co-incubated with tunicamycin, an ER stress inducer, as measured by a microRNA-chromatin immunoprecipitation microarray and quantitative real-time polymerase chain reaction; however, the effect of miR-663 on HCC cell apoptosis remains unknown. To investigate the potential involvement of miR-663 in HCC, HepG2 cells were transfected with mimics or inhibitors of miR-663. Consequently, we identified that downregulation of miR-663 suppressed HCC cell proliferation and promoted apoptosis under ER stress. Target gene analysis further predicted that the effects of miR-663 on HCC cells were mediated by directly targeting transforming growth factor beta 1 (TGFB1). Interestingly, the expression levels of TGFB1 changed inversely after downregulation or upregulation of miR-663 by inhibitors or mimics of miR-663 in HepG2 cells. Additionally, TGFB1 knockdown inhibited apoptosis in HepG2 cells. In sum, our study identifies a role for miR-663 as a critical regulator of ER stress-mediated apoptosis resistance in HCC cells via TGFB1. Accordingly, therapies aimed at the miR-663/TGFB1 axis might represent a hopeful strategy to overcome apoptosis resistance in HCC.