Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen
Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen
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miR-27a的上调有助于SV40小T抗原诱导人支气管上皮细胞的恶性转化
作者：
Chen, W.;Zhang, B.;Yang, P.;Zeng, J-L;Chen, L-P;Li, X-D;Lai, Y-D;Zhuang, Z-X;Li, Z-F;Wang, Q.;Zeng, X-W;Zhao, J.;Zhuang, S-M;Li, D-C;Xiao, Y-M;Tang, S-F;Xiao, Q.;Liu, C-X;Xing, X-M;Lin, Y-C;Lin, Z-N
猴病毒40(SV40)早期区、端粒酶催化亚单位(HTERT)和H-RAS的致癌等位基因的引入直接转化原代人类细胞。SV40小T抗原(ST)与蛋白磷酸酶2A(PP2A)形成复合体，抑制PP2A活性，被认为在人类细胞的恶性转化中起关键作用。最近的证据表明，微小RNA(MiRNA)的异常表达模式与肿瘤的发生发展有关。在这里，我们确定miR-27A是在SV40 ST表达细胞中差异表达的miRNA。在SV40 ST转化的人支气管上皮细胞(HBERST)中，miR-27A表达上调。抑制miR-27A在HBERST细胞或高表达miR-27A的肺癌细胞系(NCI-H2 26和SK-MES-1)中的表达可导致细胞生长停滞于G0-G1期。此外，HBERST细胞中miR-27A的抑制减弱了这种细胞以非锚定方式生长的能力。我们还发现，抑制PP2A B56γ的表达导致miR-27A的上调，这与ST的引入类似，表明ST表达的细胞中miR-27A的表达异常是由ST-PP2A相互作用介导的。此外，我们还发现编码F-box/WD重复蛋白7的Fbxw7基因是一个潜在的miR-27A靶点，经双荧光素酶报告系统分析证实。在两种细胞模型和人类肿瘤样本中，miR-27A表达水平和Fbxw7蛋白表达之间的负相关进一步得到证实。Fbxw7通过依赖泛素的一系列底物，包括c-Myc、c-jun、细胞周期蛋白E1和Notch 1来调节细胞周期进程。因此，miR-27A过表达抑制Fbxw7对细胞生长的促进可能是病毒癌蛋白ST诱导的恶性转化的原因。这些观察表明miR-27A在人类肿瘤发生中起癌基因的作用。
The introduction of the Simian virus 40 (SV40) early region, the telomerase catalytic subunit (hTERT) and an oncogenic allele of H-Ras directly transforms primary human cells. SV40 small T antigen (ST), which forms a complex with protein phosphatase 2A (PP2A) and inhibits PP2A activity, is believed to have a critical role in the malignant transformation of human cells. Recent evidence has shown that aberrant microRNA (miRNA) expression patterns are correlated with cancer development. Here, we identified miR-27a as a differentially expressed miRNA in SV40 ST-expressing cells. miR-27a is upregulated in SV40 ST-transformed human bronchial epithelial cells (HBERST). Suppression of miR-27a expression in HBERST cells or lung cancer cell lines (NCI-H226 and SK-MES-1) that exhibited high levels of miR-27a expression lead to cell growth arrested in the G 0–G 1 phase. In addition, suppression of miR-27a in HBERST cells attenuated the capacity of such cells to grow in an anchorage-independent manner. We also found that suppression of the PP2A B56γ expression resulted in upregulation of miR-27a similar to that achieved by the introduction of ST, indicating that dysregulation of miR-27a expression in ST-expressing cells was mediated by the ST–PP2A interaction. Moreover, we discovered that Fbxw7 gene encoding F-box/WD repeat-containing protein 7 was a potential miR-27a target validated by dual-luciferase reporter system analysis. The inverse correlation between miR-27a expression levels and Fbxw7 protein expression was further confirmed in both cell models and human tumor samples. Fbxw7 regulates cell-cycle progression through the ubiquitin-dependent proteolysis of a set of substrates, including c-Myc, c-Jun, cyclin E1 and Notch 1. Thus, promotion of cell growth arising from the suppression of Fbxw7 by miR-27a overexpression might be responsible for the viral oncoprotein ST-induced malignant transformation. These observations demonstrate that miR-27a functions as an oncogene in human tumorigenesis.
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影响因子：
3.3
作者：
Wu, Jing Qin;Dyer, Wayne B.;Chrisp, Jeremy;Belov, Larissa;Wang, Bin;Saksena, Nitin K.
通讯作者：
Saksena, Nitin K.
影响因子：
11.2
作者：
Mertens-Talcott, Susanne U.;Chintharlapalli, Sudhakar;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
6.4
作者：
Huang, Shenglin;He, Xianghuo;Gu, Jianren
通讯作者：
Gu, Jianren
影响因子：
50.3
作者：
Chen, W;Possemato, R;Hahn, WC
通讯作者：
Hahn, WC
DOI：
10.1073/pnas.75.1.117
发表时间：
1978-01-01
影响因子：
11.1
作者：
CRAWFORD, LV;COLE, CN;BERG, P
通讯作者：
BERG, P