Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5
Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5
复制标题
卡波西肉瘤相关疱疹病毒编码的 MicroRNA miR-K12-11 通过抑制 SMAD5 减弱转化生长因子 Beta 信号传导
DOI：
10.1128/jvi.06245-11
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发表时间：
2012-02-01
影响因子：
5.4
通讯作者：
Lan, Ke
中科院分区：
文献类型：
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作者：
Liu, Yunhua;Sun, Rui;Lan, Ke
卡波济肉瘤相关疱疹病毒（KSHV）编码12种前体microRNA（pre-miRNAs）。目前的研究表明，这些miRNA参与调节病毒和宿主基因的表达，暗示在维持病毒潜伏期和抑制抗病毒先天免疫中的作用。然而，这些miRNAs的功能在很大程度上仍然未知。基于致癌miR-155和KSHV编码的miR-K12 - 11之间的序列同源性，我们假设miR-K12 - 11可以减弱转化生长因子β（TGF-β）信号传导，从而促进病毒感染和肿瘤发生。在本研究中，我们证明了miR-K12 - 11在拉莫斯（一种TGF-β敏感的细胞系）中的异位表达通过直接靶向SMAD 5（TGF-β信号传导中的重要介质）下调TGF-β信号传导并促进TGF-β处理后的细胞增殖。此外，在从头KSHV感染系统或潜伏感染的KSHV阳性B淋巴瘤细胞系中进一步证实了miR-K12 - 11对SMAD5的下调。更重要的是，特异性海绵抑制剂对miR-K12 - 11的抑制恢复了SMAD5在新生感染和潜伏感染细胞中的表达。最后，我们发现，SMAD 5的恢复，以及TGF-β II型受体，其被潜伏病毒蛋白潜伏相关核抗原表观遗传学沉默，使BC3细胞对TGF-β信号传导的细胞抑制作用敏感。综上所述，我们的研究结果强调了miR-K12 - 11下调TGF-β信号的新机制，并表明病毒miRNA和蛋白质可能通过靶向相同的信号通路在病毒诱导的肿瘤发生中发挥二分法调节作用。
ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs (pre-miRNAs). Current studies have shown that these miRNAs are involved in regulation of viral and host gene expression, implicating a role in the maintenance of viral latency and suppression of antiviral innate immunity. However, the functions of these miRNAs remain largely unknown. On the basis of the sequence homology between oncogenic miR-155 and KSHV-encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate transforming growth factor β (TGF-β) signaling, facilitating viral infection and tumorigenesis. In the present study, we demonstrated that ectopic expression of miR-K12-11 in Ramos, a TGF-β-sensitive cell line, downregulated TGF-β signaling and facilitated cell proliferation upon TGF-β treatment by directly targeting SMAD5, an important mediator in TGF-β signaling. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a de novo KSHV infection system or latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 by a specific sponge inhibitor restored the expression of SMAD5 in both de novo-infected and latently infected cells. Finally, we found that restoration of SMAD5, in addition to the TGF-β type II receptor, which was epigenetically silenced by the latent viral protein latency-associated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-β signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 downregulates TGF-β signaling and suggest that viral miRNAs and proteins may exert a dichotomy regulation in virus-induced oncogenesis by targeting the same signaling pathway.