来自中科院上海巴斯德研究所的蓝柯研究组发表了题为“KSHV-encoded miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5”的文章，获得了肿瘤疱疹病毒——卡波济肉瘤病毒(Kaposi’s Sarcoma associated herpesvirus，KSHV)miRNA功能研究的最新成果。这一研究成果公布在病毒学权威刊物Journal of Virology杂志上。
KSHV是一种重要的人类肿瘤病毒，它可以引起卡波济肉瘤(KS)、原发渗出性淋巴瘤(PEL)、多中心性卡斯特曼病(MCD)等数种恶性肿瘤，其中KS是AIDS患者中最常见的恶性肿瘤。KSHV属于gamma-2型人类疱疹病毒，编码多达90个开放阅读框(ORF)和至少17个成熟的病毒miRNA。
卡波济肉瘤由 KSHV 引起
KSHV miRNA的功能研究是当前的国际研究热点，这项研究首次报道了病毒编码的miR-K12-11可以通过调控TGF-beta信号通路而促进细胞增殖，提示病毒编码的蛋白和miRNA在诱发肿瘤发生的过程中可协同作用于同一信号通路。
这篇文章首先发现在TGF-beta1刺激作用下，表达miR-K12-11的Ramos细胞细胞增殖较快，且抑制TGF-beta信号通路的活性。通过生物信息学分析发现SMAD5是miR-K12-11可能作用靶点。双荧光报告系统发现miR-K12-11可以作用于SMAD5 3’UTR而下调其活性，且Western Blot也证实了miR-K12-11能下调SMAD5总蛋白和磷酸化活性形式。
此外，研究还发现在原发感染的293T细胞和潜伏感染KSHV的B淋巴瘤细胞中，SMAD5的表达量都偏低。进一步研究发现，在KSHV潜伏感染的B淋巴瘤细胞中，用sponge inhibitor抑制miR-K12-11可以回复SMAD5的表达水平。若同时转染TGF-beta受体后，sponge inhibitor可以恢复B淋巴瘤细胞对TGF-beta1的敏感性，从而抑制其细胞增殖；而且过表达SMAD5也会得到类似结果。
除此之外，今年年初，这一研究组还通过利用不同于之前的实验系统，验证了其他研究组报导的miR-K12-9能够下调RTA的表达。同时还报导了一个新的KSHV编码miRNA能够通过直接抑制裂解期主要调控基因RTA，并影响RTA对下游裂解期基因和病毒粒子复制来维持病毒潜伏感染状态。（生物探索）
相关英文论文摘要：
KSHV-encoded miR-K12-11 attenuates transforming growth factor beta signaling through suppression of SMAD5
Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 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. Based on the sequence homology between oncogenic miR-155 and KSHV encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate 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, down-regulated 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 down-regulation 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 both in de novo and latently infected cells. Finally, we found that restoration of SMAD5, in addition to TβRII, which was epigenetically silenced by latent viral protein LANA, sensitized BC3 cells to the cytostatic effect of TGF-β signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 down-regulates 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.
英文论文链接：https://jvi.asm.org/content/early/2011/10/14/JVI.06245-11.abstract
