LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk
LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk
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LINC01149 变体调节 MICA 表达，促进乙型肝炎病毒自发恢复，但增加肝细胞癌风险
DOI：
10.1038/s41388-019-1117-7
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发表时间：
2019-11
期刊：
影响因子：
8
通讯作者：
Miao Xiaoping
中科院分区：
文献类型：
--
作者：
Zhong Rong;Tian Jianbo;Fu Mingpeng;Ma Simin;Liu Li;Li Jiaoyuan;Shen Na;Ke Juntao;Yang Yang;Gong Yajie;Zhu Ying;Wang Ying;Gong Jing;Chang Jiang;Lei Ping;Cheng Xiang;Huang Kun;Shen Guanxin;Miao Xiaoping
通过全基因组关联研究解释致病变异，特别是非编码区的变异，已经成为最具挑战性和要求最高的任务之一。我们推测，在GWAS识别的基因座上，功能性的lncRNAs变异可能会改变与持续的乙肝病毒感染和肝细胞癌(HCC)相关的基因的表达水平。综合生物信息学方法被用来确定潜在的功能变异的优先顺序，并进行了两阶段病例对照研究(2473名乙肝病毒阳性的肝细胞癌患者、2248名持续的乙肝病毒携带者和2294名自然康复的受试者)以评估这些变异的作用。LINC01149的rs2844512G >； C变异可促进乙肝病毒的自发恢复(OR = 0.84，95%CI = 0.77~0.92)，但增加肝细胞癌的风险(OR = 1.21，95%CI = 1.11~1.32)。随后的生物学检测表明，该变异体通过作为miRNA海绵，创建了miR-128-3p的结合部位，上调了MICA的表达，可能会招募NK细胞裂解感染细胞，但通过脱落释放高度可溶性的MICA，诱导NK细胞耗尽和肿瘤免疫逃逸。这些发现突显了LINC01149和MICA之间由miR-128-3p介导的调节电路，以及上调的MICA在增加持续性乙肝病毒感染和肝癌易感性方面的重要作用。
Interpreting disease-causing variants, especially in noncoding regions by genome-wide association studies (GWAS), has become one of the most challenging and demanding tasks. We hypothesized that functional lncRNAs variants in GWAS-identified loci might alter expression level of genes associated with persistent HBV infection and hepatocellular carcinoma (HCC). Integrated bioinformatics approaches were used to prioritize potentially functional variants and a two-stage case–control study (2473 HBV positive HCC patients, 2248 persistent HBV carriers and 2294 spontaneously recovered subjects) was performed to assess the roles of these variants. The rs2844512 G > C variant inLINC01149was identified to facilitate HBV spontaneous recovery (OR = 0.84, 95% CI = 0.77–0.92) but increase the risk of HCC (OR = 1.21, 95% CI = 1.11–1.32) in combined samples. Subsequent biological assays indicated this variant created a binding site for miR-128-3p and upregulatedMICAexpression by serving as a miRNA sponge, which might recruit NK-cells to lyse infected cells, but release highly soluble MICA by shedding to induce NK-cells exhaustion and tumor immune evasion. These findings highlight a regulatory circuit between LINC01149 and MICA, mediating by miR-128-3p, and the important role of upregulated MICA in conferring susceptibility to persistent HBV infection and HCC.
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DOI：
10.1038/nrg2544
发表时间：
2009-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
Ioannidis JP;Thomas G;Daly MJ
通讯作者：
Daly MJ
影响因子：
7
作者：
Tan JY;Sirey T;Honti F;Graham B;Piovesan A;Merkenschlager M;Webber C;Ponting CP;Marques AC
通讯作者：
Marques AC
影响因子：
14.9
作者：
Volders PJ;Verheggen K;Menschaert G;Vandepoele K;Martens L;Vandesompele J;Mestdagh P
通讯作者：
Mestdagh P
影响因子：
3
作者：
Chang, Mei-Hwei
通讯作者：
Chang, Mei-Hwei
DOI：
10.1016/j.bbrc.2017.08.045
发表时间：
2017-10
影响因子：
3.1
作者：
A. Takagi;Yutaka Horiuchi;M. Matsui
通讯作者：
A. Takagi;Yutaka Horiuchi;M. Matsui