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LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk

Oncogene volume 39, pages 1944–1956 (2020)Cite this article

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Abstract

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 in LINC01149 was 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 upregulated MICA expression 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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Acknowledgements

We thank all the people who help us accomplish this research. This work was supported by National Natural Science Foundation of China (NSFC-81874278, NSFC-81601839), Wuhan Innovation Development Program of Young Professionals for YW and National Program for Support of Top-notch Young Professionals for XM.

Author’s contributions

ZR, TJB: study design, data analysis and interpretation, and drafting of the manuscript. FMP, MSM, and SN: study design and blood sample acquisition. LJY, KJT, LL, CX, and WY: blood sample acquisition, and data acquisition. YY, GYJ, and ZY: DNA preparation and genotyping. CJ, GJ, LP, HK, and SGX: study design. MXP: study concept and design, data acquisition, critical revision of the manuscript for important intellectual content, study supervision and obtained funding.

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  1. These authors contributed equally: Rong Zhong, Jianbo Tian

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Rong Zhong, Jianbo Tian, Jiaoyuan Li, Juntao Ke, Yang Yang, Yajie Gong, Ying Zhu, Jing Gong, Jiang Chang & Xiaoping Miao

  2. Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Mingpeng Fu, Simin Ma, Ping Lei & Guanxin Shen

  3. Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China

    Li Liu

  4. Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Na Shen

  5. Department of Virology, Wuhan Centers for Disease Prevention and Control, Wuhan, China

    Ying Wang

  6. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiang Cheng

  7. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Kun Huang

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Correspondence to Xiaoping Miao.

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Zhong, R., Tian, J., Fu, M. et al. LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk. Oncogene 39, 1944–1956 (2020). https://doi.org/10.1038/s41388-019-1117-7

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