LncRNA PCNAP1 modulates hepatitis B virus replication and enhances tumor growth of liver cancer

被引:151
作者
Feng, Jinyan [1 ]
Yang, Guang [1 ]
Liu, Yunxia [1 ]
Gao, Yuen [1 ,4 ]
Zhao, Man [1 ]
Bu, Yanan [1 ]
Yuan, Hongfeng [1 ]
Yuan, Ying [1 ]
Yun, Haolin [1 ]
Sun, Mingming [1 ]
Gao, Hongwei [2 ]
Zhang, Shuqin [1 ]
Liu, Zixian [1 ]
Yin, Ming [3 ]
Song, Xijun [3 ]
Miao, Zhenchuan [3 ]
Lin, Zhongqing [3 ]
Zhang, Xiaodong [1 ]
机构
[1] Nankai Univ, Dept Canc Res, Coll Life Sci, Tianjin 300071, Peoples R China
[2] Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Reg, Urumqi 830011, Peoples R China
[3] Beijing Vitalstar Biotechnol Co Ltd, Beijing, Peoples R China
[4] Michigan State Univ, Dept Anim Sci, E Lansing, MI 48824 USA
基金
中国国家自然科学基金;
关键词
LncRNA PCNAP1; HBV; HBV cccDNA; PCNA; hepatocarcinogenesis; CLOSED CIRCULAR DNA; X PROTEIN PROMOTES; CELL PROLIFERATION; DOWN-REGULATION; HEPATOMA-CELLS; RNA; TRANSCRIPTION; DEGRADATION; METABOLISM; REPRESSION;
D O I
10.7150/thno.34273
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Rationale: Hepatitis B virus (HBV) is a major risk factor for liver cancer, in which HBV covalently closed circular DNA (cccDNA) plays crucial roles. However, the effect of pseudogene-derived long noncoding RNAs (lncRNAs) acting as functional regulators of their ancestral gene expression on HBV replication and hepatocellular carcinoma (HCC) remains unclear. In this study, we speculated that the pseudogene-derived lncRNA PCNAP1 and its ancestor PCNA might modulate HBV replication and promote hepatocarcinogenesis. Methods: We investigated the roles of lncRNA PCNAP1 in contribution of HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling in hepatocarcinogenesis by using CRISPR/Cas9, Southern blot analysis, confocal assays, et al. in primary human hepatocytes (PHH), HepaRG cells, HepG2-NTCP cells, hepatoma carcinoma cells, human liver-chimeric mice model, transgenetic mice model, in vitro tumorigenicity and clinical patients. Results: Interestingly, the expression levels of PCNAP1 and PCNA were significantly elevated in the liver of HBV-infectious human liver-chimeric mice. Clinically, the mRNA levels of PCNAP1 and PCNA were increased in the liver of HBV-positive/HBV cccDNA-positive HCC patients. Mechanistically, PCNA interacted with HBV cccDNA in a HBc-dependent manner. PCNAP1 enhanced PCNA through sponging miR-154 targeting PCNA mRNA 3' UTR. Functionally, PCNAP1 or PCNA remarkably enhanced HBV replication and accelerated the growth of HCC in vitro and in vivo. Conclusion: We conclude that lncRNA PCNAP1 enhances the HBV replication through modulating miR-154/PCNA/HBV cccDNA signaling and the PCNAP1/PCNA signaling drives the hepatocarcinogenesis. Our finding provides new insights into the mechanism by which lncRNA PCNAP1 enhances HBV replication and hepatocarcinogenesis.
引用
收藏
页码:5227 / 5245
页数:19
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