长非编码RNA HULC通过调节HBV相关的肝细胞癌中的HBx / STAT3 / miR-

StephenW

Cancer Lett. 2019 Apr 11. pii: S0304-3835(19)30233-2. doi: 10.1016/j.canlet.2019.04.008. [Epub ahead of print]
Long Noncoding RNA HULC Activates HBV by Modulating HBx/STAT3/miR-539/APOBEC3B Signaling in HBV-related Hepatocellular Carcinoma.
Liu Y1, Feng J1, Sun M1, Yang G1, Yuan H1, Wang Y1, Bu Y1, Zhao M1, Zhang S1, Zhang X2.
Author information

1
    Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, PR China.
2
    Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin, 300071, PR China. Electronic address: [email protected].

Abstract

Long noncoding RNA HULC is identified and highly expressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is a key driver of liver cancer. In the present study, we found that HULC remarkably elevated the levels of HBeAg, HBsAg, HBcAg, pgRNA, HBx, HBV DNA and covalently closed circular DNA (cccDNA), which activated the HBV replication in HBV-expressing hepatoma cells or de novo HBV-infected cell lines (PHH, HepG2-NTCP and dHepaRG). Mechanistically, HULC enhanced HBV cccDNA stability by down-regulating the APOBEC3B in hepatoma cells. HULC significantly up-regulated microRNA-539, which targeted the 3'UTR of APOBEC3B mRNA. Luciferase reporter assays revealed a putative STAT3-binding site located in the upstream of miR-539 promoter. Moreover, we identified that HULC was able to elevate HBx, which co-activated the STAT3 to stimulate the miR-539 promoter. Then, miR-539 down-regulated APOBEC3B and promoted HBV replication. Functionally, HULC enhanced the growth of hepatoma cells by activating HBV in vitro and in vivo, which could be blocked by overexpressing APOBEC3B. In conclusion, HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related HCC.

Copyright © 2019 Elsevier B.V. All rights reserved.
KEYWORDS:

APOBEC3B; HBV cccDNA; Long non-coding RNA; cell proliferation; liver cancer

PMID:
    30981758
DOI:
    10.1016/j.canlet.2019.04.008

StephenW

巨蟹座Lett。 2019年4月11日.pii：S0304-3835（19）30233-2。 doi：10.1016 / j.canlet.2019.04.008。 [印刷前的电子版]
长非编码RNA HULC通过调节HBV相关的肝细胞癌中的HBx / STAT3 / miR-539 / APOBEC3B信号来激活HBV。
Liu Y1，Feng J1，Sun M1，Yang G1，Yuan H1，Wang Y1，Bu Y1，Zhao M1，Zhang S1，Zhang X2。
作者信息

1
南开大学生命科学学院癌症研究系，天津300071
2
南开大学生命科学学院癌症研究系，天津300071电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）是肝癌的主要驱动因素。在本研究中，我们发现HULC显着提高了HBeAg，HBsAg，HBcAg，pgRNA，HBx，HBV DNA和共价闭合环状DNA（cccDNA）的水平，这些DNA在HBV表达肝癌细胞或从头HBV中激活HBV复制。感染的细胞系（PHH，HepG2-NTCP和dHepaRG）。机制上，HULC增强HBV cccDNA HULC显着上调microRNA-539，其靶向APOBEC3B mRNA的3'UTR。荧光素酶报告基因测定揭示了位于miR-539启动子上游的推定的STAT3结合位点。此外，我们发现HULC能够提高HBx，其共同激活STAT3以刺激miR-539启动子。然后，miR-539下调APOBEC3B并促进HBV复制。在功能上，HULC通过在体外和体内激活HBV来增强肝细胞瘤细胞的生长，这可以通过过表达APOBEC3B来阻断。总之，HULC通过调节HBV相关HCC中的HBx / STAT3 / miR-539 / APOBEC3B信号传导来激活HBV。

版权所有©2019 Elsevier B.V.保留所有权利。
关键词：

APOBEC3B; HBV cccDNA;长的非编码RNA;细胞增殖;肝癌

结论：
30981758
DOI：
10.1016 / j.canlet.2019.04.008