C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells
C-terminal truncated HBx reduces doxorubicin cytotoxicity via ABCB1 upregulation in Huh-7 hepatocellular carcinoma cells
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DOI：
10.5483/bmbrep.2019.52.5.312
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发表时间：
2019-05
期刊：
影响因子：
3.8
通讯作者：
Myeong-Eun Jegal;Seung-Youn Jung;Yu-Seon Han;Yung-Jin Kim
中科院分区：
文献类型：
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作者：
Myeong-Eun Jegal;Seung-Youn Jung;Yu-Seon Han;Yung-Jin Kim
乙型肝炎病毒（HBV）编码HBV x蛋白（HBx）是一种已知的肝细胞癌（HCC）病原体。其在HCC中的致病作用包括干扰与细胞增殖和凋亡相关的几种信号通路。突变的c端截断的HBx亚型在人类HCC中经常发现，并且已被证明可以增强增殖和侵袭性，导致HCC恶性肿瘤。我们研究了c端截断HBx降低阿霉素细胞毒性的分子机制。与转染全长HBx的细胞相比，转染c端截断HBx的细胞对阿霉素的细胞毒性降低。表达c端截断HBx的细胞对阿霉素的耐药性与ATP结合盒亚家族B成员1（ABCB1）转运蛋白上调相关，导致阿霉素外排增强。通过小干扰核糖核酸（siRNA）抑制ABCB1活性和沉默ABCB1表达，增加了阿霉素的细胞毒性。这些结果表明，HBx c端截断导致ABCB1表达升高是HCC中阿霉素耐药的原因。因此，ABCB1抑制剂和抗癌药物联合治疗可能对含有c端截断HBx的肝癌患者有效。
Hepatitis B virus (HBV) encoding the HBV x protein (HBx) is a known causative agent of hepatocellular carcinoma (HCC). Its pathogenic activities in HCC include interference with several signaling pathways associated with cell proliferation and apoptosis. Mutant C-terminal-truncated HBx isoforms are frequently found in human HCC and have been shown to enhance proliferation and invasiveness leading to HCC malignancy. We investigated the molecular mechanism of the reduced doxorubicin cytotoxicity by C-terminal truncated HBx. Cells transfected with C-terminal truncated HBx exhibited reduced cytotoxicity to doxorubicin compared to those transfected with full-length HBx. The doxorubicin resistance of cells expressing C-terminal truncated HBx correlated with upregulation of the ATP binding cassette subfamily B member 1(ABCB1) transporter, resulting in the enhanced efflux of doxorubicin. Inhibiting the activity of ABCB1 and silencing ABCB1 expression by small interfering ribonucleic acid (siRNA) increased the cytotoxicity of doxorubicin. These results indicate that elevated ABCB1 expression induced by C-terminal truncation of HBx was responsible for doxorubicin resistance in HCC. Hence, co-treatment with an ABCB1 inhibitor and an anticancer agent may be effective for the treatment of patients with liver cancer containing the C-terminal truncated HBx.