Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2.
Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2.
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乙型肝炎病毒通过促进ENPP2的表达和分泌与肝星状细胞协同促进肝细胞癌进展
DOI：
10.3389/fmolb.2021.745990
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发表时间：
2021
影响因子：
5
通讯作者：
Xu L
中科院分区：
文献类型：
--
作者：
Deng W;Chen F;Zhou Z;Huang Y;Lin J;Zhang F;Xiao G;Liu C;Liu C;Xu L
工作背景：B型肝炎病毒（HBV）感染是导致肝细胞癌（HCC）发生的主要危险因素，但其分子机制尚未完全阐明。据报道，病毒感染诱导外核苷酸焦磷酸酶-磷酸二酯酶2（ENPP 2）的表达，后者参与肿瘤的进展。因此，本研究的目的是研究HBV是否通过ENPP 2诱导HCC恶性。 方法：收集肝癌患者的临床资料，分析其预后。在肝癌细胞系中建立了HBV基因组的瞬时转染和稳定异位表达。采用免疫组织化学染色、RT-qPCR、Western blot和ELISA检测ENPP 2的表达和分泌。最后，CCK-8，集落形成和迁移试验以及皮下异种移植小鼠模型被用于研究HBV感染，ENPP 2表达和活化的肝星状细胞（aHSC）对体外和体内HCC进展的影响。 结果：来自癌症数据库的数据表明，与正常肝组织相比，肝癌中ENPP 2的水平显着较高。对158例HCC患者的临床相关性分析显示，ENPP 2表达与总生存率和无病生存率均呈正相关。统计学分析显示，与HBV阴性的HCC组织相比，HBV阳性的HCC组织表达更高水平的ENPP 2。在体外，HBV上调肝癌细胞中ENPP 2的表达和分泌，并通过增强ENPP 2促进肝癌细胞增殖、集落形成和迁移;下调ENPP 2表达或抑制其功能可抑制HCC进展。此外，aHSC在体外增强肝癌细胞增殖、迁移，并在体内与HBV协同促进肿瘤发生;功能丧失试验进一步证实ENPP 2对HBV/aHSC诱导的HCC进展至关重要。 结论：HBV增强肝癌细胞ENPP 2的表达和分泌，并通过ENPP 2与aHSC结合促进肝癌的进展。
Background: Hepatitis B virus (HBV) infection is a major risk factor causing hepatocellular carcinoma (HCC) development, but the molecular mechanisms are not fully elucidated. It has been reported that virus infection induces ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) expression, the latter participates in tumor progression. Therefore, the aim of the present study was to investigate whether HBV induced HCC malignancy via ENPP2. Methods: HCC patient clinical data were collected and prognosis was analyzed. Transient transfection and stable ectopic expression of the HBV genome were established in hepatoma cell lines. Immunohistochemical staining, RT-qPCR, western blot, and ELISA assays were used to detect the expression and secretion of ENPP2. Finally, CCK-8, colony formation, and migration assays as well as a subcutaneous xenograft mouse model were used to investigate the influence of HBV infection, ENPP2 expression, and activated hepatic stellate cells (aHSCs) on HCC progression in vitro and in vivo. Results: The data from cancer databases indicated that the level of ENPP2 was significant higher in HCC compared within normal liver tissues. Clinical relevance analysis using 158 HCC patients displayed that ENPP2 expression was positively correlated with poor overall survival and disease-free survival. Statistical analysis revealed that compared to HBV-negative HCC tissues, HBV-positive tissues expressed a higher level of ENPP2. In vitro, HBV upregulated ENPP2 expression and secretion in hepatoma cells and promoted hepatoma cell proliferation, colony formation, and migration via enhancement of ENPP2; downregulation of ENPP2 expression or inhibition of its function suppressed HCC progression. In addition, aHSCs strengthened hepatoma cell proliferation, migration in vitro, and promoted tumorigenesis synergistically with HBV in vivo; a loss-function assay further verified that ENPP2 is essential for HBV/aHSC-induced HCC progression. Conclusion: HBV enhanced the expression and secretion of ENPP2 in hepatoma cells, combined with aHSCs to promote HCC progression via ENPP2.
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影响因子：
4.7
作者：
Liu APY;Soh SY;Cheng FWC;Pang HH;Luk CW;Li CH;Ho KKH;Chan EKW;Chan ACY;Chung PHY;Kimpo MS;Ahamed SH;Loh A;Chiang AKS
通讯作者：
Chiang AKS
影响因子：
20.3
作者：
Baumforth, KRN;Flavell, JR;Murray, PG
通讯作者：
Murray, PG
影响因子：
4.8
作者：
Benesch, Matthew G. K.;Tang, Xiaoyun;Brindley, David N.
通讯作者：
Brindley, David N.
影响因子：
4.1
作者：
Deng, Wanyu;Zhang, Xiaoyong;Lu, Mengji
通讯作者：
Lu, Mengji
影响因子：
13.5
作者：
Martin-Vilchez, Samuel;Sanz-Cameno, Paloma;Lara-Pezzi, Enrique
通讯作者：
Lara-Pezzi, Enrique