Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma.
Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma.
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乙型肝炎病毒相关肝细胞癌中肝组织与显微解剖肝细胞的病毒表达和分子谱分析。
DOI：
10.1186/s12967-014-0230-1
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发表时间：
2014-08-21
影响因子：
7.4
通讯作者：
Farci P
中科院分区：
文献类型：
--
作者：
Melis M;Diaz G;Kleiner DE;Zamboni F;Kabat J;Lai J;Mogavero G;Tice A;Engle RE;Becker S;Brown CR;Hanson JC;Rodriguez-Canales J;Emmert-Buck M;Govindarajan S;Kew M;Farci P
乙型肝炎病毒（HBV）诱导肝细胞癌（HCC）的分子机制尚不明确。我们使用基因组和分子技术通过研究HCC患者同一肝脏的多个区域来研究宿主-病毒相互作用。我们比较了全肝组织（WLT）和激光捕获显微解剖（LCM）肝细胞的基因特征以及肝内HBV的表达。研究人员从11例HCC患者的个体肝脏和LCM样本中，在距离肿瘤中心不同距离处获得了多达17个WLT样本，并对其进行了基因表达谱分析。采用实时聚合酶链反应（PCR）和共聚焦免疫荧光法检测肝脏和血清中HBV标志物。对肝脏5个区域的分析显示，直接病灶周围区域和肿瘤周围的基因表达发生了急剧变化，这与肝内HB表面抗原（HBsAg）表达的显著下降有关。肿瘤的特点是大量下调基因，主要涉及脂质和脂肪酸、葡萄糖、氨基酸和药物的代谢，PXR/RXR和PPARα/RXRα核受体的激活途径下调，包括PGC-1α和FOXO1，这两个关键的调节因子不仅参与肝脏的代谢功能，而且参与HBV的生命周期，是病毒基因表达的必需转录因子。这些发现被微解剖肝细胞的基因表达证实。此外，恶性肝细胞的LCM还显示了与癌症和信号通路相关的独特基因的上调，包括两个新的hcc相关癌睾丸抗原基因NUF2和TTK。对全肝组织和微解剖肝细胞的综合基因表达谱分析表明，hbv相关HCC的特征是代谢关闭和HBsAg显著降低。LCM被证明是验证与HCC相关的基因特征和鉴定可能在肝癌发生中起作用的基因的关键工具，为发现新的诊断标记和治疗靶点开辟了新的视角。本文的在线版本（doi:10.1186/s12967-014-0230-1）包含补充材料，可供授权用户使用。
The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets. The online version of this article (doi:10.1186/s12967-014-0230-1) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
Chen, C-H;Lu, P-J;Chou, C-K
通讯作者：
Chou, C-K
影响因子：
13.5
作者：
Mensa, Laura;Crespo, Gonzalo;Forns, Xavier
通讯作者：
Forns, Xavier
影响因子：
13.5
作者：
Nam, SW;Park, JY;Lee, JY
通讯作者：
Lee, JY
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
11.5
作者：
Fukumoto, S;Yamauchi, N;Aburatani, H
通讯作者：
Aburatani, H