Caselmann W H
Department of Medicine II, University of Munich, Germany.
J Hepatol. 1995;22(1 Suppl):34-7.
Epidemiologic data indicate the crucial role of chronic hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level, HBV sequences are frequently integrated in hepatocellular DNA. However, in contrast to the woodchuck model, in which specific HBV-DNA integration is detectable in most cases, insertional (in-) activation of cellular genes seems to be a rare event in man. The recent discovery of transactivating functions exerted by HBx and truncated HBs(urface) proteins supports the notion that transactivation of cellular gene expression could be relevant to hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21/26) of HCC tissues or hepatoma-derived cell lines. At least one transactivator protein was functional in all cases investigated so far. The 16.5-kDa HBx transactivator has been shown to stimulate gene expression from various cellular target sequences. In vitro, HBx displays oncogenic potential. A second type of transactivator is encoded in the preS/S region of HBV. In contrast to HBx, HBs transactivators require carboxyterminal truncation to gain their transactivating function. Unlike full-length M(iddle)HBs, the truncated MHBst is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated by regulatory elements of the human proto-oncogenes c-fos and c-myc, as well as by the hepatic acute-phase interleukin-6 gene. Synthetic binding sites for the transcription factors NF-kappa B, AP-1, AP-2, SRE, and Sp1 render minimal promoters activatable. NF-kappa B-mediated transactivation by MHBst can be suppressed by radical scavenging antioxidants, indirectly suggesting that reactive oxygen intermediates are involved.(ABSTRACT TRUNCATED AT 250 WORDS)
流行病学数据表明，慢性乙型肝炎病毒（HBV）感染在肝细胞癌（HCC）发生过程中起关键作用。在分子水平上，HBV序列常整合于肝细胞DNA中。然而，与土拨鼠模型不同，在土拨鼠模型中多数情况下可检测到特异性HBV-DNA整合，而在人类中细胞基因的插入激活似乎是罕见事件。最近发现HBx和截短的HBs（表面）蛋白具有反式激活功能，这支持了细胞基因表达的反式激活可能与肝癌发生相关的观点。HBV反式激活序列存在于81%（21/26）的HCC组织或肝癌衍生细胞系中。在迄今研究的所有病例中，至少有一种反式激活蛋白具有功能。16.5 kDa的HBx反式激活蛋白已被证明可刺激多种细胞靶序列的基因表达。在体外，HBx具有致癌潜力。第二种反式激活蛋白由HBV的前S/S区编码。与HBx不同，HBs反式激活蛋白需要羧基末端截短才能获得其反式激活功能。与全长M（中）HBs不同，截短的MHBst保留在内质网中，不分泌到周围介质中。细胞基因表达受到人类原癌基因c-fos和c-myc的调控元件以及肝脏急性期白细胞介素-6基因的刺激。转录因子NF-κB、AP-1、AP-2、SRE和Sp1的合成结合位点可使最小启动子具有活性。MHBst介导的NF-κB反式激活可被自由基清除抗氧化剂抑制，这间接表明活性氧中间体参与其中。（摘要截短于250字）
