Tian Xiaochen, Li Jinjun, Ma Zhang-Mei, Zhao Chao, Wan Da-Fang, Wen Yu-Mei
Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, PR China.
J Exp Clin Cancer Res. 2009 Apr 29;28(1):58. doi: 10.1186/1756-9966-28-58.
There are around 350 million of hepatitis B surface antigen (HBsAg) carriers worldwide, and among them, high risk of developing hepatocellular carcinoma (HCC) has been identified by epidemiological studies. To date, the molecular role of HBsAg in HCC development has not been fully studied. We have previously reported that in cell cultures, HBsAg up-regulated the expression of lymphoid enhancer-binding factor 1 (LEF-1), a key component of the Wnt pathway. In this study we aimed to study this effect of HBsAg on LEF-1 in the development of HCC.
Expression of HBsAg, LEF-1 and its downstream effector genes were compared among 30 HCCs, their peritumor tissue counterparts and 9 normal control liver tissues by quantitative real-time PCR. In addition, immunohistochemical staining studies on HBsAg and LEF-1 expression were conducted among these samples.
The expression of LEF-1 was compared between 13 HBsAg positive HCC tissues and 17 HBsAg negative HCC tissues. Simultaneous detection of LEF-1 and HBsAg was observed in HBsAg positive HCC tissues and, additionally, the simultaneous detection of HBsAg and LEF-1 was more pronounced in peritumor tissues, compared to that in the tumor tissues. The distribution of cellular LEF-1 in peritumor tissues was predominantly in the cytoplasm; while LEF-1 in the tumor tissues was located either exclusively in the nucleus or both in the nucleus and cytoplasm. By real-time PCR, the expression levels of LEF-1 downstream effector genes cyclin D1 and c-myc were higher in peritumor cells compared to that of the tumor cells. However, a 38 kDa truncated isoform of LEF-1, rather than the 55 kDa wild-type LEF-1, was significantly elevated in the HBsAg positive tumor cells.
Data indicate that deregulation of the Wnt pathway by HBsAg occurred in HBV-associated HCCs, but was more pronounced in the peritumor cells. It is speculated that HBsAg could stimulate proliferation and functional modification of hepatocytes via LEF-1 through the Wnt pathway at the pre-malignant stage.
全球约有3.5亿乙肝表面抗原（HBsAg）携带者，流行病学研究已确定他们患肝细胞癌（HCC）的风险很高。迄今为止，HBsAg在HCC发生发展中的分子作用尚未得到充分研究。我们之前报道过，在细胞培养中，HBsAg上调了淋巴样增强子结合因子1（LEF-1）的表达，LEF-1是Wnt信号通路的关键组成部分。在本研究中，我们旨在研究HBsAg对LEF-1在HCC发生发展中的影响。
通过定量实时PCR比较30例HCC及其癌旁组织对应物和9例正常对照肝组织中HBsAg、LEF-1及其下游效应基因的表达。此外，对这些样本进行了HBsAg和LEF-1表达的免疫组化染色研究。
比较了13例HBsAg阳性HCC组织和17例HBsAg阴性HCC组织中LEF-1的表达。在HBsAg阳性HCC组织中观察到LEF-1和HBsAg的同时检测，此外，与肿瘤组织相比，癌旁组织中HBsAg和LEF-1的同时检测更为明显。细胞LEF-1在癌旁组织中的分布主要在细胞质中；而肿瘤组织中的LEF-1要么仅位于细胞核中，要么同时位于细胞核和细胞质中。通过实时PCR，与肿瘤细胞相比，癌旁细胞中LEF-1下游效应基因细胞周期蛋白D1和c-myc的表达水平更高。然而，在HBsAg阳性肿瘤细胞中，显著升高的是38 kDa截短异构体的LEF-1，而非55 kDa野生型LEF-1。
数据表明，HBsAg对Wnt信号通路的失调发生在HBV相关的HCC中，但在癌旁细胞中更为明显。推测HBsAg可在癌前阶段通过Wnt信号通路经LEF-1刺激肝细胞的增殖和功能改变。
