Role of hepatitis B surface antigen in the development of hepatocellular carcinoma: regulation of lymphoid enhancer-binding factor 1.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tian
Xiaochen
X
Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, PR China. xiaochentian@hotmail.com
Li
Jinjun
J
Ma
Zhang-Mei
ZM
Zhao
Chao
C
Wan
Da-Fang
DF
Wen
Yu-Mei
YM
D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism
D006514:Hepatitis B Surface Antigens; D051821:Lymphoid Enhancer-Binding Factor 1; C489427:MYC protein, human; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D051153:Wnt Proteins; D019938:Cyclin D1