Gene-expression profiles of a hepatitis B small surface antigen-secreting cell line reveal upregulation of lymphoid enhancer-binding factor 1

Abstract

The genome of hepatitis B virus (HBV) consists of four open reading frames, encoding the envelope proteins (Pre-S/S), the core proteins (Pre-C/C), the polymerase (P) and the transactivating X protein (X). In the sera of HBV-infected patients, hepatitis B surface antigen (HBsAg) particles without the viral genome can outnumber virions by more than 1000-fold. To analyse the interactions between HBsAg and host cells, global gene-expression profiles of a small HBsAg (SHBs)-secreting stable cell line (HepG2-S-G2) and its counterpart control cell line (HepG2-Neo-F4) were compared. Marked upregulation of lymphoid enhancer-binding factor 1 (LEF-1), a transcription factor in the Wnt pathway, was found in SHBs-expressing cells and was confirmed by interference experiments with small interfering RNA. However, compared with the control cells, HepG2-S-G2 did not show higher proliferative competence in culture or increased tumorigenesis in nude mice. A possible mechanism to explain the discrepancy between the upregulation of LEF-1 and the lack of increased tumorigenesis is SHBs expression resulting in altered expression and distribution of LEF-1 protein in cell compartments and upregulation of LEF-1 isoforms that could suppress, rather than enhance, the Wnt pathway.

Dose‐response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women

“…26,28 It was demonstrated that HBsAg could stimulate proliferation and functional modification of hepatocytes via lymphoid enhancer-binding factor 1 through the Wnt pathway at the pre-malignant stage. 29,30 Taken together, these data suggested that higher expression of HBsAg could promote malignant transformation in hepatocytes via direct or indirect effect on many cellular functions, which was consistent with the epidemiological observation of a higher risk of HCC in patients with increasing levels of HBsAg in present study.…”

The Wnt pathway: a key network in cell signalling dysregulated by viruses

“…Other HBV proteins linked to Wnt include the core (HBcAg) protein shown to bind to 41 Wnt pathway gene promoters, although functional effects remain unproven , and HBsAg that has been shown to upregulate LEF‐1, CCND1 and MYC in vitro . Other studies linking HBV to Wnt report upregulated DVL3 , upregulation of Wnt1 protein on HBV infected HCC patients (20) and upregulation of Wnt3a and FZD7 in HBV associated HCC samples (21).…”

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

“…By microarray study of cells transfected with the S gene coding for HBsAg, we have previously shown that marked up-regulation of lymphoid enhancer-binding factor 1 (LEF-1), a transcriptional factor in Wnt pathway, was closely correlated with HBsAg expression [ 10 ]. Furthermore, the expression level and cellular distribution of LEF-1 protein, mainly the dominant negative truncated isoform, was changed by the expression of HBsAg.…”