Hepatocellular carcinoma and hepatitis B surface protein

Table 1 PreS1/S2/S and hepatocellular carcinoma carcinogenesis

Function	PreS1/S2/S mutation	Ref.
A trans-activator function	Integration of HBV preS/S sequences	Caselmann et al[72] 1990,
		Kekulé et al[75] 1990
Transactivation of NF-κB, or AP and other transcription factors for transactivation, stimulating promoter sequences of the c-myc, c-fos, and c-Ha-ras oncogenes	MHBst	Meyer et al[77] 1992,
		Lauer et al[78] 1994
A transcriptional activator, activated tumor promoter pathways via the PKC-dependent c-Raf-1/ Erk2, MAP1- kinase signal pathway, increase the proliferation rate of hepatocytes	LHBs, the preS2	Hildt et al[17,73,79] 1996, 1998, 2002
Transactivator with DNA-binding properties	HBV surface (S)	Alka et al[76] 2000
Transactivated the simian virus 40 and human c-Myc promoters truncation mutant	Polymerase rtA181T/surface	Lai et al[80] 2008
Activated cell proliferation and transformational abilities	sL95*, sW182*, and sL216*	Huang et al[81] 2014
Interacted with the proteins related to tumor development/progression in vitro	MHBst167	Li et al[83] 2014
Biomarkers of HCC and predictor of recurrence survival	GGHs harbored preS2 mutants in the ER	Malhi et al[90] 2011,
		Su et al[85] 2014
Trigger the ER stress-dependent pathway
VEGF/Akt/mTOR and NF-κB/COX-2 signal pathway in GGHs		Yang et al[96] 2009
Enhance the oncogenic effects in transgenic and human HCCs	Co-expressing hepatitis B virus X protein and surface antigens	Wu et al[97] 2014
An ER stress-independent pathway
Activate JAB1 nuclear translocation and activation of p27/retinoblastoma/Cdk2/cyclin A, D pathways, results in cell cycle progression, cell proliferation, and centrosome over-duplication, a growth advantage in type II GGs	LHBs with preS2 mutants	Wang et al[99] 2005,
		Hsieh et al[101] 2011,
		Wang et al[100] 2012
Immune-associated carcinogenesis
HBV-induced chronic necroinflammation	Pre S/S transgenic mice	Chisari et al[102] 1989
The clonal proliferation of hepatocytes with the preS mutants	The HBV mutants escape from the host’s immune surveillance	Zhong et al[104] 1999
Contributing to HCC in an IL-6-dependent manner only in male patients	A W4P/R mutation in the LHB region of HBV genotype C	Lee et al[82] 2015
Other
Increase microR499a expression, which might play an oncogenic role by targeting MAPK6	HBs proteins	Xiang et al[106] 2014

HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; LHBs: Hepatitis B virus large surface protein; PKC: Protein kinase C; MHBst167: C terminally truncated surface antigen middle protein of hepatitis B virus; MAPK: Mitogen-activated protein kinase; ERK: Extracellular Signal-regulated Kinase signaling; GGHs: “Ground glass” hepatocytes; VEGF: Vascular epithelial growth factor; JAB1: c-Jun activation domain binding protein 1; LHBs: MHBs, large (including the preS1 + preS2 + S domain), middle (including the preS2 + S domain) surface proteins.