title: Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice.
abstract: Hepatitis B virus X (HBx) protein is implicated in hepatitis B virus (HBV)-associated liver carcinogenesis. However, it remains unclear whether HBx-expressing hepatic progenitor cells (HPCs) are attributed to liver tumor formation. In this study, by using HBx transgenic mice and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury model, the relationship between HBx expression and tumorigenicity of HPCs was analyzed. Compared with control mice, an elevated number of EpCAM(+) cells with characteristics of HPCs was observed in HBx mice after 1 month and 4 months of DDC diet feeding. All HBx transgenic mice developed liver tumors characterized by histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma after 7 months of DDC feeding. Notably, EpCAM(+) HPCs isolated from premalignant HBx mice exposed to a DDC diet for 4 months formed subcutaneous mixed-lineage tumors (four out of six) in nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and none of the cells from wildtype (WT) induced tumor, indicating that HBx may induce malignant transformation of HPCs that contributes to tumorigenesis. We also found higher titers of circulating interleukin (IL)-6, activities of IL-6/STAT3, and Wnt/β-catenin signaling pathways in HBx transgenic mice, suggesting HBx may induce intrinsic changes in HPCs by way of the above signaling that enables HPCs with tumorigenicity potential. Finally, clinical evidence showed that high HBx expression in human HBV-related HCC was statistically associated with expansion of EpCAM(+) or OV6(+) tumor cells and aggressive clinicopathologic features.
  
  
  CONCLUSIONS
  HBx induces intrinsic cellular transformation promoting the expansion and tumorigenicity of HPCs in DDC-treated mice, which may be a possible origin for liver cancer induced by chronic hepatitis infection.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Wu
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.forename: Le-Xing
authors.initials: LX
authors.lastname: Yu
authors.forename: Long-Yi
authors.initials: LY
authors.lastname: Zheng
authors.forename: Yu-Qiong
authors.initials: YQ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Dong
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: He
authors.forename: Qiong
authors.initials: Q
authors.lastname: Liu
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zou
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Meng-Chao
authors.initials: MC
authors.lastname: Wu
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000503:physiopathology / Q000821:virology; D001653:Bile Ducts, Intrahepatic; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000503:physiopathology / Q000821:virology*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000503:physiopathology / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D011725:Pyridines / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology / Q000821:virology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; D011725:Pyridines; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein