Hepatitis B Virus X (HBx) Induces Tumorigenicity of Hepatic Progenitor Cells in 3,5–Diethoxycarbonyl–1,4–Dihydrocollidine–Treated HBx Transgenic Mice

作者：Chao Wang, Wen Yang, He–Xin Yan, Tao Luo, Jian Zhang, Liang Tang, Fuquan Wu, Hui‐Lu Zhang, Le‐Xing Yu, Longyi Zheng, Yuqiong Li, Wei Dong, Yaqin He, Qiong Liu, Shan–Shan Zou, Yan Lin, Liang Hu, Zhong Li, Mengchao Wu, Hong‐Yang Wang · 发表于：Hepatology · 年份：2011 · DOI：10.1002/hep.24675 · 被引用次数：146 · 研究领域：Hepatitis B Virus Studies、Hepatocellular Carcinoma Treatment and Prognosis、Liver physiology and pathology

UNLABELLED: 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 ...