HCV core通过活化Wnt/β-catenin信号通路诱导肝前体细胞向肝癌干细胞分化

丙型病毒性肝炎（hepatitis C virus，HCV）慢性感染及肝前体细胞向肝癌干细胞分化是原发性肝癌(hepatocellular carcinoma，HCC)的重要致病因素。且Wnt信号参与维持肝癌干细胞特性，但HCV能否通过活化Wnt信号诱导肝前体细胞向肝癌干细胞分化尚不清楚。本室研究发现，在HCV core诱导分化的肝前体细胞中，HCV core抑制成熟肝细胞标志物Alb、CK18的表达，糖原储存能力显著下降（P<0.05），且上调肝癌干细胞标志物EpCAM、CD133、CD44等表达。另外，HCV core增强β-联蛋白活性及表达水平，促使β-联蛋白向核内聚集，上调其下游靶基因EpCAM、细胞周期蛋白D1、C-myc的表达，沉默β-联蛋白后，Wnt/β-catenin通路其下游靶基因表达明显受到抑制，糖原储存能力部分恢复，荧光共聚焦显示HCV core与β-联蛋白在细胞核内存在共定位。因此，HCV core可能与β-联蛋白相互作用，直接活化Wnt/β-catenin通路，上调其下游靶基因EpCAM等表达，诱导肝前体细胞向肝癌干细胞分化。

HCV Core-mediated Transdifferentiation of Hepatic Progenitor Cells into Hepatic Cancer Stem Cells through Activating the Wnt/β-catenin Signaling Pathway

Chronic hepatitis C virus （HCV） infection and transdifferentiation of hepatic progenitor cells (HPCs) into hepatic cancer stem cells (HCSCs) are important causes of primary hepatocellular carcinoma (HCC). Although the Wnt signaling pathway plays an important role in the maintenance of HCSCs, whether HCV could induce the differentiation of HPCs into HCSCs through activating the Wnt signal pathway remains unclear. In core-expressing HPCs, we found that the HCV core inhibited the expression of Alb and CK18, significantly decreased the capacity of glycogen storage (P<0.05), and upregulated the expression of HCSC biomarkers including EpCAM, CD133 and CD44. In addition, the HCV core significantly increased the activity and expression of β-catenin, promoted its nuclear translocation and activated the expression of Wnt-targeted genes including EpCAM, CyclinD1 and C-myc. After β-catenin knockdown, its target genes were significantly suppressed and the capacity of glycogen storage was recovered. Moreover, data of the fluorescence confocal test indicated that the HCV core and β-catenin co-localized in the nucleus. In conclusion, our study suggests that the HCV core may interact with β-catenin, induce Wnt/β-catenin activation, promote the expression of Wnt target genes, such as EpCAM and result in the transdifferentiation of HPCs into HCSCs.