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Int J Cancer. 2017 Mar 15;140(6):1346-1355. doi: 10.1002/ijc.30553.

HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway.

Zhu M1,2, Li W1,2, Lu Y1,2, Dong X1,2, Lin B1,2, Chen Y1,2, Zhang X1,2, Guo J1,2, Li M1,2,3.

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Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.
Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
Hainan Medical College, Institution of Tumour, Haikou, 570102, Hainan Province, People's Republic of China.


Hepatitis B virus (HBV)-X protein (HBx) plays critical role in inducing the malignant transformation of liver cells. Alpha fetoprotein (AFP) expression is closely related to hepatocarcinogenesis. We report that Oct4, Klf4, Sox2 and c-myc expression positively associated with AFP(+)/HBV(+) hepatocellular carcinoma(HCC) tissues, and the expression of the stemness markers CD44, CD133 and EpCAM was significantly higher in AFP(+)/HBV(+) HCC tissues compared to normal liver tissues or AFP (-)/HBV(-) HCC tissues. AFP expression turned on prior to expression of Oct4, Klf4, Sox2 and c-myc, and the stemness markers CD44, CD133 and EpCAM in the normal human liver L-02 cell line or CHL cell lines upon transfection with MCV-HBx vectors. Stem-like cells generated more tumour colonies compared to primary cells, and xenografts induced tumourigenesis in nude mice. Expression of reprogramming-related proteins was significantly enhanced in HLE cells while transfected with pcDNA3.1-afp vectors. The specific PI3K inhibitor Ly294002 inhibited the effects of pcDNA3.1-afp vectors. AFP-siRNA vectors were able to inhibit tumour colony formation and reprogramming-related gene expression. Altogether, HBx stimulates AFP expression to induce natural reprogramming of liver cells, and AFP plays a critical role in promoting the initiation of HCC progenitor/stem cells. AFP may be a potential novel biotarget for combating HBV-induced hepatocarcinogenesis.


alpha fetoprotein; cancer stem cells; hepatitis B virus x protein (HBx); hepatocarcinogenesis; natural reprogramming

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