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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.

Author information

1
Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, 571199, Hainan Province, People's Republic of China.
2
Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, 571199, People's Republic of China.
3
Hainan Medical College, Institution of Tumour, Haikou, 570102, Hainan Province, People's Republic of China.

Abstract

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.

KEYWORDS:

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

PMID:
27925189
DOI:
10.1002/ijc.30553
[Indexed for MEDLINE]
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