Activated Notch signaling is required for hepatitis B virus X protein to promote proliferation and survival of human hepatic cells

Hepatitis B virus X protein (HBx) is a multifunctional oncoprotein which plays a crucial role in the pathogenesis of hepatocellular carcinoma (HCC). However, the exact mechanisms remain controversial. Here we show that HBx strongly stimulated cell growth, promoted cell cycle progression and inhibited apoptosis of human non-tumor hepatic cell line L02 cells. It also accelerated tumor formation of L02 cells in BALB/c nude mice. Furthermore, Notch signaling components were upregulated in HBx-expressing L02 cells compared to normal L02 cells. However, blocking Notch signaling with a γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) attenuated cell growth, shortened the S phase of cell cycle and promoted apoptosis of HBx-expressing L02 cell in a dose- and time-dependent manner, but normal L02 cells were not significantly affected by Notch signaling blocking. Therefore, our findings demonstrate that HBx could promote the growth of human non-tumor hepatic cell line L02 cells both in vitro and in vivo, which may require the activation of Notch signaling pathway.