Published online Sep 14, 2018. doi: 10.3748/wjg.v24.i34.3861
Peer-review started: May 25, 2018
First decision: June 21, 2018
Revised: July 5, 2018
Accepted: July 16, 2018
Article in press: July 16, 2018
Published online: September 14, 2018
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) has been studied for many decades. However, the molecular mechanism is still unclear. Notch signaling in HCC pathogenesis is controversial, but we found that HBx promoted HBV-associated HCC proliferation through Delta-like ligand 4 (DLL4) (Notch ligand) in an in vitro study. However, the effect of DLL4 inhibition in HCC has not been explored.
DLL4 has a potential function for angiogenesis that supports tumour growth. The understanding of DLL4 mechanism might lead to identifying a new target for HCC therapy.
We investigated the role of DLL4 on tumour growth in HCC associated with HBV in a xenograft model and detailed the molecular mechanism of HCC.
We inhibited the DLL4 expression in HBV-associated HCC, and then subcutaneously implanted in nude mice. We analysed the ability for tumour growth, angiogenesis regulators (VEGF-A, VEGF-R2) expression, neovasculature, and HBV expression in tumour xenografts.
The tumour volume, VEGF-A, and VEGF-R2 were significantly decreased in mice implanted with suppressed DLL4 HCC compared with the control group. The suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, viral replication increased in DLL4 suppressed tumours.
This study demonstrates that DLL4 is important in regulating the tumour growth and neovascularization in HBV-associated HCC, as well as suppressing HBV replication in vivo.
This study showed that DLL4 is essential for the tumour growth of the implanted HBV-associated HCC cell line, especially in the initiation stage of tumour growth. However, the role of DLL4 as a tumour oncogene and tumour suppressor gene in HCC needs to further clarification.