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Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication

AIM: To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo. METHODS: We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tum...

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Autores principales: Kunanopparat, Areerat, Issara-Amphorn, Jiraphorn, Leelahavanichkul, Asada, Sanpavat, Anapat, Patumraj, Suthiluk, Tangkijvanich, Pisit, Palaga, Tanapat, Hirankarn, Nattiya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Baishideng Publishing Group Inc 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141339/
https://www.ncbi.nlm.nih.gov/pubmed/30228780
http://dx.doi.org/10.3748/wjg.v24.i34.3861
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author Kunanopparat, Areerat
Issara-Amphorn, Jiraphorn
Leelahavanichkul, Asada
Sanpavat, Anapat
Patumraj, Suthiluk
Tangkijvanich, Pisit
Palaga, Tanapat
Hirankarn, Nattiya
author_facet Kunanopparat, Areerat
Issara-Amphorn, Jiraphorn
Leelahavanichkul, Asada
Sanpavat, Anapat
Patumraj, Suthiluk
Tangkijvanich, Pisit
Palaga, Tanapat
Hirankarn, Nattiya
author_sort Kunanopparat, Areerat
collection PubMed
description AIM: To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo. METHODS: We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively. RESULTS: Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours. CONCLUSION: This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication.
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spelling pubmed-61413392018-09-18 Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication Kunanopparat, Areerat Issara-Amphorn, Jiraphorn Leelahavanichkul, Asada Sanpavat, Anapat Patumraj, Suthiluk Tangkijvanich, Pisit Palaga, Tanapat Hirankarn, Nattiya World J Gastroenterol Basic Study AIM: To investigate the role of Delta-like ligand 4 (DLL4) on tumour growth in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) in vivo. METHODS: We suppressed DLL4 expression in an HBV expressing HCC cell line, HepG2.2.15 and analysed the growth ability of cells as subcutaneous tumours in nude mice. The expression of tumour angiogenesis regulators, VEGF-A and VEGF-R2 in tumour xenografts were examined by western blotting. The tumour proliferation and neovasculature were examined by immunohistochemistry. The viral replication and viral protein expression were measured by quantitative PCR and western blotting, respectively. RESULTS: Eighteen days after implantation, tumour volume in mice implanted with shDLL4 HepG2.2.15 was significantly smaller than in mice implanted with control HepG2.2.15 (P < 0.0001). The levels of angiogenesis regulators, VEGF-A and VEGF-R2 were significantly decreased in implanted tumours with suppressed DLL4 compared with the control group (P < 0.001 and P < 0.05, respectively). Furthermore, the suppression of DLL4 expression in tumour cells reduced cell proliferation and the formation of new blood vessels in tumours. Unexpectedly, increased viral replication was observed after suppression of DLL4 in the tumours. CONCLUSION: This study demonstrates that DLL4 is important in regulating the tumour growth of HBV-associated HCC as well as the neovascularization and suppression of HBV replication. Baishideng Publishing Group Inc 2018-09-14 2018-09-14 /pmc/articles/PMC6141339/ /pubmed/30228780 http://dx.doi.org/10.3748/wjg.v24.i34.3861 Text en ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved. http://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
spellingShingle Basic Study
Kunanopparat, Areerat
Issara-Amphorn, Jiraphorn
Leelahavanichkul, Asada
Sanpavat, Anapat
Patumraj, Suthiluk
Tangkijvanich, Pisit
Palaga, Tanapat
Hirankarn, Nattiya
Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title_full Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title_fullStr Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title_full_unstemmed Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title_short Delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis B virus replication
title_sort delta-like ligand 4 in hepatocellular carcinoma intrinsically promotes tumour growth and suppresses hepatitis b virus replication
topic Basic Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141339/
https://www.ncbi.nlm.nih.gov/pubmed/30228780
http://dx.doi.org/10.3748/wjg.v24.i34.3861
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