Local delivery of recombinant adenovirus expressing hepatitis B virus             X protein and interleukin-12 results in antitumor effects via inhibition of hepatoma             cell growth and intervention of tumor microenvironment.
Hepatocellular carcinoma (HCC) is a typical hypervascular tumor. Our previous studies have demonstrated that hepatitis B virus X protein (HBx) was able to inhibit the growth of HCC cells via inducing apoptosis and inhibiting tumor angiogenesis. Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine with potent immunostimulatory activity and anti-angiogenic properties. In this study, to further investigate the regulatory effect of IL-12 on HBx-mediated intervention of hepatoma microenvironment especially on intervention of neovessels and immune microenvironment, we constructed the recombinant adenovirus expressing HBx and mouse IL-12 named Ad-HBx-mIL-12. HBx-mIL-12 could effectively suppress tumor growth and induce apoptosis in vivo. Moreover, treatment with Ad-HBx-mIL-12 not only induced a massive accumulation of immune cells (CD8(+) T leukocytes, macrophages and dendritic cells) in tumors in situ, also apparently reduced the number of angiogenic blood vessels within tumor tissues. These results suggest that HBx-mIL-12 can not only induce cell cycle arrest and apoptosis in HCC cells, but also effectively shift the tumor microenvironment from pro-oncogenic to antitumor through recruitment of immune cells and inhibiting stromal cell growth, such as vascular endothelial cells.
State Key Laboratory of Biotherapy and Cancer Center, West China                     Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan,                     P.R. China.
Hong
H
He
Ping
P
Fan
Tao
T
Yin
Qiaoling
Q
Chen
Huashan
H
Shi
Sijia
S
Liu
Haoyu
H
Li
Qiuping
Q
Jing
Yingying
Y
Yan
Hailong
H
Zhang
Li
L
Yang
Yanjun
Y
Wen
Yuhua
Y
Li
Ping
P
Cheng
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015534:Trans-Activators / Q000235:genetics*; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins
D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D018664:Interleukin-12