Adenovirus-mediated Il-24 expression suppresses hepatocellular carcinoma growth via induction of cell apoptosis and cycling arrest and reduction of angiogenesis.
Previous studies have shown that interleukin (IL)-24 as a novel tumor suppressor gene has tumor-suppressor activity in a broad spectrum of human cancer cells both in vitro and in vivo. In this study, we explored the potential effect of adenovirus-mediated IL-24 gene therapy on human hepatocellular carcinoma (HCC) by using a HCC cell line, SMMC-7721. We constructed a recombinant adenovirus, AdVGFP/IL-24 expressing the marker green fluorescent protein (GFP) and the tumor-suppressor gene, IL-24. We demonstrated that AdVGFP/IL-24 treatment of SMMC-7721 cells in vitro significantly induced HCC cell cytotoxicity and apoptosis, and altered HCC cell cycling with an S-phase reduction and G2/M phase arrest, compared with AdVGFP, without IL-24 expresssion (p < 0.05). Furthermore, we also showed that the treatment of SMMC-7721 tumors by an intratumoral injection of AdVGFP/IL-24 significantly suppressed in vivo HCC growth in athymic nude mice, compared with AdVGFP treatment (p < 0.05). In addition, we also elucidated the molecular mechanism responsible for AdVGFP/IL-24-associated tumor suppression. These include: (1) upregulation of p53-independent apoptosis-associated caspase-3 and (2) downregulation of angiogenesis-associated vascular endothelial growth factor and CD34. Therefore, this study will provide a framework for future clinical applications of AdVGFP/IL-24 in HCC gene therapy.
Wang
Xiaohua
X
Cell and Molecular Biology Institute, College of Medicine, Soochow University, SuZhou, China.
Ye
Zhenmin
Z
Zhong
Jiang
J
Xiang
Jim
J
Yang
Jicheng
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D018952:Antigens, CD34; D053148:Caspase 3; D007378:Interleukins; D042461:Vascular Endothelial Growth Factor A; D000099180:Interleukin-24