Potent antitumor effect of TRAIL mediated by a novel adeno-associated viral vector targeting to telomerase activity for human hepatocellular carcinoma.
BACKGROUND
Adeno-associated virus (AAV) has rapidly become a promising gene delivery vehicle for its excellent advantages of low pathogenicity and long-term gene expression. However, lack of tissue specificity caused low efficiency of AAV transfer to target cells. The promoter of human telomerase reverse transcriptase (hTERT) has been implicated in mediating gene expression in cancer cells as hTERT is transcriptionally upregulated in most cancer cells. Thereby, the hTERT promoter becomes a good candidate to enhance the targeting efficiency of AAV in cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) functions as a soluble cytokine to selectively kill various cancer cells without toxicity to most normal cells. It remains to be determined whether the hTERT promoter can efficiently mediate TRAIL gene therapy in cancer cells using AAV vector.


METHODS
A novel AAV vector containing the TRAIL gene under the control of the hTERT promoter (AAV-hTERT-TRAIL) was generated. The specific expression of hTERT-controlled genes was evaluated in cell lines. The antitumor efficacy of AAV-hTERT-TRAIL was assessed in tumor cell lines and human hepatocellular carcinoma xenograft mouse model.


RESULTS
TRAIL expression was observed in tumor cells infected with AAV-hTERT-TRAIL at both the protein and mRNA level. AAV-hTERT-TRAIL displayed cancer-specific cytotoxicity and induced tumor cell apoptosis. Moreover, in animal experiments, intratumoral administration of AAV-hTERT-TRAIL significantly suppressed the growth of xenograft tumors and resulted in tumor cell death.


CONCLUSIONS
AAVs in combination with hTERT-mediated therapeutic gene expression provide a promising targeting approach for developing effective therapy for human cancers. These data suggest that AAV-hTERT-TRAIL is a potent therapeutic agent for cancer therapy.
Wang
Yigang
Y
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Huang
Fang
F
Cai
Haibo
H
Zhong
Suyang
S
Liu
Xinyuan
X
Tan
Wen-Song
WS
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D019098:Telomerase / Q000235:genetics*
D053221:TNF-Related Apoptosis-Inducing Ligand; C509186:TERT protein, human; D019098:Telomerase