High mobility group box2 promoter-controlled suicide gene expression enables targeted glioblastoma treatment.
Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5'-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5' sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy.
Balani
Poonam
P
Institute of Bioengineering and Nanotechnology, Singapore.
Boulaire
Jerome
J
Zhao
Ying
Y
Zeng
Jieming
J
Lin
Jiakai
J
Wang
Shu
S
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D041722:Genes, Transgenic, Suicide / Q000235:genetics / Q000502:physiology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D024261:HMGB2 Protein / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D024261:HMGB2 Protein; D015774:Ganciclovir