Suppressing the malignant phenotypes of glioma cells by lentiviral delivery of small hairpin RNA targeting hypoxia-inducible factor-1α.
Hypoxic microenvironment of solid tumors is known to shape malignant phenotypes of cancer cells through the dimeric transcription factor hypoxia-inducible factor (HIF)-1. In the present study, the therapeutic effect of targeting α subunit of HIF-1 in glioma cells via lentiviral delivery of small hairpin RNA (shRNA) was evaluated. Data from quantitative real-time PCR and immunohistochemistry demonstrated that HIF-1α was progressively upregulated during the development of gliomas. Lentiviral shRNA targeting HIF-1α led to substantial loss of cell viability, G0/G1-phase cell cycle arrest, apoptosis, and impairment of cell motility and invasiveness in human glioma U87MG cells. Xenograft experiments in nude mice further showed that HIF-1α-shRNA inhibited tumor growth and caused persistent repression of HIF-1α and its target genes, including VEGF, GLUT1 and MMP2, up to 25 days post-inoculation. Taken together, lentiviral delivery of shRNA is a promising therapeutic approach for targeting HIF-1α in glioma.
Institute of Molecular Ecology and Evolution, IAIR, East China Normal University Shanghai 200062, PR China.
Chang Gui
CG
Dong
William K K
WK
Wu
Su Yin
SY
Feng
Jun
J
Yu
Jun Fei
JF
Shao
Gui Mei
GM
He
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering
Hypoxia-inducible factor; glioma; lentivirus; short hairpin RNA