title: Phosphatase and tensin homolog reconstruction and vascular endothelial growth factor knockdown synergistically inhibit the growth of glioblastoma.
abstract: Glioblastoma (GBM) is a highly malignant tumor with poor prognosis. Two hallmarks of this disease are a high expression of vascular endothelial growth factor (VEGF) and a depletion of the phosphatase and tensin homolog (PTEN). In the present study, combined gene therapy using wild-type PTEN reconstruction and VEGF siRNA was examined for its effectiveness in inhibiting tumor growth and tumorigenicity of PTEN-null GBM cells. In U251 GBM cells, PTEN restoration reduced proliferation, arrested the cell cycle at G0/G1 stage, and promoted apoptosis via inhibition of PIK/AKT signaling pathway. Unexpectedly, anchorage-dependent and -independent colony formation ability and the capacity for wound-healing migration of U251 cells with stable expression of VEGF siRNA were significantly inhibited, suggesting that VEGF also appeared to function as an autocrine growth factor in addition to its well-known pro-angiogenic paracrine function. Further, a combined treatment of PTEN restoration and VEGF siRNA had the best tumor suppression effect. In a xenograft study in null mice, both the restoration of PTEN and the expression of VEGF siRNA could significantly inhibit the growth of U251 GBMs, whereas tumor growth was entirely suppressed by a combination of the two treatments. Therefore, the combination of PTEN expression and VEGF knockdown represents an effective gene therapy strategy for malignant gliomas.
authors.affiliation: Tsinghua University, Beijing, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chen
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Shen
authors.forename: Caiping
authors.initials: C
authors.lastname: Guo
authors.forename: Huijun
authors.initials: H
authors.lastname: Zhu
authors.forename: Lanzhen
authors.initials: L
authors.lastname: Zhou
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Huixia
authors.initials: H
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Laiqiang
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D055879:Gene Knock-In Techniques / Q000379:methods*; D055785:Gene Knockdown Techniques / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D004318:Doxycycline