Adenovirus-mediated delivery of bFGF small interfering RNA reduces STAT3 phosphorylation and induces the depolarization of mitochondria and apoptosis in glioma cells U251

作者：Liu, Jun; Xu, Xinnv; Feng, Xuequan; Zhang, Biao; Wang, Jinhuan^*

来源：Journal of Experimental & Clinical Cancer Research, 2011, 30(1): 80.

DOI：10.1186/1756-9966-30-80

• bFGF
• STAT3
• IL-6
• Glioblastoma multiforme

Glioblastoma multiforme (GBM) carries a dismal prognosis primarily due to its aggressive proliferation in the brain regulated by complex molecular mechanisms. One promising molecular target in GBM is over-expressed basic fibroblast growth factor (bFGF), which has been correlated with growth, progression, and vascularity of human malignant gliomas. Previously, we reported significant antitumor effects of an adenovirus-vector carrying bFGF small interfering RNA (Ad-bFGF-siRNA) in glioma in vivo and in vitro. However, its mechanisms are unknown. Signal transducer and activator of transcription 3 (STAT3) is constitutively active in GBM and correlates positively with the glioma grades. In addition, as a specific transcription factor, STAT3 serves as the convergent point of various signaling pathways activated by multiple growth factors and/or cytokines. Therefore, we hypothesized that the proliferation inhibition and apoptosis induction by Ad-bFGF-siRNA may result from the interruption of STAT3 phosphorylation. In the current study, we found that in glioma cells U251, Ad-bFGF-siRNA impedes the activation of ERK1/2 and JAK2, but not Src, decreases IL-6 secretion, reduces STAT3 phosphorylation, decreases the levels of downstream molecules CyclinD1 and Bcl-xl, and ultimately results in the collapse of mitochondrial membrane potentials as well as the induction of mitochondrial-related apoptosis. Our results offer a potential mechanism for using Ad-bFGF-siRNA as a gene therapy for glioma. To our knowledge, it is the first time that the bFGF knockdown using adenovirus-mediated delivery of bFGF siRNA and its potential underlying mechanisms are reported. Therefore, this finding may open new avenues for developing novel treatments against GBM.

• 出版日期2011-9-9
• 单位天津市第一中心医院; 天津市环湖医院; 天津医科大学