Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models.
Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models.
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DOI：
10.3892/ijo.33.1.161
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发表时间：
2008-07
影响因子：
5.2
通讯作者：
Liwei Wang;Xiao-Hui Guan;Jun Zhang;Z. Jia;D. Wei;Qiang Li;James C. Yao;K. Xie
中科院分区：
文献类型：
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作者：
Liwei Wang;Xiao-Hui Guan;Jun Zhang;Z. Jia;D. Wei;Qiang Li;James C. Yao;K. Xie
转录因子Sp1的过表达可能在人胃癌血管生成中起关键作用。在目前的研究中，我们确定靶向Sp1是否具有治疗益处。米霉素A （MIT）抑制Sp1及其下游靶基因在人胃癌细胞培养和裸鼠肿瘤生长中的表达。分子反应伴随着对胃癌血管生成、生长和转移的显著抑制。相反，贝伐珠单抗（BVZ）是一种抗VEGF a的中和抗体，在裸小鼠中以剂量依赖的方式抑制人胃癌的生长。基因表达分析显示，低剂量BVZ治疗显著上调Sp1及其下游靶基因（包括VEGF和EGFR）在肿瘤组织中的表达，而对培养的胃癌细胞没有这种影响。BVZ与MIT联合治疗可协同抑制肿瘤，这与抑制Sp1及其下游靶基因的表达一致。因此，用BVZ治疗可能会阻断VEGF功能，但通过正反馈激活其表达途径。综上所述，Sp1是多种血管生成因子表达的重要调控因子，Sp1信号通路的功能状态可能深刻影响人胃癌的血管生成表型和抗血管生成策略的有效性。
Overexpression of the transcription factor Sp1 may play a critical role in human gastric cancer angiogenesis. In the present studies, we determined whether targeting Sp1 has a therapeutic benefit. Treatment with mithramycin A (MIT) suppressed the expression of Sp1 and its downstream target genes in both human gastric cancer cell culture and tumors growing in nude mice. The molecular responses were accompanied by a significant inhibition of gastric cancer angiogenesis, growth and metastasis. Conversely, treatment with bevacizumab (BVZ), a neutralizing antibody against VEGF A, suppressed human gastric cancer growth in nude mice in a dose-dependent manner. Gene expression analyses revealed that treatment with low dose of BVZ substantially upregulated the expression of Sp1 and its downstream target genes, including VEGF and EGFR, in tumor tissues, whereas it did not have this effect on gastric cancer cells in culture. Combined treatment with BVZ and MIT produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Thus, treatment with BVZ may block VEGF function but activate the pathway of its expression via positive feedback. Collectively, Sp1 is an important regulator of the expression of multiple angiogenic factors and functional status of Sp1 signaling pathway may profoundly affect the angiogenic phenotype of and effectiveness of antiangiogenic strategies for human gastric cancer.