JAK2／STAT3信号通路对非小细胞肺癌血管生成的影响

Effects of JAK2/STAT3 signaling pathway on angiogenesis in non-small cell lung cancer

目的探讨两面神激酶2／信号转导及转录活化因子3（JAK2／STAT3）信号通路与非小细胞肺癌（NSCLC）微血管形成之间的关系，以及干预JAK2／STAT3信号通路对血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）表达的影响。方法应用免疫组织化学方法检测68例NSCLC和27例正常肺组织中P—JAK2、P—STAT3的表达及微血管密度（MVD）值，并分析与各临床、病理参数的关系；使用不同浓度的JAK2抑制剂AG490处理人肺腺癌细胞A549后，M1Tr法检测细胞的增殖状态，Westernblot法检测JAK2／STAT3信号通路的活化状态，RT—PCR法检测AG490对VEGF、bFGF mRNA的表达的影响；在A549细胞中转染STAT3小干扰RNA（siRNA），Westernblot法检测STAT3及磷酸化-STAT3（P—STAT3）蛋白的表达，RT—PCR法检测VEGF、bFGF mRNA的表达。结果NSCLC的免疫组化结果显示JAK2／STAT3信号通路的活化与MVD计数正相关（P〈0．05）；使用AG490和STAT3 siRNA干预该通路的活化后，VEGF和bFGF mRNA的表达下降（P〈0．05）。结论JAK2／STAT3信号转导通路与肺癌微血管生成密切相关，阻断该通路的活化能抑制血管生成相关因子的表达，提示JAK2／STAT3信号通路是抑制肺癌微血管生成的重要靶点。

Objective To investigate the relationship between janus kinase2/signal transducer and activator of transcription 3 （JAK2/STA33） signaling pathway and angiogenesis in non-small cell lung cancer （NSCLC） and explore the effects on the mRNA expression of vascular endothelial growth factor （VEGF） and basic fibroblast growth factor （bFGF） by blocking JAK2/STA33 signaling pathway. Methods Immunohistochemistry was used to determine the expression of P-JAK2, P-STA33 and microvessel density （MVD） in 68 NSCLC tissues and 27 normal lung tissues. And the relationship with their clinical pathological features was analyzed. Human lung cancer A549 cells were treated with different concentrations of AG490. Cell proliferation was measured by MTF assay. Western blot was performed to detect the activation of JAK2/STArI3 signaling pathway. The mRNA expressions of VEGF and bFGF were determined by RT-PCR （reverse transcription-polymerase chain reaction）. A549 cells were transfected with STA33 siRNA. And the protein of STA33, Phos-STA33 （ P-STA33 ） and mRNA levels of VEGF and bFGF were detected. Results The activation of JAK2/STAT3 signaling pathway was closely related to MVD in NSCLC. AG490 and STA33 siRNA could block the JAK2/STAT3 signaling pathway and down-regulated the mRNA expressions of VEGF and bFGF in lung cancer cells. Conclusion JAK2/STA33 signaling pathway plays an important role in the angiogenesis of NSCLC. Blocking this pathway may inhibit the expression of angiogenic cytokines. JAK2/STA33 signaling pathway may be a critical therapeutic target for the treatment of angiogenesis in NSCLC.