Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway
Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway
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DOI：
10.1038/sj.onc.1206226
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发表时间：
2003-03-13
期刊：
影响因子：
8
通讯作者：
Hsieh, CY
中科院分区：
文献类型：
--
作者：
Wei, LH;Kuo, ML;Hsieh, CY
白介素6(IL-6)在宫颈癌的发病机制中受到了特别的关注，但其潜在的机制仍不清楚。本研究表明，IL-6促进了人宫颈癌C33A细胞体内肿瘤的生长，但不显著改变其体外生长动力学。体内血管生成试验表明，IL-6增强了人宫颈癌细胞的血管生成活性，这种作用与血管内皮生长因子(VEGF)的上调有关。同时，用抗血管内皮生长因子抗体阻断血管内皮生长因子功能可显著抑制IL-6介导的血管生成和裸鼠体内肿瘤生长，有力地支持了血管内皮生长因子在IL-6介导的宫颈肿瘤发生中的关键作用。因此，我们研究了IL-6/IL-6R下游调控血管内皮生长因子的信号通路。值得注意的是，药物抑制PI3-K或MAPK不能抑制IL-6介导的血管内皮生长因子的转录上调。同时，用显性-负性突变体STAT3D阻断STAT3通路可有效阻断IL-6诱导的血管内皮细胞生长因子基因表达。在瞬时转染中，含有全长1.5kb的VEGF启动子的荧光素酶报告结构或缺少已知的低氧反应元件的1.2kb片段也对IL-6表现出相同程度的反应。此外，瞬时转染STAT3D下调了IL-6刺激的1.2kb的VEGF启动子荧光素酶报告基因的表达。基于上述现象，结合宫颈癌组织中IL-6和VEGF的表达增加，我们认为IL-6可能通过STAT3途径激活VEGF介导的血管生成来促进宫颈肿瘤的发生。
Interleukin-6 (IL-6) has received particular attention in the pathogenesis of cervical cancer, although the underlying mechanism remains elusive. This study revealed that IL-6 promotes in vivo tumor growth of human cervical cancer C33A cells, but does not substantially alter their in vitro growth kinetics. The in vivo angiogenic assays showed that IL-6 increases angiogenic activity in human cervical cancer cells, an effect that is specifically associated with upregulation of vascular endothelial growth factor (VEGF). Also, using anti-VEGF antibody to block VEGF function significantly inhibited IL-6-mediated angiogenesis and tumor growth in nude mice, strongly supporting the critical role of VEGF in the IL-6-mediated cervical tumorigenesis. Accordingly, the signaling pathway downstream of IL-6/ IL-6R responsible for the regulation of VEGF was investigated. Notably, pharmacological inhibition of PI3-K or MAPK failed to inhibit IL-6-mediated transcriptional upregulation of VEGF. Meanwhile, blocking STAT3 pathway with dominant-negative mutant STAT3D effectively abolished IL-6-induced VEGF mRNA. In transient transfections, a luciferase reporter construct containing the full-length 1.5-kb VEGF promoter or a 1.2-kb fragment lacking the known hypoxic-response element also exhibited the same degree of response to IL-6. Additionally, transient transfection of STAT3D downregulated the 1.2-kb VEGF promoter luciferase reporter stimulated by IL-6. Based on the above phenomenon combined with the concomitant increased tumor expression of IL-6 and VEGF in cervical cancer tissues, we conclude that IL-6 may promote cervical tumorigenesis by activating VEGF-mediated angiogenesis via a STAT3 pathway.