Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas
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DOI：
10.1172/jci31871
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Bromberg, Jacqueline F.
中科院分区：
文献类型：
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作者：
Gao, Sizhi Paul;Mark, Kevin G.;Bromberg, Jacqueline F.
在50%的肺腺癌中发现了持续活化或酪氨酸磷酸化的STAT 3（pSTAT 3）。pSTAT 3存在于原发性腺癌和EGFR酪氨酸激酶结构域中含有体细胞激活突变的细胞细颗粒中。用EGFR抑制剂或src激酶抑制剂处理细胞微粒对pSTAT 3水平没有影响，而pan-JAK抑制剂（P6）阻断了STAT 3的激活并抑制了肿瘤发生。表达这些持续激活的突变EGFR的细胞微粒也产生高IL-6水平，并且IL-6/gp 130/JAK途径的阻断导致pSTAT 3水平的降低。此外，通过RNA干扰降低IL-6水平导致肿瘤发生减少。将持续活化的EGFR引入永生化乳腺上皮细胞导致肿瘤发生、IL-6表达和STAT 3活化，所有这些都可以用P6或gp 130阻断剂抑制。此外，在多种细胞系中抑制EGFR活性部分阻断了IL-6的转录，同时降低了IL-6的产生和释放。最后，免疫组化分析显示pSTAT 3和IL-6阳性之间的正相关性在原发性肺腺癌。因此，突变型EGFR可以通过IL-6上调激活原发性人肺腺癌中的gp 130/JAK/STAT 3通路，使该通路成为癌症治疗的潜在靶点。
Persistently activated or tyrosine-phosphorylated STAT3 (pSTAT3) is found in 50% of lung adenocarcinomas. pSTAT3 is found in primary adenocarcinomas and cell fines harboring somatic-activating mutations in the tyrosine kinase domain of EGFR. Treatment of cell fines with either an EGFR inhibitor or an src kinase inhibitor had no effect on pSTAT3 levels, whereas a pan-JAK inhibitor (P6) blocked activation of STAT3 and inhibited tumorigenesis. Cell fines expressing these persistently activated mutant EGFRs also produced high IL-6 levels, and blockade of the IL-6/gp130/JAK pathway led to a decrease in pSTAT3 levels. In addition, reduction of IL-6 levels by RNA interference led to a decrease in tumorigenesis. Introduction of persistently activated EGFR into immortalized breast epithelial cells led to tumorigenesis, IL-6 expression, and STAT3 activation, all of which could be inhibited with P6 or gp130 blockade. Furthermore, inhibition of EGFR activity in multiple cell lines partially blocked transcription of IL-6 and concurrently decreased production and release of IL-6. Finally, immunohistochemical analysis revealed a positive correlation between pSTAT3 and IL-6 positivity in primary lung adenocarcinomas. Therefore, mutant EGFR could activate the gp130/JAK/STAT3 pathway by means of IL-6 upregulation in primary human lung adenocarcinomas, making this pathway a potential target for cancer treatment.