Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer
Secretion of cytokines and growth factors as a general cause of constitutive NFκB activation in cancer
复制标题
DOI：
10.1038/sj.onc.1207332
复制
发表时间：
2004-03-18
期刊：
影响因子：
8
通讯作者：
Stark, GR
中科院分区：
文献类型：
--
作者：
Lu, T;Sathe, SS;Stark, GR
核因子κ B（NF κ B）的组成性激活有助于多种肿瘤抵抗凋亡并使其对化疗不敏感，但其原因在很大程度上仍然未知。我们已经分析了这一现象，在8个突变细胞系来自人类293细胞，选择NF κ B依赖性表达的标记基因，也在7个肿瘤衍生的细胞系。来自所有这些细胞的条件培养基刺激携带NF κ B应答性报道基因的指示细胞中NF κ B的活化（高达30倍）。因此，细胞外因子的分泌作为组成性激活的原因似乎是普遍的。编码几种不同细胞因子和生长因子的mRNA在肿瘤和突变细胞中大量过表达。过表达的模式在每个细胞系中是不同的，表明该现象是复杂的。两个分泌因子，其在NF κ B的组成性激活中的作用还没有很好地定义，作为纯蛋白进一步研究：转化生长因子β 2（TGF β 2）和成纤维细胞生长因子5（FGF 5）都在一些突变克隆和肿瘤细胞系中高度表达，各自单独激活NF κ B，并且组合是协同的。我们的数据表明，一组不同的因素，在异常高的水平表达，可以单独和协同的组成性激活NF κ B在所有的突变体和肿瘤细胞系，我们研究。由于几种NF κ B靶基因编码诱导NF κ B的分泌蛋白，自分泌环可能在癌症中NF κ B的组成性激活中普遍重要。我们提供了第一个证据的一般，复杂的，和协同激活的NF κ B在肿瘤和突变细胞系通过分泌因子的作用，并建议同样的解释是可能的组成性激活的NF κ B在癌症。
The constitutive activation of nuclear factor kappaB ( NFkappaB) helps a variety of tumors to resist apoptosis and desensitizes them to chemotherapy, but the causes are still largely unknown. W e have analysed this phenomenon in eight mutant cell lines derived from human 293 cells, selected for NFkappaB- dependent expression of a marker gene, and also in seven tumor- derived cell lines. Conditioned media from all of these cells stimulated the activation of NFkappaB ( up to 30- fold) in indicator cells carrying an NFkappaB- responsive reporter. Therefore, secretion of extracellular factors as the cause of constitutive activation seems to be general. The mRNAs encoding several different cytokines and growth factors were greatly overexpressed in the tumor and mutant cells. The pattern of overexpression was distinct in each cell line, indicating that the phenomenon is complex. Two secreted factors whose roles in the constitutive activation of NFkappaB are not well defined were investigated further as pure proteins: transforming growth factor beta2 ( TGFbeta2) and fibroblast growth factor 5 ( FGF5) were both highly expressed in some mutant clones and tumor cell lines, each activated NFkappaB alone, and the combination was synergistic. Our data indicate that a group of different factors, expressed at abnormally high levels, can contribute singly and synergistically to the constitutive activation of NFkappaB in all of the mutant and tumor cell lines we studied. Since several NFkappaB target genes encode secreted proteins that induce NFkappaB, autocrine loops are likely to be ubiquitously important in the constitutive activation of NFkappaB in cancer. We provide the first evidence of the general, complex, and synergistic activation of NFkappaB in tumor and mutant cell lines through the action of secreted factors and suggest that the same explanation is likely for the constitutive activation of NFkappaB in cancers.