TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion.: A role for TNF-α in keratinocyte migration?
TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion.: A role for TNF-α in keratinocyte migration?
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DOI：
10.1038/sj.onc.1207915
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发表时间：
2004-09-09
期刊：
影响因子：
8
通讯作者：
Balkwill, FR
中科院分区：
文献类型：
--
作者：
Scott, KA;Arnott, CH;Balkwill, FR
缺乏肿瘤坏死因子-α的小鼠(-/-小鼠)对皮肤癌变具有抵抗力，并且在皮肤肿瘤的发展过程中，肿瘤坏死因子-α(-/-)小鼠的基质金属蛋白酶-9的表达受到抑制。在肿瘤促进的早期阶段，MMP-9蛋白最初定位于毛囊表皮，但随后开始在野生型小鼠的毛囊间表皮中积聚，而不是肿瘤坏死因子-α(-/-)小鼠。抑制肿瘤坏死因子-α或基质金属蛋白酶-9的功能可减少角质形成细胞在体外的迁移。此外，缺乏肿瘤坏死因子-α延迟了体内的再上皮化，这与基质金属蛋白酶-9的表达减少有关。总而言之，这些数据表明，基质金属蛋白酶-9以一种依赖于肿瘤坏死因子的方式调节角质形成细胞的迁移。表情专家。与野生型角质形成细胞相比，控制细胞黏附和迁移的基因LING显示，在体外，整合素亚单位αv和β6在肿瘤坏死因子-α(-/-)中的水平显著降低。角质形成细胞在体外和体内肿瘤促进过程中以肿瘤坏死因子α依赖的方式上调αvbeta6的表达。此外，αvbeta6阻断剂在体外显著抑制角质形成细胞迁移和肿瘤坏死因子-α刺激的基质金属蛋白酶-9的表达。这些数据说明了一种新的依赖于肿瘤坏死因子α的机制来控制αvbeta6的表达，并提示了一种肿瘤坏死因子α调控基质金属蛋白酶-9的途径。在肿瘤形成过程中，增加的基质金属蛋白酶-9和α-vbeta6的表达可能会刺激上皮细胞的迁移，这可能是肿瘤坏死因子-α作为内源性肿瘤促进剂的机制之一。
Mice deficient in TNF-alpha (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis and expression of MMP-9 is inhibited in TNF-alpha(-/-) mice during skin tumour development. In the early stages of tumour promotion, MMP-9 protein initially localized to the follicular epidermis but subsequently began to accumulate in the interfollicular epidermis of wild-type but not TNF-alpha(-/-) mice. Inhibition of TNF-alpha or MMP-9 function reduced keratinocyte migration in vitro. In addition, a deficiency of TNF-alpha delayed re-epithelialization in vivo and this correlated with reduced MMP-9 expression. Collectively, these data suggest that MMP-9 regulates keratinocyte migration in a TNF-alpha-dependent manner. Expression pro. ling of genes that control cell adhesion and migration revealed markedly lower levels of the integrin subunits alphav and beta6 in TNF-alpha(-/-) compared with wild-type keratinocytes in vitro. alphavbeta6 expression was upregulated by keratinocytes in vitro and during tumour promotion in vivo in a TNF-alpha-dependent manner. Furthermore, alphavbeta6 blockade significantly inhibited keratinocyte migration and TNF-alpha-stimulated MMP-9 expression in vitro. These data illustrate a novel TNF-alpha-dependent mechanism for the control of alphavbeta6 expression and suggest one pathway for TNF-alpha regulation of MMP-9. Increased MMP-9 and alphavbeta6 expression may stimulate epithelial cell migration during tumour formation and may be one mechanism whereby TNF-alpha acts as an endogenous tumour promoter.