Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development
Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development
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DOI：
10.1038/sj.onc.1207317
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发表时间：
2004-03-11
期刊：
影响因子：
8
通讯作者：
Balkwill, FR
中科院分区：
文献类型：
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作者：
Arnott, CH;Scott, KA;Balkwill, FR
角质形成细胞衍生的TNF-α作为内源性肿瘤促进剂，也可以调节小鼠表皮中的AP-1活性。为了进一步了解皮肤肿瘤形成过程中的TNF-α信号传导，对TNFR 1（TNFR 1（-/-）小鼠）或TNFR 2（TNFR 2（-/-）小鼠）缺陷的小鼠进行化学致癌。与野生型（wt）小鼠相比，TNFR 1（-/-）和TNFR 2（-/-）小鼠的肿瘤多样性显着降低，表明这两种受体都具有促肿瘤活性。然而，TNFR 1（-/-）小鼠比TNFR 2（-/-）小鼠对肿瘤发展的抵抗力明显更强，表明TNFR 1是TNF-α诱导的肿瘤形成的主要介质。TNFR 1和TNFR 2在肿瘤促进过程中均在wt表皮中表达，并且在体外由原代角质形成细胞表达。与wt表皮相比，TPA诱导的c-Jun表达在TNFR 1（-/-）和TNFR 2（-/-）中是瞬时的，这通过AP-1应答基因粒细胞/巨噬细胞集落刺激因子、基质金属蛋白酶-9和基质金属蛋白酶-3的诱导减少来反映。与TNFR 2（-/-）表皮相比，se基因在TNFR 1（-/-）表皮中受到差异调节，这表明TNF-α受体在肿瘤促进期间通过不同的AP-1复合物独立作用以抑制TNF-α信号。此外，TNFR 2与TNFR 1协同作用以优化TNFR 1介导的TNF-α在体外角质形成细胞上的生物活性。我们的数据提供了进一步了解肿瘤坏死因子-α信号在恶性肿瘤和肿瘤坏死因子-α拮抗剂在癌症治疗中的使用提供了一些理由。
Keratinocyte-derived TNF-alpha acts as an endogenous tumour promoter and can also regulate AP-1 activity in mouse epidermis. To gain further insight into TNF-alpha signalling during skin tumour formation, mice deficient in TNFR1 (TNFR1(-/-) mice) or TNFR2 (TNFR2(-/-) mice) were subjected to chemical carcinogenesis. Tumour multiplicity was significantly reduced in TNFR1(-/-) and TNFR2(-/-) mice compared to wild-type (wt) mice, suggesting that both receptors have protumour activity. However, TNFR1(-/-) mice were markedly more resistant to tumour development than TNFR2(-/-) mice indicating that TNFR1 is the major mediator of TNF-alpha-induced tumour formation. TNFR1 and TNFR2 were both expressed in wt epidermis during tumour promotion and by primary keratinocytes in vitro. TPA-induced c-Jun expression was transient in TNFR1(-/-) and TNFR2(-/-) compared to wt epidermis and this was reflected by reduced induction of the AP-1-responsive genes granulocyte/macrophage-colony stimulating factor, matrix metalloproteinase-9 and matrix metalloproteinase-3. The se genes were differentially regulated in TNFR1(-/-) compared to TNFR2(-/-) epidermis, suggesting that the TNF-alpha receptors act independently via different AP-1 complexes to transduce TNF-alpha signals during tumour promotion. In addition, TNFR2 cooperated with TNFR1 to optimise TNFR1-mediated TNF-alpha bioactivity on keratinocytes in vitro. Our data provide further insight into TNF-alpha signalling in malignancy and provide some rationale for the use of TNF-alpha antagonists in the treatment of cancer.