Expression of both TNF-α receptor subtypes is essential for optimal skin tumour development

被引：151

作者：

Arnott, CH ^{[1
]}

Scott, KA ^{[1
]}

Moore, RJ ^{[1
]}

Robinson, SC ^{[1
]}

Thompson, RG ^{[1
]}

Balkwill, FR ^{[1
]}

机构：

[1] Barts & London Queen Marys Sch Med & Dent, John Vane Sci Ctr, Canc Res UK Translat Oncol Lab, London EC1M 6BQ, England

来源：

ONCOGENE | 2004年 / 23卷 / 10期

关键词：

TNFR1; TNFR2; keratinocyte; GM-CSF; MMP-9; c-jun;

D O I：

10.1038/sj.onc.1207317

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1902 / 1910

页数：9

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