Autocrine IL-1β-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFα signalling to carcinoma-associated fibroblasts

摘要

The invasion of squamous cell carcinoma (SCC) is a significant cause of morbidity and mortality. Here, we identify an E3 ligase, Traf6 and a de-ubiquitinating enzyme, Cezanne/ZA20D1, as important regulators of this process in organotypic models. Traf6 can promote the formation of Cdc42-dependent F-actin microspikes. Furthermore, Traf6 has a key role in autocrine interleukin-1尾 signalling in SCC cells, which in turn is required to drive the expression of tumour necrosis factor 伪 (TNF伪). TNF伪 acts in a paracrine manner to increase the invasion-promoting potential of carcinoma-associated fibroblasts (CAFs). Exogenous TNF伪 signalling can restore invasion in cells depleted of Traf6. In conclusion, Traf6 has two important roles in SCC invasion: it promotes cell intrinsic Cdc42-dependent regulation of the actin cytoskeleton and enables production of the paracrine signal, TNF伪, that enhances the activity of CAFs.