title: Autocrine IL-1β-TRAF6 signalling promotes squamous cell carcinoma invasion through paracrine TNFα signalling to carcinoma-associated fibroblasts.
abstract: 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-1β signalling in SCC cells, which in turn is required to drive the expression of tumour necrosis factor α (TNFα). TNFα acts in a paracrine manner to increase the invasion-promoting potential of carcinoma-associated fibroblasts (CAFs). Exogenous TNFα 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, TNFα, that enhances the activity of CAFs.
authors.affiliation: Tumour Cell Biology Laboratory, Cancer Research UK London Research Institute, London, UK.
authors.forename: S I
authors.initials: SI
authors.lastname: Chaudhry
authors.forename: S
authors.initials: S
authors.lastname: Hooper
authors.forename: E
authors.initials: E
authors.lastname: Nye
authors.forename: P
authors.initials: P
authors.lastname: Williamson
authors.forename: K
authors.initials: K
authors.lastname: Harrington
authors.forename: E
authors.initials: E
authors.lastname: Sahai
mesh_terms: D019898:Autocrine Communication; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D010450:Endopeptidases; C476458:OTUD7B protein, human; D020764:cdc42 GTP-Binding Protein