The interaction between tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) regulates the fate of keratinocytes, depending on the relative expression of TNF receptor (TNFR) 1 or TNFR2. However, the precise mechanism underlying this TWEAK-mediated regulation remains unclear. The aim of this study was to provide comprehensive insight into the roles of Fn14, TNFR1/2, and other relevant molecules in the fate of keratinocytes. Further, we sought to elucidate the structural basis for the interaction of TWEAK and Fn14 in regulating cellular outcomes. Normal keratinocytes (mainly expressing TNFR1) and TNFR2-overexpressing keratinocytes were stimulated with TWEAK. Through immunoprecipitation and Western blotting of keratinocyte lysates, we elucidated the associations between Fn14, TNFR-associated factor 2 (TRAF2), cellular inhibitor of apoptosis protein 1 (cIAP1), and TNFR1/2 molecules. Additionally, we found that TRAF2 exhibited binding to Fn14, cIAP1, and TNFR1/2. Our data suggest that TWEAK induces apoptosis in normal keratinocytes and proliferation in TNFR2-overexpressing keratinocytes in a TNF-α-independent manner; however, inhibition of TRAF2 appears to reverse this effect. Interestingly, the interaction between TWEAK and Fn14 increased TNFR1-associated death domain protein and caspase-8 expression in normal keratinocytes and promoted cytoplasmic import of cIAP1 in TNFR2-overexpressing keratinocytes. In conclusion, we found that the Fn14-TRAF2-TNFR signaling axis mediates TWEAK's regulation of the fate of keratinocytes, possibly in a manner involving the TNF-α-independent TNFR signal transduction.

women pursuing preventive and diagnostic services more frequently than men. 8 It has been suggested that women may more likely present earlier for diagnosis and thus have smaller DFSP tumours at presentation and theoretically improved prognosis. As a result, one would have expected a higher cancer-specific mortality in males than females, especially in the unadjusted model. 9 The general difficulty in ascertaining deaths that were attributable mainly to the cancer diagnosis also poses a problem in data collection. It is not uncommon for cancer patients to be stricken with multiple medical comorbidities as well as side effects of treatment that could have blurred the exact cause of death. Furthermore, inter-observer reliability of cause of death in cancer patients is another area of potential bias that still requires some work to improve data quality. 10 In summary, the male gender is a negative predictor of survival in DFSP when adjusted for age at diagnosis, race, site, size, mean household income and treatment. We suggest that more effort should be channelled into looking for reasons to explain this phenomenon and the possible recommendations to mitigate such risks.