TIFA Promotes CRC Cell Proliferation via RSK- and PRAS40- Dependent Manner

Abstract Background: Previous studies have shown that TIFA (TNF receptor associated factor (TRAF)-interacting protein with a Forkhead-associated (FHA) domain) plays different roles in various tumor types. However, the function of TIFA in colorectal cancer (CRC) remains unclear. The goal of this study is to uncover the biological function and molecular mechanism of TIFA in CRC.Methods: Tissue microarrays were used to evaluate TIFA expression. Cancer cell proferation assays were performed in TIFA knockdown and overexpressing cells in vitro and in a xenograft model in vivo. Human phosphokinase array, immunoprecipitation assays were performed to explore the underlying mechanism.Results: We disclosed that the expression of TIFA was marked increased in CRC versus normal tissue, and positively correlated with CRC TNM stages. In agreement, we found that the CRC cell lines show increased TIFA expression levels versus normal control. The knockdown of TIFA inhibited cell proliferation but have no effects on cell apoptosis in vitro and in vivo. Moreover, the ectopic expression of TIFA enhanced cell proliferation ability in vitro and in vivo. In contrast, the expression of mutant TIFA (T9A, oligomerization site mutation; D6, TRAF6 binding site deletion) alternatively abolished TIFA mediated cell proliferation enhancement. Exploration of the underlying mechanism demonstrated that the protein synthesis associated kinase RSK and PRAS40 activation were all responsible for TIFA mediated CRC progression. Conclusions: The above results described a model of TIFA in mediating CRC progression. This may provide a promising target for CRC therapy.