TRAIP promotes the development of papillary thyroid cancer by inhibiting TRAF2-mediated BRAF ubiquitination.

The annual incidence of papillary thyroid cancer (PTC) has shown a steady increase in the number of cases. Advances in minimally invasive surgical techniques and the growing frequency of late-stage diagnoses have collectively heightened the complexity of PTC management and treatment. Tumor necrosis factor receptor-associated factor-interacting protein (TRAIP), which has been implicated in the progression of various malignancies, remains inadequately characterized in terms of its expression patterns and functional roles in papillary thyroid carcinoma. In this study, we implemented a comprehensive experimental strategy integrating tissue-based analyses, cellular functional assays, and in vivo animal models. We constructed a protein-protein interaction network and established stable cell lines with TRAIP overexpression, knockdown, knockout, and mutation. These models were subsequently analyzed using Western blotting and co-immunoprecipitation (co-IP) assays. Experimental results demonstrated significantly upregulated TRAIP expression in PTC. Silencing TRAIP markedly inhibited PTC cell proliferation and migratory potential. BRAF, a critical oncogene in PTC pathogenesis, exhibited a positive correlation with TRAIP expression both in vitro and in vivo. TRAIP was shown to regulate BRAF ubiquitination and was linked to MAPK pathway activation. However, mutation-based studies indicated that BRAF degradation did not occur via TRAIP-dependent ubiquitination. Furthermore, TRAIP was found to physically interact with both TRAF2 and BRAF, with TRAF2 displaying a higher binding affinity for TRAIP than BRAF. Overexpression of TRAIP reduced the interaction between TRAF2 and BRAF, whereas TRAF2 independently mediated BRAF ubiquitination. These findings demonstrate that TRAIP attenuates TRAF2-mediated BRAF ubiquitination, thereby promoting MAPK pathway activation in PTC cells, which subsequently enhances their proliferation and migration.