USP7 promotes follicular thyroid carcinoma progression and sorafenib resistance by activating NEK2/ATG5-mediated autophagy.

To investigate the role of ubiquitin-specific protease 7 (USP7) in thyroid cancer (TC) pathogenesis and sorafenib resistance. USP7 expression was compared in normal human thyroid cells and TC cells. The TC line with maximal differential USP7 expression was selected for further study. The functional interaction between USP7 and never in mitosis A (NIMA)-related kinase 2 (NEK2)/autophagy-related 5 (ATG5) was elucidated through a Pearson correlation coefficient analysis and co-immunoprecipitation assay. The half-inhibitory concentration (IC50) of sorafenib in resistant follicular thyroid (FTC) cells was determined following USP7 knockdown and ATG5 overexpression. Furthermore, the effects of USP7 knockdown and the autophagy inducer rapamycin (RAPA) on FTC cell function were assessed by colony formation and Transwell assays. The function of USP7 was validated in vivo using a xenograft mouse model, and tumor growth was assessed through gross examination and histopathological staining. High USP7 expression promoted the proliferation, migration, and invasion of FTC cells and was positively correlated with NEK2 and ATG5 levels. USP7 enhanced NEK2 stability via deubiquitination. Knocking down USP7 downregulated ATG5, and this effect was reversed by NEK2 overexpression. USP7 inhibition reduced the IC50 of sorafenib in FTC cells, which was reversed by ATG5 overexpression. USP7 knockdown attenuated FTC cell proliferation, migration, and invasion while increasing the apoptosis rate, and these effects were reversed by RAPA treatment. Knocking down USP7 suppressed the growth of TC xenografts in vivo, improved tumor tissue differentiation, and reduced the percentage of Ki-67-positive cells. USP7 promoted the progression of FTC and induced sorafenib resistance by enhancing NEK2/ATG5-mediated autophagy. This study provides novel insights and potential therapeutic strategies for FTC treatment and overcoming drug resistance.