CCT3介导的XPO1/RB1轴稳定性调控促进透明细胞肾癌的细胞衰老与肿瘤进展

Cellular senescence's role in clear cell renal carcinoma (ccRCC) remains unclear. We identify CCT3 as a driver of ccRCC progression by enhancing XPO1 stability via correct folding, confirmed by Co-IP and GST pull-down. This promotes nuclear export of tumor suppressors such as RB1 and p21, suppressing cellular senescence. Indeed, experimental evidence showed significantly reduced senescence-associated β-galactosidase (SA-β-gal) activity and altered expression patterns of senescence markers (e.g., p21, CDK4, and cyclin D) in the presence of increased CCT3. Functionally, CCT3 depletion induced robust G1 phase arrest, promoted cellular senescence, and markedly diminished ccRCC cell proliferation, migration, and invasion in vitro. Crucially, in vivo studies demonstrated that the combined therapeutic intervention of CCT3 knockdown and the XPO1 inhibitor Selinexor significantly suppressed tumor growth in ccRCC xenograft models, validating the therapeutic potential of targeting the CCT3-XPO1 axis. In summary, our findings unveil a novel CCT3-XPO1-RB1 axis that orchestrates ccRCC progression by impairing cellular senescence, offering a promising therapeutic avenue for ccRCC treatment.