Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer

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Abstract
Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.
Funding Information
  • Natural Science Foundation of Fujian Province (2025J08052)
  • Fujian Provincial Department of Science and Technology (2024Y9080)

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