Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO

Cellular & Molecular Biology Letters

Research

Jianan Yang¹  Xiaoyi Xie²  Ping Zhou²  Wenhao Bao²  Zhiqing Gao²  Ge Zhu²  Han Chen²  Zhuojun Zhang²  Chunxiao Yang²  Lili Jiang²  Xiangqin Kuang³  Jinyuan Pan⁴  Lan Wang⁵  Difeng Li⁶  Zhongqiu Zhou⁷  Lihuan Zhou⁸  Zhengfu Feng⁸  Xiaoli Feng⁸  Ruiming Tang⁸ 

[1] Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China;Department of Urologic Oncosurgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China;Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, 511436, Guangzhou, China;Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, 511436, Guangzhou, China;Department of Medical Imaging, Health Science Center, Hubei Minzu University, 445000, Enshi, China;Department of Oncology, Huanggang Central Hospital of Yangtze University, 438000, Huanggang, China;Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, 510006, Guangzhou, China;Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Science, Guangzhou Medical University, 511436, Guangzhou, China;Department of Pathology, School of Medicine, Women’s Hospital, Zhejiang University, 310006, Hangzhou, China;Meishan Women and Children’s Hospital, Alliance Hospital of West China Second University Hospital, Sichuan University, 620000, Meishan, China;The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, 511518, Guangzhou, China;

关键词: Bladder cancer;    PI16;    NF-κB;    Ubiquitination;   

DOI  :  10.1186/s11658-023-00465-6

 received in 2023-02-26, accepted in 2023-06-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundBladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers.MethodsThe expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO.ResultsPI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO.ConclusionsThese results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

【 授权许可】

CC BY   
© The Author(s) 2023

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