期刊论文详细信息
Journal of Experimental & Clinical Cancer Research
ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling
Mao Ding1  Jianxin Qiu2  Mingyue Tan2  Jun Wang2  Wei Wang3  Junjie Ye4  Xiaoqing Zhou4  Qi Wu4  Shengjie You4  Zhaoyu Xu4  Xuedong Chen4  Peng Li4 
[1] Department of Nephrology, Renmin Hospital of Wuhan University, 430000, Wuhan, China;Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Hongkou District, 200080, Shanghai, China;Department of Urology, The First people’s Hospital of Yancheng (Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School), No.66 South Renmin Road, 224000, Yancheng, Jiangsu, China;Department of Urology, The Sixth Affiliated Hospital of Wenzhou Medical University (The People’s Hospital of Lishui), 323000, Zhejiang, China;
关键词: ROC1;    NF-κB;    Ubiquitination;    Metastasis;    Bladder cancer;   
DOI  :  10.1186/s13046-021-01935-5
来源: Springer
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【 摘 要 】

BackgroundRegulator of cullins 1 (ROC1) is an important catalytic subunit of cullin–RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression.MethodsThe expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis.ResultsWe found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis.ConclusionROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.

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