Abstract
BackgroundConstitutively activated nuclear factor kappa B (NF-κB) signalling plays vital roles in bladder urothelial carcinoma (BC) progression. We investigate the effect of receptor-interacting protein kinase 4 (RIPK4) on NF-κB activation and BC progression.MethodsThe expression of RIPK4 was examined in 25 cryopreserved paired bladder samples and 112 paraffin BC specimens. In vivo and in vitro assays were performed to validate effect of RIPK4 on NF-κB pathway-mediated BC progression.ResultsHigh expression of RIPK4 was observed in BC tissues and was an independent predictor for poor overall survival. Up or downregulating the expression of RIPK4 enhanced or inhibited, respectively, the migration and invasion of BC cells in vitro and in vivo. Mechanistically, RIPK4 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor-interacting protein (RIP) and NF-κB essential modulator (NEMO). RIPK4 also promoted nuclear localisation of NF-κB-p65, and maintained activation of NF-κB substantially, leading to upregulation of VEGF-A, ultimately promoting BC cell aggressiveness.ConclusionsOur data highlighted the molecular aetiology and clinical significance of RIPK4 in BC: upregulation of RIPK4 contributes to NF-κB activation, and upregulates VEGF-A, and BC progression. Targeting RIPK4 might represent a new therapeutic strategy to improve survival for patients with BC.
Highlights
Bladder urothelial carcinoma (BC) occupies the first position in terms of incidence and mortality among genitourinary tumours in China.[1]
We demonstrated that receptor-interacting protein kinase 4 (RIPK4) might have an important function in the control of the aggression and metastasis of bladder urothelial carcinoma (BC) by promoting K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor-interacting protein (RIP) and NF-κB essential modulator (NEMO)
RIPK4 is upregulated in BC To assess the expression pattern of RIPK4 in BC, we analysed the RIPK4 protein level in several BC cell lines, including BIU87, 5637, RIPK4 promotes BC progression via NF-κB/vascular endothelial growth factor A (VEGF-A) J-Y Liu et al Fold change Relatice RIPK4 expression a
Summary
Bladder urothelial carcinoma (BC) occupies the first position in terms of incidence and mortality among genitourinary tumours in China.[1]. Studies in human bladder tumour specimens and mouse models have implicated multiple signalling pathways in the progression and metastasis of BC.[5,6] some studies have revealed that constitutive activation of nuclear factor kappa B (NF-κB) signalling has a vital role in the progression of BC, and blockade of the NF-κB pathway could suppress angiogenesis and metastasis in BC.[7,8] Currently, the precise molecular mechanisms of NF-κB pathway regulation in BC are poorly understood.[9]. Activated nuclear factor kappa B (NF-κB) signalling plays vital roles in bladder urothelial carcinoma (BC) progression. We investigate the effect of receptor-interacting protein kinase 4 (RIPK4) on NF-κB activation and BC progression. In vivo and in vitro assays were performed to validate effect of RIPK4 on NF-κB pathway-mediated BC progression. Targeting RIPK4 might represent a new therapeutic strategy to improve survival for patients with BC
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