CAB39 mediates epithelial-mesenchymal transition via activation of NF-κB signaling to facilitate bladder cancer invasion and metastasis

Abstract Background Bladder cancer (BC) is the most common urinary cancer among men with a high mortality rate despite of constant advancement in medical and therapeutic treatment. Recent evidence demonstrated that CAB39 plays a critical role in BC pathogenesis by exhibiting various biological activities, but the underlying molecular mechanisms remain unclear. The aim of this research was to define the expression patterns of CAB39 in normal and tumor tissues and explore its biological function in epithelia-mesenchymal transition (EMT) in human BC. Methods Immunohistochemistry and Quantitative RT-PCR analyses were used respectively to examine the expression of CAB39 in BC tissues and cell lines with different metastatic potentials. In addition, the clinical significance of CAB39 expression was also evaluated. Wound-healing assay, cell invasion assay, and CCK8 proliferation assay in cell lines in which CAB39 was knocked down by shRNA, as well as xenograft tumor models in nude mice, were performed to assess the effect of CAB39 reduction on invasion, migration, and proliferation of BC cells. The GSEA database was used to analyze panel of genes enriched as a result of elevated CAB39 expression in BC cells, and the results were validated by western blot analysis. Results The level of CAB39 protein was up-regulated in invasive but not in noninvasive bladder cancer tissues. Elevated expression of CAB39 was inversely correlated with prognosis of the malignant disease. Additionally, CAB39 was differentially expressed in T24, 5637, and J82 bladder cancer cell lines with highest expression in T24, the most invasive cell line among the three. However, shRNA-mediated attenuation of endogenous CAB39 in T24 and 5637 cell lines reversed such invasive and metastatic effects as demonstrated by the inhibition of tumorigenesis in nude mice xenografts. Furthermore, we demonstrated that CAB39 could mediate EMT through upregulation of N-cadherin and downregulation of E-cadherin in BC via NF-kB signaling pathway. Conclusions Our study reveals a previously unknown mechanism of CAB39-mediated EMT in promoting invasion and metastasis of BC and provides a rationale for future investigation of CAB39 as a potential target for the development of novel therapeutic agents to fight the malignancy.