Abstract
The neuronally expressed developmentally downregulated 4 (NEDD4) gene encodes a ubiquitin ligase that targets the epithelial sodium channel for degradation and has been implicated in tumor growth in various cancers. Hence, in this study, we intended to characterize the functional relevance of the NEDD4-mediated Kruppel-like factor 8/microRNA-132/nuclear factor E2-related factor 2 (KLF8/miR-132/NRF2) axis in the development of bladder cancer. NEDD4 and KLF8 were overexpressed in bladder cancer tissues and were associated with poorer patient survival rates. In bladder cancer cells, NEDD4 intensified the stability and transcriptional activity of KLF8 through ubiquitination to augment cell viability and migratory ability. Our investigations revealed that NEDD4 promotes the binding of KLF8 to the miR-132 promoter region and inhibits the expression of miR-132. KLF8 inhibited the expression of miR-132 to augment the viability and migratory ability of bladder cancer cells. Furthermore, miR-132 downregulated the expression of NRF2 to restrict the viability and migratory ability of bladder cancer cells. In addition, in vivo findings verified that NEDD4 regulates the KLF8/miR-132/NRF2 axis by accelerating tumor growth and lung metastasis. In conclusion, this study highlights NEDD4 as a potential therapeutic target against tumor recurrence and metastasis in bladder cancer.
Highlights
Bladder cancer is recognized as the second most frequently occurring genitourinary malignant tumor, accompanied by an increasing number of survivors worldwide in recent years[1]
neuronally expressed developmentally downregulated 4 (NEDD4) and Kruppel-like factor 8 (KLF8) are overexpressed in bladder cancer and are associated with poor survival The coexpression relationship between NEDD4 and KLF8 in bladder cancer was identified through the biological website Chipbase v2.0 (Fig. 1a)
The expression of NEDD4 and KLF8 was elevated in bladder cancer cell lines (EJ-m3, T24, J82, BIU-87, and SW780) compared to that of the normal urothelial cell line SVHUC-1, with the highest expression in T24 cells, which were selected for subsequent experiments (Fig. 1d)
Summary
Bladder cancer is recognized as the second most frequently occurring genitourinary malignant tumor, accompanied by an increasing number of survivors worldwide in recent years[1]. Mounting evidence suggests that neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, is implicated in the tumorigenesis of human cancers[6]. A critical oncogenic role of NEDD4 has been noted in bladder cancer due to its promoting function in tumor cell migration and invasion[8]. The oncogenic implication of NEDD4 in hepatocellular carcinoma has been recognized through its contribution to degrading large tumor suppressor homolog 110. NEDD4 has been elucidated as a prognostic factor with therapeutic significance in breast cancer[11].
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