Purpose: microRNAs are thought to play crucial roles in tumorigenesis. Dysregulation of miR-488 has been implicated to be involved in several cancer progressions. However, the biological functions of miR-488 in renal cell carcinoma (RCC) remain unclear. This study aimed to explore the molecular mechanism underlying the role of miR-488 in RCC development.
Materials and methods: The expression levels of miR-488 were detected in 38 paired RCC tumor samples and cell lines by quantitative real-time polymerase chain reaction method. miR-488 was upregulated by mimics transfection in RCC cell lines. MTT, colony formation, transwell assay, flow cytometry assay, and a xenograft model were performed to determine cell proliferation, invasion, migration, epithelial-to-mesenchymal transition, and apoptosis in vitro and in vivo. Moreover, the potential target of miR-488 was verified by dual-luciferase reporter assay, quantitative real-time polymerase chain reaction, and Western blot. The correlation between miR-488 expression and its target gene expression was confirmed by Spearman’s correlation analysis in 38 selected RCC tissue samples.
Results: We found that miR-488 was remarkably downregulated in human RCC samples and cell lines compared with paired normal tissues and cell lines. Functional investigations revealed that overexpression of miR-488 significantly suppressed cell proliferation, invasion, and migration, and promoted cell apoptosis in RCC cells. Nucleosome binding protein 1 (high-mobility group nucleosome binding domain 5 [HMGN5]) was identified as a direct target of miR-488, and an inverse relationship was found between miR-488 expression and HMGN5 mRNA levels in RCC specimens. Rescue experiments suggested that restoration of HMGN5 partially abolished miR-488-mediated cell proliferation and invasion inhibition in RCC cells through regulating phosphatidylinositol 3-kinase/protein kinase B/the mammalian target of rapamycin and epithelial-to-mesenchymal transition signaling pathways.
Conclusion: These data indicated that miR-488 acted as a tumor suppressor in RCC proliferation and invasion by targeting HMGN5, which might provide potential therapeutic biomarker for RCC patients.
Keywords: renal cell carcinoma, miRNA-488, HMGN5, metastasis, proliferation