Abstract
MicroRNAs (miRNAs) play a pivotal role in carcinogenesis by suppressing oncogenes or tumor suppressor genes. Various studies have identified numerous miRNAs and their diverse targets; however, the consequences of dysregulated miRNAs in nasopharyngeal carcinoma (NPC) remain unclear. For this study, we found that miR-148a is downregulated through hypermethylation in NPC biopsies and NPC cell lines compared with adjacent normal and NP cells respectively. Promoter assays demonstrated that upstream stimulatory factor 1 (USF1) is a crucial transcription factor that activates miR-148a promoter activity. EMSA assays confirmed that purified USF1 binds better toward the unmethylated than the methylated CG-containing USF1 consensus probe. The ectopic expression of miR-148a inhibits cell migration in NPC cells through the suppression of integrin-mediated signaling by targeting VAV2, WASL and ROCK1. Biochemical and functional assays provided supporting evidence that these 3 genes are the downstream targets of miR-148a in NPC cells. Furthermore, immunohistochemical staining and Western blotting analysis revealed that the 3 oncogenic targets of miR-148a were overexpressed in NPC biopsies, suggesting that the inactivation of miR-148a caused by DNA methylation promotes NPC progression. Overall, our findings revealed that miR-148a can act as tumor suppressor miRNA and serve as a biomarker as well as a therapeutic target for NPC.
Highlights
Nasopharyngeal carcinoma (NPC) is a highly invasive head and neck cancer associated with EB virus infection [1]
To confirm that the miR-148a gene is hypermethylated in other NPC cell lines, we analyzed the miR-148a expression level by conducting stem-loop qRT-PCR in 6 NPC cell lines with or without treatment of the DNA methylation inhibitor 5’aza
The results showed that the expression levels of miR148a were significantly down-regulated in NPC cell lines compared with NP69 cells (Fig. 1b)
Summary
Nasopharyngeal carcinoma (NPC) is a highly invasive head and neck cancer associated with EB virus infection [1]. Previous studies have shown that miR-148a is downregulated in various of cancers such as hepatocarcinoma [15]; pancreatic ductal adenocarcinoma [16]; and gastric [17], ovarian [18], breast [19], non-small cell lung [20], and colorectal cancers [21]. According to these studies, miR148a suppresses cell growth, promotes apoptosis, and inhibits migration and invasion, indicating that it plays a tumor-suppressive role in normal tissues
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