Abstract
BackgroundOral leukoplakia (OLK) is a potentially malignant disorder of the oral cavity. However, the underlying mechanism of OLK is still unclear. In this study, we explore possible miRNAs involved in OLK.Methodology/Principal FindingsUsing miRNA microarrays, we profiled miRNA expression in OLK and malignantly transformed OLK (mtOLK) tissue samples. The upregulation of miR-31*, miR-142-5p, miR-33a, miR-1259, miR-146b-5p, miR-886-3p, miR-886-5p, miR-519d, and miR-301a along with the downregulation of miR-572, miR-611, miR-602, miR-675, miR-585, miR-623, miR-637, and miR-1184 in mtOLK were new observations. Fluorescence in situ hybridization (FISH) analyses confirmed that miR-31* is highly expressed in mtOLK. There was a significant difference between the FISH score (p<0.05) in patients with or without recurrent/newly formed OLK. Functional analyses demonstrated that a miR-31* inhibitor decreased apoptosis in the Leuk-1, which is an immortalized oral epithelial cell line spontaneously derived from an oral leukoplakia lesion. miR-31* regulated apoptosis, cell proliferation, migration, and invasion in the HOIEC, which is a HPV E6/E7-immortalized oral epithelial cell line. Furthermore, miR-31* modulated the biological functions of apoptosis, cell proliferation, cell cycle, migration, and invasion in the oral squamous cell carcinoma cell line, Cal-27. Using bioinformatic analyses and dual luciferase reporter assays, we determined that the 3′ untranslated region of fibroblast growth factor 3 (FGF3) is the target of miR-31*. Expression of FGF3 was downregulated or upregulated in the presence of a miR-31* mimic or inhibitor, respectively.Conclusions/SignificanceUpregulation of miR-31* is negatively associated with recurrent/newly formed OLK. MiR-31* may exert similar but distinguishable effects on biological function in oral cells with different malignant potential. FGF3 is the target of miR-31*. miR-31* may play an important role during OLK progression through regulating FGF3. MiRNA* strands may also have prominent roles in oral carcinogenesis.
Highlights
The development of oral squamous cell carcinoma (OSCC) is considered a multistep process starting with hyperplasia, progressing to dysplasia, and to neoplasm
We found 25 upregulated miRNAs and nine downregulated miRNAs with greater than 2-fold changes in malignantly transformed OLK (mtOLK)
Unsupervised hierarchical clustering analyses of the 122 miRNAs revealed a marked separation of mtOLK and Oral leukoplakia (OLK), suggesting this differential expression profile could be used as a possible phenotypic discriminator between OLK and mtOLK (Figure 1)
Summary
The development of oral squamous cell carcinoma (OSCC) is considered a multistep process starting with hyperplasia, progressing to dysplasia, and to neoplasm. During these steps, multiple genetic alterations may occur, including chromosomal aberrations as well as DNA mutations, amplification, or deletions [1]. Oral leukoplakia (OLK) is recognized as an excellent research model for oral carcinogenesis. OLK is a potentially malignant disorder of the oral cavity, and presents as ‘‘a predominantly white lesion of the oral mucosa that cannot be characterized as any other definable disease’’ [2]. Oral leukoplakia (OLK) is a potentially malignant disorder of the oral cavity. We explore possible miRNAs involved in OLK
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