Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
PLoS One. 2012;7(6):e38648. doi: 10.1371/journal.pone.0038648. Epub 2012 Jun 18.
Oral 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 FINDINGS: Using 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/SIGNIFICANCE: Upregulation 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.
口腔白斑病（OLK）是一种口腔潜在恶性疾病。然而，OLK 的潜在机制仍不清楚。在这项研究中，我们探讨了可能参与 OLK 的 miRNA。
方法/主要发现：我们使用 miRNA 微阵列分析了 OLK 和恶性转化的 OLK（mtOLK）组织样本中的 miRNA 表达。miR-31*、miR-142-5p、miR-33a、miR-1259、miR-146b-5p、miR-886-3p、miR-886-5p、miR-519d 和 miR-301a 的上调以及 miR-572、miR-611、miR-602、miR-675、miR-585、miR-623、miR-637 和 miR-1184 的下调是 mtOLK 中的新观察结果。荧光原位杂交（FISH）分析证实 miR-31在 mtOLK 中高表达。在有或没有复发性/新形成的 OLK 的患者之间，FISH 评分存在显著差异（p<0.05）。功能分析表明，miR-31抑制剂降低了源自口腔白斑病变的永生化口腔上皮细胞系 Leuk-1 的细胞凋亡。miR-31调节 HPV E6/E7 永生化口腔上皮细胞系 HOIEC 中的细胞凋亡、增殖、迁移和侵袭。此外，miR-31调节口腔鳞状细胞癌细胞系 Cal-27 中的细胞凋亡、细胞增殖、细胞周期、迁移和侵袭的生物学功能。通过生物信息学分析和双荧光素酶报告基因实验，我们确定成纤维细胞生长因子 3（FGF3）的 3'非翻译区是 miR-31的靶标。miR-31模拟物或抑制剂的存在分别下调或上调 FGF3 的表达。
结论/意义：miR-31的上调与复发性/新形成的 OLK 呈负相关。miR-31可能对不同恶性潜能的口腔细胞的生物学功能产生相似但可区分的影响。FGF3 是 miR-31的靶标。miR-31可能通过调节 FGF3 在 OLK 进展中发挥重要作用。miRNA*链在口腔癌变中也可能具有显著作用。
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