Abstract
BackgroundMicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%.MethodsThe expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors.ResultsWe observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3′UTR of IGF1R mRNA into the 3′UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3′UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling.ConclusionOverall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation.
Highlights
Oral cancer is one of the most common cancers worldwide with an annual estimated incidence of approximately 275 000
We demonstrated that miR-99a is downregulated in Oral squamous cell carcinoma (OSCC) tissues and cell lines and can function as a tumor metastasis suppressor for migration, invasion and lung colonization in OSCC cells
We used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to examine the expression of miR-99a in 16 OSCC cell lines, observing reduced levels of miR-99a in all OSCC cell lines when compared with normal human oral keratinocytes (HOK) (Figure 1D)
Summary
Oral cancer is one of the most common cancers worldwide with an annual estimated incidence of approximately 275 000. The initiation and progression of OSCC involve a multistep process of aberrant genetic events following the action of various carcinogens, which might be derived from the chronic use of tobacco, alcohol, and betel quid [2]. Cigarette smoking and alcohol drinking are the major risk factors for OSCC in western countries. In southeast Asia, betel quid chewing and cigarette smoking are the predominant risk factors for OSCC [2]. The 5-year survival rate for oral cancer is approximately 50% [1], with locoregional recurrence and/or distant metastasis the major causes of death in these patients [3]. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%
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