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Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells.

ABSTRACT: BACKGROUND: MicroRNAs (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%. METHODS: The 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. RESULTS: We 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. CONCLUSION: Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation.

SUBMITTER: Yen YC

PROVIDER: S-EPMC3895693 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells.

Yen Yi-Chen YC Shiah Shine-Gwo SG Chu Hsiao-Chien HC Hsu Yuan-Ming YM Hsiao Jenn-Ren JR Chang Jang-Yang JY Hung Wen-Chun WC Liao Chun-Ta CT Cheng Ann-Joy AJ Lu Ya-Ching YC Chen Ya-Wen YW

Molecular cancer 20140110

<h4>Background</h4>MicroRNAs (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%.<h4>Methods</h4>The 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/inva ...[more]

PMID: 24410957

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Project description:BackgroundNon-small cell lung cancer (NSCLC) ranks first for mortality among all malignancies. Squamous cell carcinoma (SCC) is one of the main types of NSCLC. Previous studies have found that fibroblast growth factor 9 (FGF9) is closely related to lung SCC via different molecular regulatory mechanisms. This study aimed to explore the relationship between microRNA-155-5p (miR-155-5p) and FGF9 gene expression and their effects on the proliferation and invasion of lung SCC through experiments, in order to provide theoretical basis for overcoming this disease.MethodsFluorescence quantitative polymerase chain reaction was employed for the detection miR-155-5p and FGF9 expression in lung SCC tissues (n=40) and the corresponding adjacent normal tissues. The expression of FGF9 in the cancerous and adjacent tissues was detected by western blot. Transwell assay used to verify the effect of miR-155-5p on FGF-induced invasion and migration. Finally, subcutaneous tumor formation experiments in nude mice were used to verify how miR-155-5p and FGF9 affect the proliferative ability of lung SCC cells.ResultsThe results of fluorescence quantitative PCR revealed that miR-155-5p and FGF9 were expressed at high and low levels, respectively, in lung SCC tissue samples relative to normal adjacent tissue samples. Western blot analysis of 6 lung SCC tissue samples revealed a significantly reduced level of FGF9. Correlation analysis uncovered that miR-155-5p and FGF9 share a significant negative correlation in lung SCC. At the messenger RNA and protein levels miR-155-5p could negatively regulate the expression of FGF9. Bioinformatics and dual luciferase reporter assay results confirmed FGF9 to be a downstream regulatory gene targeted by miR-155-5p. Our in vitro and in vivo results demonstrated that FGF9 overexpression exerted a significant inhibitory effect on miR-155-5p's ability to promote lung cancer cell growth, invasion, and proliferation.ConclusionsOur results show that miR-155-5p, as an oncogene, negative regulates FGF9 expression to promote SCC occurrence and development in the lungs.

Dataset Information

Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells.

Publications

Reciprocal regulation of microRNA-99a and insulin-like growth factor I receptor signaling in oral squamous cell carcinoma cells.

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