Long non-coding RNA TIRY promotes tumor metastasis by enhancing epithelial-to-mesenchymal transition in oral cancer.

Abstract

Long non-coding RNAs (lncRNAs) modulate a variety of cancerous biological processes, including the promotion of tumorigenicity in tumor parenchymal cells. However, there is a lack of studies assessing the regulation of lncRNAs in cancer-associated fibroblasts. In the present study, a novel lncRNA, TIRY, was found to act as a miRNA sponge and to downregulate miR-14 expression in oral squamous cell carcinoma (OSCC). Fluorescence in situ hybridization assay was used to evaluate TIRY expression in OSCC tissues. Survival analysis in a prospective cohort revealed a correlation between high TIRY expression and short progression-free survival. Subsequently, TIRY expression in cancer-associated fibroblasts and primary fibroblasts from adjacent normal (para-carcinoma) tissues was assessed using quantitative reverse transcription polymerase chain reaction. TIRY overexpression in cancer-associated fibroblasts isolated from OSCC tissues was induced by overexpressing the TIRY plasmid, and candidate microRNA expressions were assessed using quantitative real-time polymerase chain reaction. Moreover, the expression of proteins related to epithelial-to-mesenchymal transition (EMT) was determined; the proliferation, metastasis, and invasion of cancer cells co-cultured with TIRY-overexpressing cancer-associated fibroblasts were determined. We found significantly decreased miR-14 expression in cancer-associated fibroblast-derived exosomes and increased expression of EMT markers including transcription factors (Snail and FOXC2) and cellular scaffolding proteins (α-SMA, β-catenin, and FSP1). TIRY overexpression in cancer-associated fibroblasts activated the Wnt/β-catenin signaling pathway and promoted the invasion and metastasis of OSCC cells through miR-14 sponging based on cancer-associated exosome secretion. Our findings provide a novel molecular mechanism underlying the role of TIRY in cancer-associated fibroblasts in tumor biology; moreover, TIRY is a potential therapeutic target in OSCC. Impact statement This study demonstrated the novel lncRNA, TIRY, enhances epithelial-to-mesenchymal transition in cancer-associated fibroblasts and promotes the metastasis of tumor via miR-14 sponging in oral squamous cell carcinoma, and thus provide a novel molecular mechanism underlying the role of TIRY in CAFs in tumor biology and a potential target in OSCC. Further, the data showed that TIRY expression was negatively correlated with miR-14 transcription levels and was associated with poor prognosis in OSCC specimens. Therefore, TIRY may be a potential prognostic biomarker of overall survival and progression-free survival in OSCC. Moreover, TIRY adds to the understanding of regulatory mechanisms involved in CAFs and epithelial cancer cells in OSCC and may provide novel insights for further understanding tumor biology.