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Abstract
ObjectivesRecently long non-coding RNAs (lncRNAs) have emerged as novel gene regulators involved in tumorigenic processes, including oral squamous cell carcinoma (OSCC). Here, we identified a differentiation-related lncRNA, terminal differentiation-induced non-coding RNA (TINCR). However, its biological function and clinicopathological significance in OSCC still remain unclear.MethodsThe lncRNA expression profiles in OSCC tissues and paired adjacent non-tumor tissues (NATs) from 10 patients were detected by lncRNA microarrays. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) enrichment were performed to identify the most significant module and module functional annotation, respectively. Potential differentiation-related lncRNAs were screened by differential expression analysis. TINCR was further confirmed in OSCC cell lines and tissues of another patient cohort by using qRT-PCR. The correlation between the TINCR expression level and clinicopathological characteristics was analyzed. The effects of TINCR on cell differentiation, migration and invasion were assessed by knockdown or knock-in in vitro and in vivo.ResultsWGCNA and GO enrichment analysis showed that one co-expression network was significantly enriched for epithelial cell differentiation, among which, TINCR was significantly downregulated. qRT-PCR analyses validated down-regulation of TINCR in tumor tissues compared with paired NATs, and its expression was closely correlated with pathological differentiation and lymph node metastasis in patients with OSCC. Patients with lower TINCR expression levels had worse survival. Cell function experiments showed that TINCR played a crucial role in epithelial differentiation. Both TINCR and epithelial differentiation-associated genes, including IVL and KRT4, were significantly upregulated during OSCC cell calcium-induced differentiation but were reduced when cell dedifferentiation occurred in tumor spheres. Overexpression of TINCR dramatically suppressed cell dedifferentiation, migration and invasion in vitro, while knockdown of TINCR had the opposite effects. Upregulation of TINCR significantly elevated the expression of terminal differentiation genes and repressed tumor growth in vivo. Moreover, TINCR significantly suppressed the activation of JAK2/STAT3 signaling in OSCC cells.ConclusionOur study suggests that TINCR functions as a tumor suppressor by inducing cell differentiation through modulating JAK2/STAT3 signaling in OSCC. TINCR may serve as a prognostic biomarker and therapeutic target for OSCC.
Highlights
Head and neck cancer is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide [1]
According to the microarray data, we identified 1603 transcripts that were upregulated with a more than 2-fold change (FC) in Oral squamous cell carcinoma (OSCC) samples compared to non-cancerous adjacent tissues (NATs), while 989 transcripts were downregulated by more than 2-fold (Supplementary Figure 1)
We further showed that the expression of TINCR increased during cell differentiation and reduced during cell dedifferentiation
Summary
Head and neck cancer is the sixth most common malignancy and is a major cause of cancer morbidity and mortality worldwide [1]. Oral squamous cell carcinoma (OSCC), comprising a major portion of head and neck cancers, accounts for approximately 90% of all oral malignancies [2]. Based on the statistics from the American Cancer Society (http://seer.cancer.gov/statfacts/html/ oralcav.html), an estimated 48,000 new OSCC cases occurred in 2016, composing 3% of all new malignancies [3]. LncRNAs have been extensively studied over the past several decades, very little is known about the specific role of lncRNAs. the recent explosion of knowledge highlighting the importance of lncRNAs in the regulation of diverse major biological processes, including but not limited to development, differentiation, and metabolism, has brought these ignored molecular players to the forefront [6]
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