Abstract
Deep sequencing technologies have revealed the once uncharted non-coding transcriptome of circular RNAs (circRNAs). Despite the lack of protein-coding potential, these unorthodox yet highly stable RNA species are known to act as critical gene regulatory hubs, particularly in malignancies. However, their mechanistic implications in tumor outcome and translational potential have not been fully resolved. Using RNA-seq data, we profiled the circRNAomes of tumor specimens derived from oral squamous cell carcinoma (OSCC), which is a prevalently diagnosed cancer with a persistently low survival rate. We further catalogued dysregulated circRNAs in connection with tumorigenic progression. Using comprehensive bioinformatics analyses focused on co-expression maps and miRNA-interaction networks, we delineated the regulatory networks that are centered on circRNAs. Interestingly, we identified a tumor-associated, pro-tumorigenic circRNA, named circFLNB, that was implicated in maintaining several tumor-associated phenotypes in vitro and in vivo. Correspondingly, transcriptome profiling of circFLNB-knockdown cells showed alterations in tumor-related genes. Integrated in silico analyses further deciphered the circFLNB-targeted gene network. Together, our current study demarcates the OSCC-associated circRNAome, and unveils a novel circRNA circuit with functional implication in OSCC progression. These systems-based findings broaden mechanistic understanding of oral malignancies and raise new prospects for translational medicine.
Highlights
With approximately 250,000 annual cases reported worldwide, oral cancer is a highly prevalent cancer and a growing health concern [1,2]
oral squamous cell carcinoma (OSCC) [20], we recruited ethnic Taiwanese patients admitted to the Chang Gung Memorial Hospital (n = 39) and completed reverse-transcribed cDNA (RNA)-seq for matched pairs of tumors and adjacent normal tissues from the same patients, totaling 78 datasets
To comparatively illustrate the overall circRNA transcriptome profiles among the specimens, principal component analysis (PCA) of the RNA-seq data was performed, revealing distinct expression profiles corresponding to the disease states (Figure 1A)
Summary
With approximately 250,000 annual cases reported worldwide, oral cancer is a highly prevalent cancer and a growing health concern [1,2]. Oral squamous cell carcinoma (OSCC) is the most common subtype of oral cancer, and accounts for more than 90% of all cases. Infection is another risk factor that has been found among OSCC patients [3,4,5]. Despite progress in diagnostic and therapeutic strategies in the last three decades, the five-year survival rate in patients with OSCC has not significantly improved due to aggressive local invasion, distant metastasis, and recurrence [6]. A better mechanistic understanding of OSCC progression may shed new light on this malignancy and possibly reveal new avenues for therapeutic interventions. While intensive investigations over the past decades have focused on the role of protein-coding oncogenes or tumor-suppressor genes in the pathogenesis of OSCC, the contribution of alterations in the non-coding transcriptome to its incidence or progression has not yet been fully explored
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