Abstract
BackgroundMicroRNA (miRNA) is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC) is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary.Methodology/Principal FindingsTo explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR) on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model.Conclusions/SignificanceOur study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.
Highlights
In 2004, 28,260 new cases of oral cavity and pharyngeal cancer and 20,260 new cases of laryngeal cancer were diagnosed in the United States, resulting in 7,230 and 3,830 deaths, respectively [1,2]
Microarray analysis revealed up-regulation of 5 miRNAs and down-regulation of 2 miRNAs, miR-801 is considered to be a fragment of U11 spliceosomal RNA and removed from the miRBase [31]. miR-145 was excluded from the further studies, because it has been reported to be frequently down-regulated in cancers in multiple organs including prostate cancer [32], breast cancer [33], bladder cancer [34], colon cancer [35,36], ovarian cancer [37], esophageal cancer [38], lung cancer [39,40], nasopharyngeal cancer [41], gastric cancer [42], as well as B-cell malignancies [43] and considered to be not a proper biomarker for laryngeal cancer
MiR-455-5p instead of miR-455-3p was used in further studies, because miRNAs 3p and 5p are generated from either side of the same precursor stem to have similar sequences and recent report suggested the potential involvement of miR-455-5p in cancer progression [44]
Summary
In 2004, 28,260 new cases of oral cavity and pharyngeal cancer and 20,260 new cases of laryngeal cancer were diagnosed in the United States, resulting in 7,230 and 3,830 deaths, respectively [1,2]. While laryngeal cancer is highly curable either by surgical removal or irradiation when found and treated at the early stage, advanced cancer stays much less curable resulting in no significant improvement of overall survival rates since 1975 [3]. Current approaches to predict the outcome of HNSCC patients include examination using clinicopathological parameters such as primary tumor, regional node, distant metastasis (TNM) – stage, depth of invasion, and differentiation grade. These parameters do not accurately reflect prognosis of the patients and additional predictors and biomarkers would be useful for patient management. The molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary
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