Abstract
// Zirong Huo 1, 2, 3, * , Shuang Yan 1, 2, 3, * , Tao Yang 1, 2, 3 , Zhentao Wang 1, 2, 3 , Qi Huang 2, 3 , Zhaoyan Wang 1, 2, 3 , Hongsai Chen 1, 2, 3 , Penghui Chen 1, 2, 3 , Huan Jia 1, 2, 3 , Zhihua Zhang 1, 2, 3 and Hao Wu 1, 2, 3 1 Department of Otolaryngology-Head & Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 2 Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China 3 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China * These authors have contributed equally to this work Correspondence to: Zhihua Zhang, email: zhihua.zhang2015@aliyun.com Hao Wu, email: wuhao622@sina.cn Keywords: miRNA; cystic vestibular schwannoma; proliferation; tumor growth; pathogenesis Received: March 16, 2017 Accepted: July 29, 2017 Published: January 02, 2018 ABSTRACT Purpose: Cystic vestibular schwannoma (CVS) is an aggressive form of vestibular schwannoma (VS) with rapid growth and poor outcomes. The molecular basis of CVS remains unclear. In this study, we aimed to investigate whether microRNAs (miRNAs) contribute to the development of CVS. Methods: We identified miRNAs that were differentially expressed between CVS and solid VS (SVS) tissues using high-throughput sequencing and quantitative real-time PCR analysis. Gene targets of the identified miRNA were predicted by bioinformatics tools and validated by luciferase reporter analysis. The effects of the miRNA and its target genes on the proliferation of primary VS cells were examined using CCK-8, flow cytometry, colony formation assay, and western-blot. Results: We identified a novel miRNA, chr19_34670, downregulated in CVS compared to SVS. chr19_34670 directly targeted the 3’ untranslated region of transforming growth factor α (TGFα) mRNA and suppressed its expression. TGFα overexpression motivated VS cell proliferation, while this effect could be attenuated by chr19_34670. We also found that chr19_34670 inhibited the function of key proteins in the MAPK pathway by suppressing phosphorylation of ERK and MEK. Conclusions: chr19_34670 suppresses the aggressive proliferation observed in CVS by inhibiting TGFα expression and phosphorylated proteins in the MAPK pathway.
Highlights
Vestibular schwannoma (VS) is one of the most common intracranial tumors in the lateral skull base that arises from Schwann cells of vestibular nerve [1]
We found no significant differences in neurofibromatosis type 2 (NF2) mutations between Cystic vestibular schwannoma (CVS) and solid vestibular schwannoma (SVS), and the proportion of mutation types was similar between the two subgroups [14]
We investigated the differences in miRNA profiles between CVS and SVS by deep sequencing, and identified a novel miRNA, chr19_34670, which was decreased in patients with CVS
Summary
Vestibular schwannoma (VS) is one of the most common intracranial tumors in the lateral skull base that arises from Schwann cells of vestibular nerve [1]. CVS is much more formidable than SVS due to its aggressive clinical features, such as rapid tumor growth, intensive adherence to facial nerve, more severe symptoms and unpredictable biological behaviors [3, 4]. The most common treatment approaches for VS include observation (serial imaging), microsurgical resection, and stereotactic radiosurgery [5, 6]. In case of CVS, treatment becomes more difficult: conservative observation may delay the optimal treatment time; radiotherapy increases the risk of tumor expansion and recurrence; and microsurgical removal could hardly achieve satisfactory postoperative functional outcomes [7, 8]
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