chr19_34670, a newly identified miRNA, represses rapid tumor growth of cystic vestibular schwannomas by targeting transforming growth factor α and inhibiting MAPK pathway

// 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 u0026 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.