Identification of extracellular vesicles-transported miRNAs in Erlotinib-resistant head and neck squamous cell carcinoma
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RESEARCH ARTICLE
Identification of extracellular vesicles-transported miRNAs in Erlotinib-resistant head and neck squamous cell carcinoma Yang Zheng 1,2 & An Song 1,2 & Yan Zhou 1,2 & Yi Zhong 1,3 & Wei Zhang 1,3 & Chundi Wang 1,2 & Xu Ding 1,2 & Yifei Du 1,2 & Wei Zhang 1 & Gang Li 4 & Heming Wu 2 & Yunong Wu 1,2 & Xiaomeng Song 1,2 Received: 2 August 2019 / Accepted: 5 January 2020 # The International CCN Society 2020
Abstract Erlotinib is an oral tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) pathway. Although our previous study has proved the efficacy of Erlotinib in head and neck squamous cell carcinoma (HNSCC), it has also demonstrated poor clinical response rates and disappointing results in clinical trials for HNSCC to date. In this study, we discovered elevated cell proliferation and invasion ability in erlotinib-resistant HNSCC cells. The contributions of miRNAs within extracellular vesicles (EVs) during the formation of chemoresistance were investigated in this study. Among up-regulated miRNAs in EVs derived from resistant cells, miR-7704, miR-215p and miR-3960 showed the most pro-tumorigenic alterations after transfection. Conversely, let-7i-5p, miR-619-5p and miR-30e-3p demonstrated tumor suppressive effects. By performing qRT-PCR and Western blot analysis, we found Vimentin played a pivotal role in modulating erlotinib resistance. Additionally, immune system was highlighted in the GO and KEGG analyses. Transfection of miR7704, miR-21-5p significantly elevated CTLA-4 and LAG3 mRNA levels. Meanwhile, miR-3960 increased the relative mRNA expression of TIM3 in HNSCC cells. Transfection of let-7i-5p, miR-619-5p and miR-30e-3p decreased these checkpoint factors. To conclude, the present study described the roles of EVs-transmitted miRNAs on erlotinib resistance. Targeting the disregulated immune system could be the effective method to overcome erlotinib-resistance in HNSCC cells. Keywords HNSCC . Erlotinib . miRNAs . Extracellular vesicles (EVs) . EMT
Introduction Head and neck cancer is the 6th most common cancer worldwide (Zibelman and Mehra 2016). Squamous cell carcinomas are by far the most common subtype, accounting for >90% of head and neck tumors (Zibelman and Mehra 2016). Despite initial chemoradiation combined surgery and postoperative adjuvant
radiotherapy, the overall survival of patients with HNSCC has improved only marginally over the past 3 decades (Pilborough et al. 2019; Suh et al. 2014). The increasing understanding of the molecular biology of HNSCC has led to an interest in the development of targeted therapies (Leemans et al. 2011). Overexpression of epidermal growth factor receptor (EGFR) and its ligands have been observed in nearly 80–
Yang Zheng, An Song and Yan Zhou contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12079-020-00546-7) contains supplementary material, which is available to authorized users. * Yunong Wu [email protected]
2
Department of Oral and Maxillofacial Sur
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