microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer

// Mariko Obayashi 1, * , Maki Yoshida 1, 9, * , Takaaki Tsunematsu 2 , Ikuko Ogawa 3 , Tomonori Sasahira 4 , Hiroki Kuniyasu 4 , Issei Imoto 5 , Yoshimitsu Abiko 6 , Dan Xu 7, 8 , Saori Fukunaga 7 , Hidetoshi Tahara 7 , Yasusei Kudo 2 , Toshitaka Nagao 9 , Takashi Takata 1 1 Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan 2 Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan 3 Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan 4 Department of Molecular Pathology, Nara Medical University School of Medicine, Nara, Japan 5 Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan 6 Department of Biochemistry, School of Dentistry at Matsudo, Nihon University, Chiba, Japan 7 Department of Cellular and Molecular Biology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan 8 Institute of Environmental Systems Biology, Dalian Maritime University, Dalian, China 9 Department of Anatomic Pathology, Tokyo Medical University, Tokyo, Japan * These authors have contributed equally to this work Correspondence to: Takashi Takata, e-mail: ttakata@hiroshima-u.ac.jp Keywords: invasion, microRNA (miRNA), epithelial-mesenchymal transition (EMT), head and neck squamous cell carcinoma (HNSCC), microarray Received: August 02, 2015      Accepted: January 01, 2016      Published: January 22, 2016 ABSTRACT Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC.