title: Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma.
abstract: Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 3'-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. Cancer Res; 76(24); 7140-50. ©2016 AACR.
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yuan-Feng
authors.initials: YF
authors.lastname: Lin
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Su
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Peng
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Chan
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Tsung-Ching
authors.initials: TC
authors.lastname: Lai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Guan-Hsun
authors.initials: GH
authors.lastname: Wu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yuan-Ming
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.|The PhD Program for Translational Medicine, Taipei Medical University and Academia Sinica, Taipei, Taiwan.|Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan.
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chi
authors.affiliation: Department of Otolaryngology, Head and Neck Collaborative Oncology Group and National Cheng-Kung University Hospital, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Jenn-Ren
authors.initials: JR
authors.lastname: Hsiao
authors.affiliation: Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.|Department of Internal Medicine, National Cheng-Kung University Hospital, College of Medicine, National Cheng-Kung University, Tainan, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.|Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.|Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan. davidssg@nhri.org.tw mhsiao@gate.sinica.edu.tw ndmcyss@ndmctsgh.edu.tw.|Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D047369:Chromatin Immunoprecipitation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017403:In Situ Hybridization; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D008207:Lymphatic Metastasis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C573498:MIRN376C microRNA, human; D035683:MicroRNAs; C493709:RUNX2 protein, human; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits