title: Regulation of the tumour suppressor PDCD4 by miR-499 and miR-21 in oropharyngeal cancers.
abstract: BACKGROUND
  The rates of oropharyngeal cancers such as tonsil cancers are increasing. The tumour suppressor protein Programmed Cell Death Protein 4 (PDCD4) has been implicated in the development of various human cancers and small RNAs such as microRNAs (miRNAs) can regulate its expression. However the exact regulation of PDCD4 by multiple miRNAs in oropharyngeal squamous cell carcinoma (SCC) is not well understood.
  
  
  RESULTS
  Using two independent oropharyngeal SCC cohorts with a focus on the tonsillar region, we identified a miRNA profile differentiating SCC tissue from normal. Both miR-21 and miR-499 were highly expressed in tonsil SCC tissues displaying a loss of PDCD4. Interestingly, expression of the miRNA machinery, Dicer1, Drosha, DDX5 (Dead Box Helicase 5) and DGCR8 (DiGeorge Syndrome Critical Region Gene 8) were all elevated by greater than 2 fold in the tonsil SCC tissue. The 3'UTR of PDCD4 contains three binding-sites for miR-499 and one for miR-21. Using a wild-type and truncated 3'UTR of PDCD4, we demonstrated that the initial suppression of PDCD4 was mediated by miR-21 whilst sustained suppression was mediated by miR-499. Moreover the single miR-21 site was able to elicit the same magnitude of suppression as the three miR-499 sites.
  
  
  CONCLUSIONS
  This study describes the regulation of PDCD4 specifically in tonsil SCC by miR-499 and miR-21 and has documented the loss of PDCD4 in tonsil SCCs. These findings highlight the complex interplay between miRNAs and tumour suppressor gene regulation and suggest that PDCD4 loss may be an important step in tonsillar carcinogenesis.
authors: The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.|Department of Infectious Diseases and Immunology, University of Sydney, Sydney, NSW, Australia.
authors: Xiaoying
authors: X
authors: Zhang
authors: Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.|Central Clinical School, University of Sydney, NSW, Australia.
authors: Harriet
authors: H
authors: Gee
authors: The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.|Department of Infectious Diseases and Immunology, University of Sydney, Sydney, NSW, Australia.
authors: Barbara
authors: B
authors: Rose
authors: Discipline of Pathology, School of Medicine, University of Western Sydney and Cancer Pathology, Bosch Institute, University of Sydney, Sydney, Australia.
authors: C Soon
authors: CS
authors: Lee
authors: The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.|Central Clinical School, University of Sydney, NSW, Australia.|South Western Clinical School, University of NSW, Sydney, Australia.
authors: Jonathan
authors: J
authors: Clark
authors: The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia.|Central Clinical School, University of Sydney, NSW, Australia.
authors: Michael
authors: M
authors: Elliott
authors: Centre for the Endothelium, Vascular Biology Program, Centenary Institute, Sydney, Australia.
authors: Jennifer R
authors: JR
authors: Gamble
authors: Schizophrenia Research Institute, Sydney, NSW, Australia.|School of Biomedical Sciences, Faculty of Health, and Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW, Australia.
authors: Murray J
authors: MJ
authors: Cairns
authors: Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
authors: Adrian
authors: A
authors: Harris
authors: Centre of Health Technologies. Faculty of Engineering and Information Technology, University of Technology, NSW, Australia.
authors: Samantha
authors: S
authors: Khoury
authors: The Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, Australia. nham.tran@uts.edu.au.|Centre of Health Technologies. Faculty of Engineering and Information Technology, University of Technology, NSW, Australia. nham.tran@uts.edu.au.
authors: Nham
authors: N
authors: Tran
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D016601:RNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D043244:Ribonuclease III / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; C548683:MIRN499 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases