title: Human papillomavirus oncoprotein E6 upregulates c-Met through p53 downregulation.
abstract: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) carries a distinct clinical behaviour. c-Met oncogene is an important driver for tumour progression and its relationship with HPV in OPSCC was explored in the present study.
  
  
  
  Knockdown of HPV oncogene E6 or p53 alone and in combination was performed to examine their effects on c-Met expression by Western blot and quantitative real-time polymerase chain reaction. The effects of c-Met inhibition on cell proliferation, migration, and colony formation were examined in HPV-positive head and neck squamous cell carcinoma (HNSCC) cells. Retrospectively collected OPSCC patient specimens (N = 78) were stained for c-Met by immunohistochemistry and the staining levels were correlated with HPV status and patient outcomes.
  
  
  
  E6 knockdown decreased c-Met protein and mRNA expression in HPV-positive HNSCC cells, which was partially abolished by the elimination of p53. Reducing c-Met decreased cell proliferation, migration, and colony formation in HPV-positive HNSCC cells. In OPSCC patient samples, high c-Met expression was associated with HPV-positive status (OR = 4.11, 95%CI: 1.16-14.55, P = 0.028) and tumour stage (OR = 0.27, 95%CI: 0.08-0.93, P = 0.039) by multivariable analysis. In T3/T4 stage patients, high c-Met expression was associated with HPV positivity and low p53 levels, supporting an axis of E6-p53-c-Met regulation. Furthermore, high c-Met expression was marginally associated with poor disease-free survival in HPV-positive patients.
  
  
  
  Our results suggest that c-Met may serve as a novel target for treating HPV-associated OPSCC. The data also demonstrate that HPV E6 upregulates c-Met expression partially through p53 downregulation.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Qian
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Magliocca
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Pathology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, China.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Nannapaneni
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: nfsaba@emory.edu.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Saba
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA. Electronic address: gzchen@emory.edu.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000821:virology; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D009959:Oropharyngeal Neoplasms / Q000378:metabolism* / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D014407:Tumor Cells, Cultured / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; D019859:Proto-Oncogene Proteins c-met
keywords: Head and neck cancer; Human papillomavirus; c-Met; p53