title: Up-regulation of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis is required for human papillomavirus-associated tumorigenesis.
abstract: OBJECTIVE
  Foxhead box M1 (FOXM1) expression has been shown to be linked with human papillomavirus (HPV) 16/18-infected cervical cancer. However, the mechanism underlying the induction of FOXM1 in HPV 16/18-infected cancers remains elusive.
  
  
  METHODS
  The mechanistic actions of FOXM1 induced by the E6/NKX2-1 axis in tumor aggressiveness were elucidated in cellular and animal models. The prognostic value of FOXM1 for overall survival (OS) and relapse-free survival (RFS) in HPV-positive oral and lung cancers was assessed using Kaplan-Meier and Cox regression models.
  
  
  RESULTS
  Herein, FOXM1 expression is upregulated by E6-mediated NKX2-1 in HPV-positive cervical, oral, and lung cancer cells. Induction of FOXM1 by E6 through the MZF1/NKX2-1 axis is responsible for HPV-mediated soft agar growth, invasiveness, and stemness through activating Wnt/β-catenin signaling pathway. In a nude mice model, metastatic lung tumor nodules in HPV 18 E6-positive GNM or HPV 16 E6-positive TL-1-injected nude mice were markedly decreased in both cell types with E6 knockdown, FOXM1 knockdown, or treatment with FOXM1 inhibitor (thiostrepton). Among the four subgroup patients, the worst FOXM1 prognostic value for OS and RFS was observed in HPV 16/18-positive patients with tumors with high-expressing FOXM1.
  
  
  CONCLUSIONS
  Induction of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis may be responsible for HPV 16/18-mediated tumor progression and poor outcomes in HPV-positive patients.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan ; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Yao-Chen
authors.initials: YC
authors.lastname: Wang
authors.affiliation: School of Medicine, Chung Shan Medical University, Taichung, Taiwan ; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D052161:Human papillomavirus 18 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051741:Kruppel-Like Transcription Factors; C085969:MZF1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors