title: HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis.
abstract: BACKGROUND
  HOX genes encode homeodomain-containing transcription factors involved in the regulation of cellular proliferation and differentiation during embryogenesis. However, members of this family demonstrated oncogenic properties in some malignancies. The present study investigated whether genes of the HOXA cluster play a role in oral cancer.
  
  
  METHODS
  In order to identify differentially expressed HOXA genes, duplex RT-PCR in oral samples from healthy mucosa and squamous cell carcinoma was used. The effects of HOXA1 on proliferation, apoptosis, adhesion, invasion, epithelial-mesenchymal transition (EMT) and anchorage-independent growth were assessed in cells with up- and down-regulation of HOXA1. Immunohistochemical analysis using a tissue microarray (TMA) containing 127 oral squamous cell carcinomas (OSCC) was performed to determine the prognostic role of HOXA1 expression.
  
  
  RESULTS
  We showed that transcripts of HOXA genes are more abundant in OSCC than in healthy oral mucosa. In particular, HOXA1, which has been described as one of the HOX members that plays an important role in tumorigenesis, was significantly more expressed in OSCCs compared to healthy oral mucosas. Further analysis demonstrated that overexpression of HOXA1 in HaCAT human epithelial cells promotes proliferation, whereas downregulation of HOXA1 in human OSCC cells (SCC9 cells) decreases it. Enforced HOXA1 expression in HaCAT cells was not capable of modulating other events related to tumorigenesis, including apoptosis, adhesion, invasion, EMT and anchorage-independent growth. A high number of HOXA1-positive cells was significantly associated with T stage, N stage, tumor differentiation and proliferative potential of the tumors, and was predictive of poor survival. In multivariate analysis, HOXA1 was an independent prognostic factor for OSCC patients (HR: 2.68; 95% CI: 1.59-2.97; p = 0.026).
  
  
  CONCLUSIONS
  Our findings indicate that HOXA1 may contribute to oral carcinogenesis by increasing tumor cell proliferation, and suggest that HOXA1 expression might be helpful as a prognostic marker for patients with OSCC.
authors.affiliation: Department of Oral Diagnosis, School of Dentistry, State University of Campinas, CP 52, CEP 13414-018 Piracicaba, São Paulo, Brazil. coletta@fop.unicamp.br
authors.forename: Carolina Cavalcante
authors.initials: CC
authors.lastname: Bitu
authors.forename: Maria Fernanda de Souza Setúbal
authors.initials: MF
authors.lastname: Destro
authors.forename: Manoela
authors.initials: M
authors.lastname: Carrera
authors.forename: Sabrina Daniela
authors.initials: SD
authors.lastname: da Silva
authors.forename: Edgard
authors.initials: E
authors.lastname: Graner
authors.forename: Luiz Paulo
authors.initials: LP
authors.lastname: Kowalski
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
authors.forename: Ricardo D
authors.initials: RD
authors.lastname: Coletta
mesh_terms: D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D005801:Genes, Homeobox / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein