title: Prognostic impact of ΔTAp73 isoform levels and their target genes in colon cancer patients.
abstract: OBJECTIVE
  Cumulative data support the role of ΔTAp73 variants in tumorigenic processes such as drug resistance. We evaluate the impact of TP73 isoforms and their putative target genes ABCB1, HMGB1, and CASP1 on the survival of colon cancer patients and the correlation between their expressions.
  
  
  METHODS
  We determined in 77 colon cancer patients the expression of ΔEx2p73, ΔEx2/3p73, ΔNp73, TAp73, ABCB1, HMGB1, and CASP1 by quantitative real-time reverse transcriptase-PCR. Tumor characteristics, disease-free survival, and overall survival (OS) were examined in each patient. Functional experiments were carried out to check whether ectopic expression of ΔNp73 modifies the proliferation, drug resistance, migration, and invasion properties of colon tumor cells and the expression of ABCB1, HMGB1, and CASP1.
  
  
  RESULTS
  Positive correlations were observed between the expression levels of ΔTAp73 variants and HMGB1. Furthermore, a trend was observed for ABCB1. Overexpression of ΔEx2/3p73 and ΔNp73 isoforms was significantly associated with advanced stages (P = 0.04 and P = 0.03, respectively) and predicted shortened OS (P = 0.04 and P = 0.05, respectively). High levels of ABCB1 and HMGB1 were associated with shorter OS (P = 0.04 and P = 0.05, respectively). Multivariate analysis showed that, in addition to the tumor stage, ABCB1 and HMGB1 had independent relationships with OS (P = 0.008). Ectopic expression of ΔNp73 was associated with an increase in proliferation and drug resistance.
  
  
  CONCLUSIONS
  The positive correlation between ΔTAp73 variants and HMGB1 and ABCB1 expression supports them as TP73 targets. The fact that upregulation of ΔTAp73 isoforms was associated with shortened OS, increase in proliferation, and drug resistance confirms their oncogenic role and plausible value as prognostic markers. ABCB1 and HMGB1, putative ΔTAp73 target genes, strongly predict OS in an independent manner, making clear the importance of studying downstream TP73 targets that could predict the outcome of colon cancer patients better than ΔTAp73 variants themselves do.
authors.affiliation: Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro Majadahonda, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Soldevilla
authors.forename: Raquel
authors.initials: R
authors.lastname: Díaz
authors.forename: Javier
authors.initials: J
authors.lastname: Silva
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Campos-Martín
authors.forename: Concepción
authors.initials: C
authors.lastname: Muñoz
authors.forename: Vanesa
authors.initials: V
authors.lastname: García
authors.forename: José M
authors.initials: JM
authors.lastname: García
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.forename: Mercedes
authors.initials: M
authors.lastname: Herrera
authors.forename: Marta
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Irene
authors.initials: I
authors.lastname: Gómez
authors.forename: Nagat
authors.initials: N
authors.lastname: Mohamed
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Marques
authors.forename: Félix
authors.initials: F
authors.lastname: Bonilla
authors.forename: Gemma
authors.initials: G
authors.lastname: Domínguez
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045325:HCT116 Cells; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger; D012008:Recurrence; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D020170:Caspase 1