title: Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.
abstract: OBJECTIVE
  Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance.
  
  
  METHODS
  This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival.
  
  
  RESULTS
  Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis.
  
  
  CONCLUSIONS
  Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.
authors.affiliation: Unidad de Oncología, Hospital Infanta Sofía, Madrid, Spain. enrique.casado@salud.madrid.org
authors.forename: Enrique
authors.initials: E
authors.lastname: Casado
authors.forename: Victor Moreno
authors.initials: VM
authors.lastname: Garcia
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sánchez
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Gómez Del Pulgar
authors.forename: Jaime
authors.initials: J
authors.lastname: Feliu
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
authors.forename: Beatriz
authors.initials: B
authors.lastname: Castelo
authors.forename: Juan
authors.initials: J
authors.lastname: Moreno Rubio
authors.forename: Rocío A B
authors.initials: RA
authors.lastname: López
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: García-Cabezas
authors.forename: Emilio
authors.initials: E
authors.lastname: Burgos
authors.forename: Javier
authors.initials: J
authors.lastname: de Castro
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Belda-Iniesta
authors.forename: Miriam
authors.initials: M
authors.lastname: López-Gómez
authors.forename: César
authors.initials: C
authors.lastname: Gómez-Raposo
authors.forename: Francisco
authors.initials: F
authors.lastname: Zambrana
authors.forename: María
authors.initials: M
authors.lastname: Sereno
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Martos
authors.forename: Pilar
authors.initials: P
authors.lastname: Vázquez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lacal
authors.forename: Manuel
authors.initials: M
authors.lastname: González-Barón
authors.forename: Paloma
authors.initials: P
authors.lastname: Cejas
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D059186:Chemoradiotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D040081:Protein Array Analysis / Q000379:methods; D012004:Rectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D012189:Retrospective Studies; D014162:Transfection / Q000379:methods; D000071165:Trefoil Factor-3; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D009363:Neoplasm Proteins; D010455:Peptides; C082495:TFF3 protein, human; D000071165:Trefoil Factor-3