title: Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival.
abstract: Aberrant expression of Eph and ephrin proteins has well-established functions in oncogenesis and tumour progression. We describe EphA1 expression in 6 colorectal cancer (CRC) cell lines, 18 controls and 125 CRC specimens. In addition, a well-characterised cohort of 53 paired normal colon and CRCs was also assessed. Expression of EphA1 mRNA was assessed by quantitative real-time PCR and correlated with protein expression by flow cytometry, immunoprecipitation, western blotting and immunohistochemistry. Significant upregulation (2- to 10-fold) of EphA1 was seen in over 50% of cases (P=0.005) whereas many of the remainder showed downregulation of EphA1. Intriguingly, EphA1 over-expression was more prevalent in stage II compared to stage III CRCs (P=0.02). Low EphA1 expression significantly correlated with poor survival (P=0.02). Epigenetic silencing appeared to explain the loss of EphA1 expression as methylation of the EphA1 CpG island strongly correlated with low EphA1 expression (P<0.01). Furthermore, EphA1 re-expression could be induced by treatment with demethylating agents. Our findings identify EphA1 as a potential prognostic marker in CRC. Although therapies targeting high EphA1 expression seem plausible in CRC, the loss of expression in advanced disease suggests a potential risk that targeted therapy, by selecting for loss of expression, might contribute to disease progression.
authors.affiliation: Leukaemia Foundation Research Laboratory, The Queensland Institute of Medical Research, Brisbane, QLD, Australia. Nirmitha.Herath@qimr.edu.au
authors.forename: N I
authors.initials: NI
authors.lastname: Herath
authors.forename: J
authors.initials: J
authors.lastname: Doecke
authors.forename: M D
authors.initials: MD
authors.lastname: Spanevello
authors.forename: B A
authors.initials: BA
authors.lastname: Leggett
authors.forename: A W
authors.initials: AW
authors.lastname: Boyd
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D036082:Receptor, EphA1 / Q000032:analysis / Q000235:genetics*
chemical_list: D000077209:Decitabine; D036082:Receptor, EphA1; D001374:Azacitidine