title: Nuclear localization of human AP endonuclease 1 (HAP1/Ref-1) associates with prognosis in early operable non-small cell lung cancer (NSCLC).
abstract: The present study examined the immunohistochemical expression of human AP endonuclease 1 (HAP1/Ref-1), the major endonuclease in the repair of apurinic/apyrimidinic (AP) sites in cellular DNA, in normal lung and lung carcinomas. Cellular expression of HAP1 was determined using a standard avidin-biotin-peroxidase complex (ABC) technique and an anti-HAP1 rabbit polyclonal antibody on paraffin-embedded tissue sections from normal lung and in 103 primary non-small cell lung carcinomas (NSCLCs). In normal lung, the staining for HAP1 was found to be both nuclear and cytoplasmic in the pneumocytes of the alveoli. Superficial ciliated cells of the bronchial epithelium presented cytoplasmic staining, while staining for the basal cells was mostly nuclear. Bronchial glandular cells demonstrated mixed nuclear and cytoplasmic staining. Lung carcinomas showed all patterns of expression for HAP1. Loss of HAP1 expression was associated with low proliferation index (p=0.01) and with squamous histology (p=0.04). In squamous carcinomas, a significant correlation was observed between positive nuclear HAP1 and negative p53 expression (p=0.03). A survival benefit was seen in patients presenting nuclear HAP1 expression and those presenting the nuclear HAP1+/p53- phenotype (p=0.01 and 0.007, respectively). It is concluded that nuclear HAP1 localization may be relevant to its role as a DNA repair protein and/or to the recently proposed role as an activator of wild-type p53, and thus to the better outcome seen in this group of patients.
authors.affiliation: Department of Cellular Science, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, U.K.
authors.forename: S
authors.initials: S
authors.lastname: Kakolyris
authors.forename: A
authors.initials: A
authors.lastname: Giatromanolaki
authors.forename: M
authors.initials: M
authors.lastname: Koukourakis
authors.forename: L
authors.initials: L
authors.lastname: Kaklamanis
authors.forename: P
authors.initials: P
authors.lastname: Kanavaros
authors.forename: I D
authors.initials: ID
authors.lastname: Hickson
authors.forename: G
authors.initials: G
authors.lastname: Barzilay
authors.forename: V
authors.initials: V
authors.lastname: Georgoulias
authors.forename: K C
authors.initials: KC
authors.lastname: Gatter
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000368:Aged; D019757:Carbon-Oxygen Lyases / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D002467:Cell Nucleus / Q000201:enzymology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043223:Deoxyribonuclease IV (Phage T4-Induced); D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000201:enzymology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D043223:Deoxyribonuclease IV (Phage T4-Induced); D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase