title: Response of CAIX and CAXII to in vitro re-oxygenation and clinical significance of the combined expression in NSCLC patients.
abstract: The disorganized neo-vasculature in tumours causes fluctuations in the concentration of oxygen, which contributes to tumour development and metastatic potential. Although hypoxic regulation of the expression of the carbonic anhydrases CAIX and CAXII is well established, the effect of re-oxygenation on these proteins remains to be elucidated. A549 and H1975 human lung cancer cell lines were exposed to hypoxia for 24 h and then re-oxygenated. CAIX or CAXII expression and cell cycle progression at different time-points were monitored. A549-shCA9 cells were analyzed for cell cycle progression in the same conditions. We demonstrate for the first time an association between the stability of CAIX and restoration of the S/G2 phase of hypoxia-arrested cells subjected to re-oxygenation. In exchange, we have found that the loss of CA9 did not cause a decreased progression into S/G2 phase during re-oxygenation, but rather affected the hypoxic growth arrest. We previously demonstrated that CAIX expression is a poor prognostic factor and that CAXII expression is a good prognostic factor in non-small cell lung cancer (NSCLC) patients. We further detail the relevance of the combined expression of these proteins for predicting outcome in a large population of NSCLC patients after long-term follow-up. The high CAIX/low CAXII expression sub-group was associated with a high cumulative incidence of relapse and with poor overall survival of NSCLC patients (P < 0.0001). Our results demonstrate a critical role for re-oxygenation on CAIX and CAXII levels that may select for an aggressive lung cancer phenotype. These findings suggest that CAIX and CAXII play dual roles in tumour progression and emphasize their significant prognostic and potential therapeutic value.
authors.affiliation: Centre Hospitalier Universitaire de Nice, Louis Pasteur Hospital, Laboratory of Clinical and Experimental Pathology, Nice, France; Institute of Research on Cancer and Ageing in Nice IRCAN, INSERM U1081-CNRS UMR 7284, Team 3, Nice, France; University of Nice Sophia-Antipolis, Faculty of Medicine, Nice, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.forename: Véronique
authors.initials: V
authors.lastname: Hofman
authors.forename: Joséphine
authors.initials: J
authors.lastname: Zangari
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Jérôme
authors.initials: J
authors.lastname: Mouroux
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Mazure
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
authors.forename: Patrick
authors.initials: P
authors.lastname: Brest
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models
chemical_list: D000951:Antigens, Neoplasm; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; D010100:Oxygen
keywords: Carbonic anhydrase IX; Carbonic anhydrase XII; NSCLC; Prognosis; Re-oxygenation