The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma

¹ Dept of Intensive Care and Thoracic Oncology; and Research Fellow FNRS (National Fund of Scientific Research)
² Institute for Microbiological Research J-M Wiame and Laboratory of Microbiology
³ Dept of Intensive Care and Thoracic Oncology
⁴ Laboratory of Molecular and Cellular Biology, Faculté Universitaire des Sciences Agronomiques de Gembloux (FUSAGx)
⁵ Dept of Pathology
⁶ Data Center (Biostatistician), Institut Jules Bordet
⁷ Laboratory of Molecular Immunology and; and Scientific Collaborator of the FNRS-Télévie, ULB (Université Libre de Bruxelles), Brussels, Belgium
⁸ Dept of Pneumology, CHU Saint-Pierre

^* To whom correspondence should be addressed. E-mail: celine.mascaux{at}bordet.be.

	Abstract

MDM2 (Murine Double Minute, clone 2), p14^arf (alternate reading frame), NPM (nucleophosmin) regulate p53 activity.

Two hundred biopsies, including normal bronchial, pre-invasive and invasive tissues, were examined for changes in NPM, p14^arf, MDM2 and p53 expression patterns by immunohistochemistry and immunofluorescence with confocal microscopy.

NPM and p14^arf displayed a diffuse nuclear staining in most normal bronchial tissue. The fraction of biopsies displaying higher MDM2 staining or a nucleolar relocalization of NPM increased at mild and moderate dysplasia, respectively. Two different modifications occurred in p14^arf expression, its loss or its nucleolar relocalization, both increasing at severe dysplasia and both being associated with high MDM2 expression. In addition, the nucleolar relocalization of p14^arf was associated with that of NPM. Immunofluorescence staining indicated that NPM and p14^arf either colocalized in the nucleoplasm or in the nucleoli, before and from severe dysplasia, respectively. MDM2 was never detected in the nucleoli.

Changes occur thus in MDM2, p14^arf and NPM level of expression and/or cellular distribution during early steps of lung carcinogenesis. Their relative localization by immunofluorescence supports the hypothesis that p14^arf nucleolar relocalization impairs p14^arf-MDM2 complexes formation and that NPM might sequester p14^arf. But the demonstration of this hypothesis requires further functional studies.