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

Abstract

Murine double minute clone 2 (MDM2), p14 alternate reading frame (p14arf), and nucleophosmin (NPM) regulate p53 activity.A total of 200 biopsies, including normal bronchial, pre-invasive and invasive tissues, were examined for changes in NPM, p14arf, MDM2 and p53 expression patterns by immunohistochemistry and immunofluorescence with confocal microscopy.NPM and p14arf displayed a diffuse nuclear staining in most normal bronchial tissue. The fraction of biopsies displaying an increased MDM2 staining or a nucleolar relocalisation of NPM increased at mild and moderate dysplasia, respectively. Two different modifications occurred in p14arf expression, i.e. its loss or its nucleolar relocalisation, both increasing at severe dysplasia and both being associated with high MDM2 expression. In addition, the nucleolar relocalisation of p14arf was associated with that of NPM. Immunofluorescence staining indicated that NPM and p14arf either co-localised in the nucleoplasm or in the nucleoli, before and as a result of severe dysplasia, respectively. MDM2 was not detected in the nucleoli.Thus, changes occur in murine double minute clone 2, p14 alternate reading frame and nucleophosmin level of expression and/or cellular distribution during early steps of lung carcinogenesis. Their relative localisation as determined by immunofluorescence, supports the hypothesis that p14 alternate reading frame nucleolar relocalisation impairs p14 alternate reading frame-murine double minute clone 2 complex formation and that nucleophosmin might sequester p14 alternate reading frame. The demonstration of this hypothesis requires further functional studies.

An IKKα-Nucleophosmin Axis Utilizes Inflammatory Signaling to Promote Genome Integrity

“…The immunohistochemical staining showed that NPM was well expressed in normal human epidermal and epithelial tissues, in the hyperproliferating epidermis with inflammation, and in tumor-adjacent tissues (Figures 6A and 6B, left). This NPM staining pattern was consistent with the pattern in the NPM-stained human lung epithelial cells reported previously (Mascaux et al, 2008). Approximately 45% of skin SCCs and a proportion of BCCs and melanomas expressed reduced NPM (Figure 6A, left).…”

Nucleophosmin, p53, and Ki-67 expression patterns on an oral squamous cell carcinoma tissue microarray

“…frequently experience squamous differentiation, although the study did not mention the frequency of such carcinomas. Mascaux et al (2008) [17] found that changes in NPM expression and cellular distribution occur during the early stages of lung carcinogenesis-NPM showed diffuse nuclear staining in most bronchial tissues, and nucleolar relocalization of NPM increased in moderate dysplasia. p14arf colocalized with NPM in the nucleoli, preventing p14arf from inhibiting murine double minute clone 2 in the nucleoplasm and leading to the inhibition of p53.…”

“…Although changes in NPM expression have been observed in lung squamous cell carcinoma [17], only one study has evaluated the immunoexpression of NPM in OSCC [14]. The aim of this study was to characterize the immunoexpression of NPM, Ki67, and p53 in OSCC samples and to identify correlations between the expression of these proteins and clinicopathologic features of OSSC.…”

Investigation of the effect of P14 promoter aberrant methylation on the biological function of human lung cancer cells

“…As a tumor suppressor gene, the P14ARF gene locus on the short arm 2 region 1 of human chromosome 9 (9p21), plays a major role in cell cycle regulation by regulating the p53 gene . Abnormal methylation of the P14ARF gene promoter region is significantly different between lung cancer and paracancerous tissues, which suggests that abnormal methylation of the P14ARF gene promoter region is related to the occurrence and development of lung cancer . SPCA1 is a lung adenocarcinoma cell line.…”