| Research Abstract |
Molecular biological analysis was performed using specimens derived from transbronchial biopsy (TBB) to confirm the following hypotheses;
(1)Chromosomal and cancer related gene abnormalities occur in concordance with the degree of epithelial atypia in respiratory system such as bronchial and alveolar epithelium.
(2)Epithelial atypia found in cancer patients is molecularbiologically different from that found in non-cancerous patients.
TBB specimens were classified according to the degree of their cellular atypia into hyperplasia, metaplasia, and dysplasia. After isolation of atypical epithelia by microdissection method, DNA was extracted and analyzed. Loss of heterozygosity (LOH) in 3pl4.2 (FHIT), 3p21.3, 8p22, 9p22, 18q21.1 were evaluated. In addition, the expression of p53, PCNA and p21 was compared to the degree of apoptosis.
LOH in 3p21.3 and 9p22 occurred in early stage of lung carcinogenesis and was significantly related to the degree of cellular atypia. LOH in 8p22 and 18q21.1 occurr
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ed in middle or late stage of lung carcinogenesis. LOH of 3pl4.2 (FHIT) was not related to the degree of cellular atypia, and found selectively in smokers. Interestingly, these LOH were frequently found in patients with lung cancer and with idiopathic pulmonary fibrosis (IPF), and infrequently found in patients with other benign lung diseases. The results suggest that the frequent occurrence of lung cancer in patients with IPF, at least in part, reflects the frequent occurrence of chromosomal abnormalities in atypical epithelium in IPF.
Previously, we reported that epithelial atypical epithelium frequently express wild-type p53 protein (Wakamatsu et al, Am J Respir Cell Mol Biol, 1999). In the present study, we found that p53 expression significantly related to PNCA expression, but not to p21 expression or to apoptosis. From the in vitro experiments, we showed that smoking related chemical carcinogens such as benzo[a]pyrene induce the expression of p53 protein, but that ubiquitinate p21 protein immediately after its expression resulting in the blockade of cell cycle arrest. This result elucidate the reason why the expression of (wild-type) p53 is not related to the expression of p21 in atypical epithelium in the respiratory system.
These results indicated that various chromosomal abnormalities are found in atypical epithelium in the respiratory system, and that the frequency of chromosomal abnormalities are more common in cellular atypia found in patients with lung cancer and IPF than those with other benign diseases. Less
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