Reduced Fhit protein expression in human malignant mesothelioma.
Human malignant mesothelioma (MM) is an aggressive neoplasm related to occupational exposure to asbestos and characterised by a long latency time. Multiple chromosomal deletions and DNA losses have been revealed in MM by studies performed with karyotypic, comparative genomic hybridisation and loss of heterozygosity (LOH) analyses. Among frequently deleted chromosomal sites, LOH at chromosome 3p has been detected in MM, suggesting the presence of one or several tumour suppressor genes that have an important role in development of the disease. The FHIT (fragile histidine triad) tumour suppressor gene, located at 3p14.2, has been proposed to be a target to major human lung carcinogens, such as tobacco smoke and asbestos. Although many studies have indicated decreased Fhit protein expression in a variety of malignancies, there is no report of FHIT gene aberrations or Fhit protein abnormalities in MM. We examined expression of the Fhit protein and LOH at the FHIT gene in malignant mesothelioma. Altogether, 13 paraffin embedded MM tumours were analysed for Fhit protein expression, and 21 fresh tumours and 10 cell cultures for LOH at the FHIT gene with two intragenic microsatellite markers. All tumours showed less intense immunostaining than normal bronchial epithelium or mesothelium. Fhit expression was absent or reduced in 54% (7 of 13) of the tumours, with the weakest staining observed in poorly differentiated areas. Allele loss was seen in 3 of 10 (30%) of the MM cell lines, but only in 1 of the 21 fresh tumours studied, suggesting concealment of LOH by normal cells present in MM tumours. In conclusion, our present data indicate a frequent decrease of Fhit protein expression, thus supporting the significance of FHIT inactivation in development of MM.
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
Lea
L
Pylkkänen
Henrik
H
Wolff
Tuula
T
Stjernvall
Aija
A
Knuuttila
Sisko
S
Anttila
Kirsti
K
Husgafvel-Pursiainen
D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D001194:Asbestos / Q000009:adverse effects; D001980:Bronchi / Q000737:chemistry; D002893:Chromosomes, Human, Pair 3; D004848:Epithelium / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced / Q000737:chemistry / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D016273:Occupational Exposure; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D001194:Asbestos; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase