title: Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers.
abstract: One isoform of the 14-3-3 family, 14-3-3sigma, plays a crucial role in the G2 checkpoint by sequestering Cdc2-cyclinB1 in the cytoplasm, and the expression of 14-3-3sigma is frequently lost in breast cancers. This loss of expression is thought to cause a G2 checkpoint defect, resulting in chromosomal aberrations. Since lung cancers frequently carry numerous chromosomal aberrations, we examined the DNA methylation status and expression level of the 14-3-3sigma gene in 37 lung cancer cell lines and 30 primary lung tumor specimens. We found that small cell lung cancer (SCLC) cell lines frequently showed DNA hypermethylation (9 of 13 lines, 69%), and subsequent silencing of the 14-3-3sigma gene. Among non-small cell lung cancers (NSCLC), large cell lung cancer cell lines showed frequent hypermethylation and silencing of 14-3-3sigma (4 or 7 lines, 57%). In contrast, in other NSCLC cell lines, hypermethylation occurred very rarely (1 of 17 lines, 6%). All eight primary SCLC specimens examined also showed a loss or significant reduction in 14-3-3sigma expression in vivo, while a loss or reduction of 14-3-3sigma expression was very rare in primary NSCLC specimens (1 of 22 tissues, 5%). This is the first description that indicates lung cancers frequently show significant inactivation of the 14-3-3sigma gene mainly due to DNA hypermethylation in SCLC, but rarely in NSCLC, suggesting involvement of the 14-3-3sigma gene in lung tumorigenesis in a histological type-specific manner.
authors.affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. hosada@aichi-cc.jp
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tatematsu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Taku
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Harano
authors.forename: Ekmel
authors.initials: E
authors.lastname: Tezel
authors.forename: Minoru
authors.initials: M
authors.lastname: Takada
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D005092:Exonucleases; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011506:Proteins; D012334:RNA, Neoplasm; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human