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Published on: September 20, 2016
Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers
Hirotaka Osada1, Yoshio Tatematsu, Yasushi Yatabe
1Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. hosada@aichi-cc.jp
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.
Insights
The 14-3-3sigma gene, crucial for cell cycle control, is frequently inactivated in small cell lung cancer (SCLC) via DNA hypermethylation. This gene inactivation is rare in non-small cell lung cancer (NSCLC), suggesting a role in lung tumorigenesis specific to cancer type.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The 14-3-3sigma protein is vital for the G2 cell cycle checkpoint, preventing uncontrolled cell division.
- Loss of 14-3-3sigma expression is observed in breast cancers, linked to chromosomal instability.
- Lung cancers often exhibit numerous chromosomal aberrations, suggesting potential involvement of checkpoint regulators like 14-3-3sigma.
Purpose of the Study:
- To investigate the DNA methylation status and expression of the 14-3-3sigma gene in lung cancer.
- To determine if 14-3-3sigma inactivation contributes to lung tumorigenesis.
- To explore potential differences in 14-3-3sigma regulation between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
Main Methods:
- Analysis of DNA methylation and 14-3-3sigma gene expression in 37 lung cancer cell lines.
- Examination of 14-3-3sigma expression in 30 primary lung tumor specimens.
- Histological classification of lung cancers into SCLC and various NSCLC subtypes.
Main Results:
- Frequent DNA hypermethylation and silencing of 14-3-3sigma were observed in SCLC cell lines (69%).
- Large cell lung cancer (a subtype of NSCLC) also showed frequent hypermethylation and silencing (57%).
- Other NSCLC subtypes rarely exhibited 14-3-3sigma hypermethylation (6%).
- Loss or significant reduction of 14-3-3sigma expression was common in primary SCLC (100%) but rare in primary NSCLC (5%).
Conclusions:
- The 14-3-3sigma gene is frequently inactivated, primarily through DNA hypermethylation, in SCLC.
- Inactivation of 14-3-3sigma is uncommon in NSCLC.
- These findings suggest a histological type-specific role for 14-3-3sigma in lung tumorigenesis.
