Epigenetic inactivation of the thyroid hormone receptor beta1 gene at 3p24.2 in lung cancer.
BACKGROUND
Frequent allelic loss on chromosome 3p in various human cancers suggests the presence of tumor suppressor genes in this region. The thyroid hormone receptor beta1 (TRbeta1) gene is located at 3p24.2, where allelic loss frequently occurs in lung cancer, and aberrant TRbeta1 methylation was observed in several human cancers.


METHODS
We examined the expression, mutation, and promoter methylation of TRbeta1 in 18 small cell lung cancer (SCLC) and 29 non-small cell lung cancer (NSCLC) cell lines by reverse-transcription polymerase chain reaction (RT-PCR), direct sequencing, or methylation-specific PCR. Four lung cancer cell lines lacking TRbeta1 expression were treated with 5-aza-2-deoxy-cytidine and/or trichostatin-A, and the TRbeta1 expression was determined by RT-PCR. We also examined the TRbeta1 methylation in 116 NSCLC surgical specimens and analyzed the correlation between methylation status and clinicopathological parameters or mutations of KRAS and EGFR.


RESULTS
TRbeta1 expression was absent in 61% of SCLCs and 48% of NSCLCs, and 67% of SCLCs and 45% of NSCLCs carried TRbeta1 promoter methylation, while no somatic mutation was found in all cell lines. TRbeta1 methylation status was significantly associated with loss of TRbeta1 expression. TRbeta1 expression was restored by treatment with 5-aza-2-deoxy-cytidine and/or trichostatin-A in four cell lines. TRbeta1 methylation was found in 47% of NSCLC surgical specimens; however, the methylation was not significantly associated with any clinicopathological parameters or mutations of KRAS and EGFR.


CONCLUSIONS
This is the first study to demonstrate epigenetic inactivation of TRbeta1 through aberrant methylation in lung cancer, while TRbeta1 mutations are not common in lung cancer.
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan.
Yasuki
Y
Iwasaki
Noriaki
N
Sunaga
Yoshio
Y
Tomizawa
Hisao
H
Imai
Hironobu
H
Iijima
Noriko
N
Yanagitani
Kazuhiko
K
Horiguchi
Masanobu
M
Yamada
Masatomo
M
Mori
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002893:Chromosomes, Human, Pair 3 / Q000378:metabolism; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D008745:Methylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D037042:Thyroid Hormone Receptors beta; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins