Epigenetic inactivation of TSLC1 gene in nasopharyngeal carcinoma.
Deletion of 11q23 is a common genetic aberration in nasopharyngeal carcinoma (NPC). Multiple candidate tumor suppressor genes (TSG) were mapped to this region but few of them were investigated in NPC. TSLC1 (tumor suppressor in lung cancer) is recently reported to be a putative TSG on 11q23. This gene was found to be inactivated by promoter hypermethylation in non-small cell lung carcinoma (NSCLC), liver cancer, and breast cancer. To study the role of TSLC1 gene in NPC tumorigenesis, we screened for mutations and aberrant methylation of TSLC1 gene in 5 NPC cell lines, 3 NPC xenografts, and 38 primary NPC cases. No somatic mutations of TSLC1 were detected in the NPC samples, but a 9-bp (CCACCACCA) deletion in exon 8 was found in a primary NPC and its corresponding blood sample. Bisulfite sequencing revealed aberrant methylation of TSLC1 promoter in four NPC cell lines. Loss of TSLC1 gene expression was found in two cell lines (HK-1 and CNE-2) with dense methylation. Expression of this gene was restored in these cell lines after treatment with demethylating agent 5-aza-2'-deoxycytidine. Our results showed that silencing of TSLC1 gene expression in NPC was associated with promoter hypermethylation. Promoter hypermethylation of TSLC1 gene was further illustrated in 34.2% (13/38) of primary NPCs. No aberrant promoter methylation was found in any of the four investigated normal nasopharyngeal epithelia. Frequent epigenetic inactivation of TSLC1 gene in NPC suggested that this gene is one of the target tumor suppressor genes of this endemic cancer.
Hui
Angela Bik-Yu
AB
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
Lo
Kwok-Wai
KW
Kwong
Joseph
J
Lam
Eric Ching-Wan
EC
Chan
Sylvia Yat-Yee
SY
Chow
Lillian Shuk-Nga
LS
Chan
Andrew Siu-Chung
AS
Teo
Peter Man-Lung
PM
Huang
Dolly P
DP
D000328:Adult; D000368:Aged; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001483:Base Sequence; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D007136:Immunoglobulins; D019656:Loss of Heterozygosity; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism; D009305:Nasopharynx / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D008565:Membrane Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine