Genetic and epigenetic alterations of BRG1 promote oral cancer development.
Loss of heterozygosity (LOH) analysis is a sensitive method to detect deletions of specific chromosome regions which are considered to harbor of putative tumor suppressor gene (TSG)s. Previous allelotype analyses in various human cancers suggested the presence of at least one TSG in chromosome 19p13 region. Functional analysis of BRG1, a member of SWI/SNF complex proteins, located at 19p13.2, suggested it to be a candidate TSG in different types of human cancers. We examined LOH at 19p13 region in 39 oral cancers by using six microsatellite markers and found allelic deletion in 25 of 39 (64%) samples. A microsatellite marker near BRG1 locus showed the highest LOH in tumor samples. To clarify the role of BRG1 gene in oral carcinogenesis, we checked its mutation status in tumor samples. As mutation of the BRG1 gene was not detected in oral cancers, we examined the mRNA expression level. Quantitative RT-PCR analysis surprisingly demonstrated increased expression of BRG1 mRNA in 62% of primary tumors as compared with that of matched normal samples. Since functions of BRG1 and BRM, another member of SWI/SNF highly homologous to BRG1, may be interrelated, we also examined BRM mRNA expression in the same samples. In most samples, the expressions of BRG1 and BRM changed in the same direction consistent with reported data on human cancer cell lines. An important finding is that expression of an alternative in frame splicing form of BRG1 which includes exon 26 is selectively decreased or lost in most tumor samples. This unique 33 amino-acid sequence of BRG1 protein shows very high homology with heterogeneous nuclear ribonucleoprotein E and may affect the function and level of BRG1 through modifications on post-transcriptional control. All these findings suggest that the genetic and epigenetic alterations of BRG1 may have a role in oral cancer development.
Gunduz
Esra
E
Department of Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama, Japan.
Gunduz
Mehmet
M
Ouchida
Mamoru
M
Nagatsuka
Hitoshi
H
Beder
Levent
L
Tsujigiwa
Hidetsugu
H
Fukushima
Kunihiro
K
Nishizaki
Kazunori
K
Shimizu
Kenji
K
Nagai
Noriyuki
N
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004265:DNA Helicases; D044127:Epigenesis, Genetic; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
D014408:Biomarkers, Tumor; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases