title: Estrogen receptor 1 gene as a tumor suppressor gene in hepatocellular carcinoma detected by triple-combination array analysis.
abstract: Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. Recent developments in the treatment of HCC remain insufficient to cure unresectable disease or to prevent HCC. Consistent efforts are, therefore, needed to deepen understanding of pathogenesis of the disease. Genome-wide gene expression profile analyses can now detect various candidate genes that are modified by HCC. We have developed a new technique to identify tumor suppressor genes, triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism and methylation arrays to identify genes with altered expression. Using HCC tissue samples, triple-combination array analysis was performed to identify a candidate tumor suppressor gene. Subsequently, samples from 48 HCC patients were subjected to quantitative polymerase chain reaction (qPCR) and methylation-specific PCR to further elucidate clinical relevance of the gene. Estrogen receptor 1 (ESR1) was detected as a candidate tumor suppressor gene. Of the 48 clinical samples, 40 (83.3%) showed ESR1 promoter hypermethylation. In 24 (50%) HCC samples, the expression levels of the ESR1 gene was decreased by >90%. The decreased expression was significantly related to high liver damage score, pathological invasion of the intrahepatic portal vein, the size of tumor (>3 cm in diameter) and hepatitis B virus infection. The present study represents another example that triple-combination array is a convenient technique for detecting genes with altered expression in disease. The ESR1 gene was identified as a candidate tumor suppressor gene in HCC and further validation is warranted.
authors.affiliation: Gastroenterological Surgery (Department of Surgery II), Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hishida
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Inokawa
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayashi
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Okamura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Shin
authors.initials: S
authors.lastname: Takeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D059467:Transcriptome
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha