title: TET family proteins and 5-hydroxymethylcytosine in esophageal squamous cell carcinoma.
abstract: Mammalian DNA is epigenetically marked by 5'-cytosine methylation (5-methylcytosine [5-mC]). The Ten-eleven translocation (TET) enzymes (TET1, TET2, and TET3) are implicated in DNA demethylation, through dioxygenase activity that converts 5-mC to 5-hydroxymethylcytosine (5-hmC). Although decreased TET is reportedly associated with decreased 5-hmC levels in various cancers, functions of 5-hmC and TET expression in esophageal squamous cell carcinoma (ESCC) are unclear. We used ELISA and immunohistochemistry tests to analyze 5-hmC status in ESCC tissues, RT-qPCR to analyze TET family mRNA expression in normal and tumor tissues, and pyrosequencing to quantify LINE-1 (i.e., global DNA methylation) levels. ELISA and immunohistochemical testing showed 5-hmC levels were significantly lower in ESCC than in paired normal tissues (P < 0.0001). TET2 expression was significantly lower in ESCCs than paired normal tissues (P < 0.0001), and significantly associated with 5-hmC levels in ESCCs (P = 0.003, r = 0.33). 5-hmC levels were also significantly associated with LINE-1 methylation level (P = 0.0002, r = 0.39). Patients with low 5-hmC levels had shorter overall survival than those with higher levels, although not significantly so (P = 0.084). In conclusion, 5-hmC expression was decreased in ESCC tissues, and was associated with TET2 expression level. TET2 reduction and subsequent 5-hmC loss might affect ESCC development.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Murata
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kosumi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Iwagami
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Surgery, National Hospital Organization Kyushu Cancer Center, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Cancer Biology, National Kyushu Cancer Center Clinical Research Institute, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D044503:5-Methylcytosine / Q000737:chemistry / Q000031:analogs & derivatives; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002470:Cell Survival; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D049308:Dioxygenases; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology; D053208:Kaplan-Meier Estimate; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human
keywords: TET; demethylation; epigenetics; markers