title: Identification of Aging-Associated Gene Expression Signatures That Precede Intestinal Tumorigenesis.
abstract: Aging-associated alterations of cellular functions have been implicated in various disorders including cancers. Due to difficulties in identifying aging cells in living tissues, most studies have focused on aging-associated changes in whole tissues or certain cell pools. Thus, it remains unclear what kinds of alterations accumulate in each cell during aging. While analyzing several mouse lines expressing fluorescent proteins (FPs), we found that expression of FPs is gradually silenced in the intestinal epithelium during aging in units of single crypt composed of clonal stem cell progeny. The cells with low FP expression retained the wild-type Apc allele and the tissues composed of them did not exhibit any histological abnormality. Notably, the silencing of FPs was also observed in intestinal adenomas and the surrounding normal mucosae of Apc-mutant mice, and mediated by DNA methylation of the upstream promoter. Our genome-wide analysis then showed that the silencing of FPs reflects specific gene expression alterations during aging, and that these alterations occur in not only mouse adenomas but also human sporadic and hereditary (familial adenomatous polyposis) adenomas. Importantly, pharmacological inhibition of DNA methylation, which suppresses adenoma development in Apc-mutant mice, reverted the aging-associated silencing of FPs and gene expression alterations. These results identify aging-associated gene expression signatures that are heterogeneously induced by DNA methylation and precede intestinal tumorigenesis triggered by Apc inactivation, and suggest that pharmacological inhibition of the signature genes could be a novel strategy for the prevention and treatment of intestinal tumors.
authors: Departments of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Yoshihisa
authors: Y
authors: Okuchi
authors: Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors: Masamichi
authors: M
authors: Imajo
authors: Departments of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Rei
authors: R
authors: Mizuno
authors: Departments of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Innovative Techno-Hub for Integrated Medical Bio-Imaging, Kyoto University, Kyoto, Japan.
authors: Yuji
authors: Y
authors: Kamioka
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Hiroyuki
authors: H
authors: Miyoshi
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Makoto Mark
authors: MM
authors: Taketo
authors: Gastroenterological Center, Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Nagayama
authors: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Yoshiharu
authors: Y
authors: Sakai
authors: Departments of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
authors: Michiyuki
authors: M
authors: Matsuda
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice
chemical_list: D005819:Genetic Markers