キクチ　ヨシノリ   Kikuchi Yoshinori   菊池　由宣    所属   東邦大学  医学部 医学科    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Down-regulation of MutS homolog 3 by hypoxia in human colorectal cancer.
掲載誌名	正式名：Biochimica et biophysica acta 略　 称：Biochim Biophys Acta ISSNコード：01674889
掲載区分	国外
巻・号・頁	1823(4),pp.889-899
著者・共著者	Li J†, Koike J†, Kugoh H, Arita M†, Ohhira T, Kikuchi Y†, Funahashi K†, Takamatsu K†, Boland CR, Koi M, Hemmi H†
発行年月	2012/04
概要	Down-regulation of hMSH3 is associated with elevated microsatellite alterations at selected tetranucleotide repeats and low levels of microsatellite instability in colorectal cancer (CRC). However, the mechanism that down-regulates hMSH3 in CRC is not known. In this study, a significant association between over-expression of glucose transporter 1, a marker for hypoxia, and down-regulation of hMSH3 in CRC tissues was observed. Therefore, we examined the effect of hypoxia on the expression of hMSH3 in human cell lines. When cells with wild type p53 (wt-p53) were exposed to hypoxia, rapid down-regulation of both hMSH2 and hMSH3 occurred. In contrast, when null or mutated p53 (null/mut-p53) cells were exposed to hypoxia, only hMSH3 was down-regulated, and at slower rate than wt-p53 cells. Using a reporter assay, we found that disruption of the two putative hypoxia response elements (HREs) located within the promoter region of the hMSH3 abrogated the suppressive effect of hypoxia on reporter activity regardless of p53 status. In an EMSA, two different forms of HIF-1α complexes that specifically bind to these HREs were detected. A larger complex containing HIF-1α predominantly bound to the HREs in hypoxic null/mut-p53 cells whereas a smaller complex predominated in wt-p53 cells. Finally, HIF-1α knockdown by siRNA significantly inhibited down-regulation of hMSH3 by hypoxia in both wt-p53 and mut-p53 cells. Taken together, our results suggest that the binding of HIF-1α complexes to HRE sites is necessary for down-regulation of hMSH3 in both wt-p53 and mut-p53 cells.
文献番号	22343000