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ID 115966
タイトル別表記
Sessile serrated adenoma/polyp-cancer sequenceにおいてS100Pは遺伝子脱メチル化により発現し、細胞増殖を促進する
著者
高橋, 早代 徳島大学大学院医科学教育部(医学専攻)
棚橋, 俊仁 Tokushima University
Fujimoto, Shota Tokushima University
Bando, Masahiro Tokushima University
Ma, Beibei Tokushima University
川口, 智之 Tokushima University
Sato, Toshiro Keio University
Fujimori, Takahiro Shinko Hospital
キーワード
SSA/P
DNA hypomethylation
S100P
3-dimensional organoid
Genome-wide DNA methylation array
Sessile serrated adenoma/polyp
資料タイプ
学位論文
抄録
Background/Aims: Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. Methods: We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. Results: The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5′-flanking promoter region. Conclusion: These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.
掲載誌名
Digestion
ISSN
00122823
14219867
cat書誌ID
AA00628636
AA12781324
出版者
Karger
102
5
開始ページ
789
終了ページ
802
発行日
2021-01-04
備考
内容要旨・審査要旨・論文本文の公開
本論文は,著者Sayo Takahashiの学位論文として提出され,学位審査・授与の対象となっている。
権利情報
© 2020 S. Karger AG, Basel
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3486号
学位記番号
甲医第1490号
学位授与年月日
2021-03-17
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系