Total for the last 12 months
number of access : ?
number of downloads : ?
ID 119258
Title Alternative
LansoprazoleはSkp2/p27シグナル伝達経路を介してG1期停止を誘導しsessile serrated lesionsの発生を抑制する
Author
Fujimoto, Shota Tokushima University
Bando, Masahiro Tokushima University
Wada, Hironori Tokushima University
Horimoto, Katsuhisa National Institute of Advanced Industrial Science and Technology (AIST)|SOCIUM Inc
Keywords
Sessile serrated lesion
Chemoprevention
Connectivity map
Organoid
Lansoprazole
Content Type
Thesis or Dissertation
Description
Background: Although the serrated-neoplasia pathway reportedly accounts for 15%-30% of colorectal cancer (CRC), no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. We searched for effective compounds comprehensively from a large series of compounds by employing Connectivity Map (CMAP) analysis of SSL-specific gene expression profiles coupled with in vitro screening using SSL patient-derived organoids (PDOs), and validated their efficacy using a xenograft mouse model of SSL.
Methods: We generated SSL-specific gene signatures based on DNA microarray data, and applied them to CMAP analysis with 1309 FDA-approved compounds to select candidate compounds. We evaluated their inhibitory effects on SSL-PDOs using a cell viability assay. SSL-PDOs were orthotopically transplanted into NOG mice for in vivo evaluation. The signal transduction pathway was evaluated by gene expression profile and protein expression analysis.
Results: We identified 221 compounds by employing CMAP analysis of SSL-specific signatures, which should cancel the gene signatures, and narrowed them down to 17 compounds. Cell viability assay using SSL-PDOs identified lansoprazole as having the lowest IC50 value (47 μM) among 17 compounds. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. Administration of lansoprazole to mice inhibited the growth of SSL xenograft whereas the tumor in control mice treated with vehicle alone grew gradually over time. The Ki67 index in xenograft lesions from the lansoprazole group was significantly lower compared with the control group. Cell cycle analysis of SSL-PDOs treated with lansoprazole exhibited a significant increase in G1 phase cell population. Microarray and protein analysis revealed that lansoprazole downregulated Skp2 expression and upregulated p27 expression in SSL-PDOs.
Conclusions: Our data strongly suggest that lansoprazole is the most effective chemopreventive agent against SSL, and that lansoprazole induces G1 cell cycle arrest by downregulating Skp2 and upregulating p27 in SSL cells.
Journal Title
Journal of Gastroenterology
ISSN
14355922
09441174
NCID
AA11627089
AA10988015
Publisher
Springer Nature|Japanese Society of Gastroenterology
Volume
59
Issue
1
Start Page
11
End Page
23
Published Date
2023-11-22
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Tomoyuki Kawaguchi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。
論文本文は後日公開予定
This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Natureʼs AM terms of use (https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms), but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s00535-023-02052-0
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
jpn
TextVersion
その他
MEXT report number
甲第3773号
Diploma Number
甲医第1595号
Granted Date
2024-02-22
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital