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Coordinated expression of REG4 and aldehyde dehydrogenase 1 regulating tumorigenic capacity of diffuse-type gastric carcinoma-initiating cells is inhibited by TGF-β
MedLine Citation:
PMID:  22430847     Owner:  NLM     Status:  Publisher    
Aldehyde dehydrogenase 1 (ALDH1) has been shown to serve a marker for cancer-initiating cells (CICs), but little is known about the regulation of the CIC functions of ALDH1+ cancer cells. We isolated ALDH1+ cells from human diffuse-type gastric carcinoma cells and characterized these cells using an Aldefluor assay. ALDH1+ cells constituted 5 to 8% of the human diffuse-type gastric carcinoma cells, OCUM-2MLN and HSC-39, were more tumorigenic than ALDH1- cells, and were able to self-renew and generate heterogeneous cell populations. Using gene expression microarray analyses, we identified REG4 (regenerating islet-derived family, member 4) as one of genes up-regulated in ALDH1+ cells, and thus as a novel marker for ALDH1+ tumor cells. Induced expression of REG4 enhanced the colony-forming ability of OCUM-2MLN cells, while knockdown of REG4 inhibited the tumorigenic potential of ALDH1+ cells. We further found that TGF-β signaling reduces the expression of ALDH1 and REG4, and the size of the ALDH1+ cell population. In human diffuse-type gastric carcinoma tissues, the expression of ALDH1 and REG4 correlated with each other, as assessed by immunohistochemistry, and ALDH1 expression correlated inversely with Smad3 phosphorylation as a measure of TGF-β signaling. These findings illustrate that, in diffuse-type gastric carcinoma, REG4 is up-regulated in ALDH1+ CICs, and that the increased tumorigenic ability of ALDH1+ cells depends on REG4. Moreover, TGF-β down-regulates ALDH1 and REG4 expression, which correlates with a reduction in CIC population size and tumorigenicity. Targeting REG4 in ALDH1+ CICs may provide a novel strategy in treatment of diffuse-type gastric carcinoma. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Yoko Katsuno; Shogo Ehata; Masakazu Yashiro; Kazuyoshi Yanagihara; Kosei Hirakawa; Kohei Miyazono
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-19
Journal Detail:
Title:  The Journal of pathology     Volume:  -     ISSN:  1096-9896     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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