title: Inhibitory effect of Nodal on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma of uterus.
abstract: Cancers consist of heterogeneous populations. Recently, it has been demonstrated that cells with tumorigenic potential are limited to a small population, called cancer-initiating cells (CICs). Aldehyde dehydrogenase 1 (ALDH1) is one of the markers of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and ALDH1-high population of endometrioid adenocarcinoma cell line was more tumorigenic, resistant to anti-cancer drugs, and invasive than ALDH1-low population. Here, the regulatory signaling for ALDH1 was examined. The inhibition of TGF-β signaling increased ALDH1-high population. Among TGF-β family members, Nodal expression and ALDH1 expression levels were mutually exclusive. Immunohistochemical analysis on clinical samples revealed Nodal-high tumor cells to be ALDH-low and vise versa, suggesting that Nodal may inhibit ALDH1 expression via stimulating TGF-β signaling in uterine endometrioid adenocarcinoma. In fact, the addition of Nodal to endometrioid adenocarcinoma cell line reduced ALDH1-high population. Although ALDH1 mRNA level was not affected, the amount of ALDH1 protein appeared to be reduce by Nodal through ubiquitine-proteasome pathway. The regulation of TGF-β signaling might be a novel therapeutic target of CICs in endometrioid adenocarcinoma.
authors.affiliation: Department of Pathology, Osaka University Graduate School of Medicine, Yamada-Oka 2-2, Suita 565-0871, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Tian
authors.initials: T
authors.lastname: Tian
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hori
authors.forename: Naoki
authors.initials: N
authors.lastname: Wada
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Ikeda
authors.forename: Eiichi
authors.initials: E
authors.lastname: Morii
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D018269:Carcinoma, Endometrioid / Q000201:enzymology*; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000201:enzymology*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D055457:Nodal Protein / Q000378:metabolism*; D059748:Proteolysis; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054875:Ubiquitination; D014599:Uterus / Q000201:enzymology*
chemical_list: D007527:Isoenzymes; C526007:NODAL protein, human; D055457:Nodal Protein; D016212:Transforming Growth Factor beta; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
keywords: ALDH1; Aldehyde dehydrogenase 1; CICs; DEAB; Endometrioid adenocarcinoma; Nodal; TGF-β family; aldehyde dehydrogenase 1; cancer-initiating cells; diethylaminobenzaldehyde