The Androgen Receptor Antagonizes Wnt/β-Catenin Signaling in Epidermal Stem Cells.
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ABSTRACT:
SUBMITTER: Kretzschmar K
PROVIDER: S-EPMC4641324 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEmbryonic stem cells (ESCs) are pluripotent stem cells and can form tumors containing cells from all three germ layers. Similarities between pluripotent stem cells and malignant tumor cells have been identified. The purpose of this study was to obtain ESCs-converted tumor cell lines and to investigate the mechanism of malignancy in pluripotent stem cells.MethodsMouse ESCs were subcutaneously injected into nude mice to obtain tumors from which a tumor-like cell line (ECCs1) was established by culturing the cells in chemical-defined N2B27 medium supplied with two small molecular inhibitors CHIR99021 and PD0325901 (2i). The ECCs1 were then subcutaneously injected into nude mice again to obtain tumors from which another tumor-like cells line (ECCs2) was established in the same 2i medium. The malignant degree of ESCs, ECCs1 and ECCs2 was compared and the underlying mechanism involved in the malignancy development of ESCs was examined.ResultsThe three ESCs, ECCs1 and ECCs2 cell lines were cultured in the same 2i condition and showed some likeness such as Oct4-expression and long-term expansion ability. However, the morphology and the tumor-formation ability of the cell lines were different. We identified that ECCs1 and ECCs2 gradually acquired malignancy. Moreover, Wnt signaling-related genes such as CD133 and ?-catenin expression were up-regulated and Frizzled related protein (FRP) was down-regulated during the tumor development of ESCs.ConclusionsThe two tumor-like cell lines ECCs1 and ECCs2 stand for early malignant development stage of ESCs and the ECCs2 was more malignant than the ECCs1. Moreover, we identified that Wnt/?-catenin signaling played an important role in the malignancy process of ESCs.
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Project description:PurposeBreast cancer stem cells (BCSCs) contribute to the initiation, development, and recurrence of breast carcinomas. β1,4-Galactosyltransferase V (B4GalT5), which catalyzes the addition of galactose to GlcNAcβ1-4Man of N-glycans, is involved in embryogenesis. However, its role in the modulation of BCSCs remains unknown.Materials and methodsThe relationship between B4GalT5 and breast cancer stemness was investigated by online clinical databases and immunohistochemistry analysis. Mammosphere formation, fluorescence-activated cell sorting (FACS), and in-vivo assays were used to evaluate B4GalT5 expression in BCSCs and its effect on BCSCs. B4GalT5 regulation of Wnt/β-catenin signaling was examined by immunofluorescence and Ricinus communis agglutinin I pull-down assays. Cell surface biotinylation and FACS assays were performed to assess the association of cell surface B4GalT5 and BCSCs.ResultsB4GalT5, but not other B4GalTs, was highly correlated with BCSC markers and poor prognosis. B4GalT5 significantly increased the stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) and promoted the production of CD44+CD24-/low cells and the formation of mammospheres. Furthermore, B4GalT5 overexpression resulted in dramatic tumor growth in vivo. Mechanistically, B4GalT5 modified and protected Frizzled-1 from degradation via the lysosomal pathway, promoting Wnt/β-catenin signaling which was hyperactivated in BCSCs. B4GalT5, located on the surface of a small subset of breast carcinoma cells, was not responsible for the stemness of BCSCs.ConclusionB4GalT5 modulates the stemness of breast cancer through glycosylation modification to stabilize Frizzled-1 and activate Wnt/β-catenin signaling independent of its cell surface location. Our studies highlight a previously unknown role of B4GalT5 in regulating the stemness of breast cancer and provide a potential drug target for anticancer drug development.
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