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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway

Authors: Shanshan Xu, Yongfang Yue, Songfa Zhang, Caiyun Zhou, Xiaodong Cheng, Xing Xie, Xinyu Wang, Weiguo Lu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Cancer stem cells (CSCs) possess abilities of self-renewal and differentiation, have oncogenic potential and are regarded to be the source of cancer recurrence. However, the mechanism by which CSCs maintain their stemness remains largely unclear.

Methods

In this study, the cell line-derived ovarian CSCs (OCSCs), 3AO and Caov3, were enriched in serum-free medium (SFM). Differentially expressed proteins were compared between the OCSC subpopulation and parental cells using liquid chromatography (LC)-mass spectrometry (MS)/MS label-free quantitative proteomics. Sphere-forming ability assays, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), western blotting, and in vivo xenograft experiments were performed to evaluate stemness. RNA-sequencing (RNA-seq) and pyrosequencing were used to reveal the mechanism by which STON2 negatively modulates the stem-like properties of ovarian cancer cells.

Results

Among the 74 most differentially expressed proteins, stonin 2 (STON2) was confirmed to be down-regulated in the OCSC subpopulation. We show that STON2 negatively modulates the stem-like properties of ovarian cancer cells, which are characterized by sphere formation, a CD44+CD24− ratio, and by CSC- and epithelial mesenchymal transition (EMT)-related markers. STON2 knockdown also accelerated tumorigenesis in NOD/SCID mice. Further investigation revealed a downstream target, mucin 1 (MUC1), as up-regulated upon the down regulation of STON2. A decrease in both DNA methyltransferase 1 (DNMT1) expression and methylation in the promoter region of MUC1 was associated with subsequently elevated MUC1 expression, as detected in STON2 knockdown in 3AO and Caov3 cells. Direct DNMT1 knockdown simultaneously elevated MUC1 expression. The functional significance of this STON2-DNMT1/MUC1 pathway is supported by the observation that STON2 overexpression suppresses MUC1-induced sphere formation of OCSCs. The paired expression of STON2 and MUC1 in ovarian cancer specimens was also detected revealing the prognostic value of STON2 expression to be highly dependent on MUC1 expression.

Conclusions

Our results imply that STON2 may negatively regulate stemness in ovarian cancer cells via DNMT1-MUC1 mediated epigenetic modification. STON2 is therefore involved in OCSC biology and may represent a therapeutic target for innovative treatments aimed at ovarian cancer eradication.
Appendix
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Metadata
Title
STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway
Authors
Shanshan Xu
Yongfang Yue
Songfa Zhang
Caiyun Zhou
Xiaodong Cheng
Xing Xie
Xinyu Wang
Weiguo Lu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0977-y

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