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Stemness, Pluripotentiality, and Wnt Antagonism: sFRP4, a Wnt antagonist Mediates Pluripotency and Stemness in Glioblastoma

1
Division of Cancer Stem Cells and Cardiovascular and Neuronal Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
2
Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
3
School of Human Sciences, The University of Western Australia, Perth, WA 6009, Australia
4
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
5
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
6
Cancer Program, Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
7
Curtin Medical School, Curtin University, Perth, WA 6102, Australia
8
Cuor Stem Cellutions Pvt Ltd., School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(1), 25; https://doi.org/10.3390/cancers11010025
Received: 12 November 2018 / Revised: 17 December 2018 / Accepted: 21 December 2018 / Published: 27 December 2018
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Abstract

Background: Chemotherapeutic resistance of glioblastoma has been attributed to a self-renewing subpopulation, the glioma stem cells (GSCs), which is known to be maintained by the Wnt β−catenin pathway. Our previous findings demonstrated that exogeneous addition of the Wnt antagonist, secreted fizzled-related protein 4 (sFRP4) hampered stem cell properties in GSCs. Methods: To understand the molecular mechanism of sFRP4, we overexpressed sFRP4 (sFRP4 OE) in three human glioblastoma cell lines U87MG, U138MG, and U373MG. We also performed chromatin immunoprecipitation (ChIP) sequencing of sFRP4 OE and RNA sequencing of sFRP4 OE and sFRP4 knocked down U87 cells. Results: We observed nuclear localization of sFRP4, suggesting an unknown nuclear role. ChIP-sequencing of sFRP4 pulldown DNA revealed a homeobox Cphx1, related to the senescence regulator ETS proto-oncogene 2 (ETS2). Furthermore, miRNA885, a p53-mediated apoptosis inducer, was upregulated in sFRP4 OE cells. RNA sequencing analysis suggested that sFRP4-mediated apoptosis is via the Fas-p53 pathway by activating the Wnt calcium and reactive oxygen species pathways. Interestingly, sFRP4 OE cells had decreased stemness, but when knocked down in multipotent mesenchymal stem cells, pluripotentiality was induced and the Wnt β-catenin pathway was upregulated. Conclusions: This study unveils a novel nuclear role for sFRP4 to promote apoptosis by a possible activation of DNA damage machinery in glioblastoma. View Full-Text
Keywords: Wnt; sFRP4; glioblastoma; pluripotency; p53 Wnt; sFRP4; glioblastoma; pluripotency; p53
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Bhuvanalakshmi, G.; Gamit, N.; Patil, M.; Arfuso, F.; Sethi, G.; Dharmarajan, A.; Prem Kumar, A.; Warrier, S. Stemness, Pluripotentiality, and Wnt Antagonism: sFRP4, a Wnt antagonist Mediates Pluripotency and Stemness in Glioblastoma. Cancers 2019, 11, 25.

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