Abstract
Hypoxia and NOTCH signaling have been reported to be associated with the self-renewal and drug resistance of cancer stem cells (CSCs). However, the molecular mechanisms by which hypoxia and NOTCH signaling stimulate the self-renewal and drug resistance of ovarian CSCs are poorly understood. In the present study, we identified SOX2 as a key transcription factor for CSC-like characteristics in the downstream of hypoxia-induced NOTCH signaling in epithelial ovarian cancer cells. Hypoxic treatment or overexpression of intracellular domain of NOTCH1 (NICD1) in ovarian cancer cells increased sphere formation, drug resistance, and expression of CSC-associated genes such as SOX2, ALDH, and ABC transporters. Hypoxic treatment increased the expression of NICD1, and hypoxic treatment or NICD1 overexpression increased SOX2 promoter activity, which was inhibited by deletion of HIF-1 or CSL binding sites. Furthermore, DAPT treatment decreased the effect of hypoxic treatment, and SOX2 knockdown decreased the effect of hypoxic treatment and NICD overexpression on sphere formation and drug resistance in established ovarian cancer cell lines and primary ovarian cancer cells. These results suggest that hypoxia-NOTCH1-SOX2 signaling axis is important for activation of ovarian CSCs, which may provide a novel opportunity for developing therapeutics to eradicate CSCs in ovarian cancer patients.
Highlights
Ovarian cancer is the leading cause of death among cancer-related diseases in women [1]
We explored the roles of hypoxia, NOTCH1, and SOX2 in the sphere-forming ability, drug resistance, and cancer stem cells (CSCs) marker expression of CSC-like cells isolated from ovarian cancer cell lines and primary ovarian cancer cells
We demonstrated that culturing CSC-enriched spheres in hypoxic condition further enhanced CSC-characteristics including sphere size, expression of SOX2 and aldehyde dehydrogenase 1 (ALDH1), and cell proliferation
Summary
Ovarian cancer is the leading cause of death among cancer-related diseases in women [1]. Though ovarian cancer is initially chemoresponsive, the majority of patients experience relapses with chemoresistance within 5 years, which renders ovarian cancer as a cancer stem cell (CSC)-related disease [2]. CSCs have been shown to be enriched in sphere cultures, which are often more resistant to chemotherapeutic reagents [3]. Enriched spheres are considered to disseminate cancers in the peritoneal cavity and cause recurrence with drug resistance [4]. It has been shown that the drug resistance property of CSCs is conferred by increased expression of multidrug resistance proteins, such as ABCG2 [5]. Ovarian cancer cells with high ALDH1 expression displayed CSC-like properties, such as anchorageindependent growth and enhanced drug resistance [7]
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