Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer
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Eun Jin Seo1,*, Dae Kyoung Kim1,*, Il Ho Jang1, Eun Jung Choi1, Sang Hun Shin1, Su In Lee1, Sang-Mo Kwon1, Ki-Hyung Kim2, Dong-Soo Suh2, Jae Ho Kim1,3
1Department of Physiology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
2Department of Obstetrics and Gynecology, School of Medicine, Pusan National University, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
3Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Gyeongsangnam-do, Republic of Korea
*These authors have contributed equally to this work
Jae Ho Kim, email: firstname.lastname@example.org
Keywords: cancer stem cells, ovarian cancer, hypoxia, NOTCH1, SOX2
Abbreviations: ALDH, aldehyde dehydrogenase; CSCs, cancer stem cells; EOC, epithelial ovarian cancer; HIF, hypoxia-inducible factor; NICD1, intracellular domain of NOTCH1
Received: February 11, 2016 Accepted: July 18, 2016 Published: July 30, 2016
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.
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