T Mizuno1, N Suzuki2, H Makino2, T Furui2, E Morii3, H Aoki4, T Kunisada4, M Yano5, S Kuji6, Y Hirashima6, A Arakawa7, S Nishio8, K Ushijima8, K Ito9, Y Itani10, K Morishige2. 1. Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Japan. Electronic address: mizutomo@gifu-u.ac.jp. 2. Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Japan. 3. Department of Pathology, Osaka University Graduate School of Medicine, Japan. 4. Department of Tissue and Organ Development, Gifu University Graduate School of Medicine, Japan. 5. Department of Obstetrics and Gynecology, Faculty of Medicine, Oita University, Japan. 6. Division of Gynecology, Shizuoka Cancer Center, Japan. 7. Department of Obstetrics and Gynecology, Nagoya City University, Graduate School of Medicine, Aichi, Japan. 8. Department of Obstetrics and Gynecology, Kurume University School of Medicine, Japan. 9. Department of Obstetrics and Gynecology, Kansai Rosai Hospital, Japan. 10. Department of Obstetrics and Gynecology,Nara Prefecture General Medical Center,Japan.
Abstract
OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.
OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.
Authors: Haiyan Zhu; Xiang Gu; Lu Xia; You Zhou; Hakim Bouamar; Junhua Yang; Xiaofei Ding; Christian Zwieb; Jianan Zhang; Andrew P Hinck; Lu-Zhe Sun; Xueqiong Zhu Journal: Clin Cancer Res Date: 2018-03-16 Impact factor: 12.531
Authors: Yun-Jung Choi; Patrick N Ingram; Kun Yang; Lan Coffman; Mangala Iyengar; Shoumei Bai; Dafydd G Thomas; Euisik Yoon; Ronald J Buckanovich Journal: Proc Natl Acad Sci U S A Date: 2015-11-30 Impact factor: 11.205