MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1
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Xin Sun1,*, Shiwen Jiang2,*, Jian Liu1, Huangzhen Wang1, Yiwen Zhang1, Shou-Ching Tang3,4, Jichang Wang5, Ning Du1, Chongwen Xu1, Chenguang Wang6, Sida Qin1, Jia Zhang1, Dapeng Liu1, Yunfeng Zhang1, Xiaojun Li1, Jiansheng Wang1, Jun Dong7, Xin Wang8, Shaohua Xu9, Zhen Tao10, Fei Xu11, Jie Zhou12, Tao Wang13, Hong Ren1
1Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China
2Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325027, China
3Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia, 30912, United States
4Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China
5Neurosurgery Department of the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China
6Institute of Radiation Medicine, the Chinese Academy of Medical Sciences, Nankai District, Tianjing 300192, China
7Department of Orthopaedics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China
8Department of Gastroenterology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, 710061, China
9Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China
10Department of Radiation Oncology, Tianjin Cancer Institute and Hospital Affiliated to Tianjin Medical University, Tianjin, 300060, China
11Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
12Department of Breast Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, 510182, China
13Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
*These authors have contributed equally to this work
Hong Ren, e-mail: [email protected]
Keywords: cancer stem cells, feedback loop, breast tumor, miRNA-208a, let-7a
Received: June 05, 2015 Accepted: July 28, 2015 Published: October 08, 2015
MiR-208a stimulates cardiomyocyte hypertrophy, fibrosis and β-MHC (β-myosin heavy chain) expression, being involved in cardiovascular diseases. Although miR-208a is known to play a role in cardiovascular diseases, its role in cancer and cancer stem cells (CSCs) remains uncertain. We identified an inverse relationship between miR-208a and let-7a in breast cancer specimens, and found that SOX2, β-catenin and LIN28 are highly expressed in patients with advanced breast cancer opposed to lesser grades. Further, we isolated ALDH1+ CSCs from ZR75–1 and MDA-MB-231 (MM-231) breast cancer cell lines to test the role of miR-208a in breast CSCs (BrCSCs). Our studies showed that overexpression of miR-208a in these cells strongly promoted the proportion of ALDH1+ BrCSCs and continuously stimulated the self-renewal ability of BrCSCs. By using siRNAs of SOX2 and/or β-catenin, we found that miR-208a increased LIN28 through stimulation of both SOX2 and β-catenin. The knockdown of either SOX2 or β-catenin only partially attenuated the functions of miR-208a. Let-7a expression was strongly inhibited in miR-208a overexpressed cancer cells, which was achieved by miR-208a induction of LIN28, and the restoration of let-7a significantly inhibited the miR-208a induction of the number of ALDH1+ cells, inhibiting the propagations of BrCSCs. In let-7a overexpressed ZR75–1 and MM-231 cells, DICER1 activity was significantly inhibited with decreased miR-208a. Let-7a failed to decrease miR-208a expression in ZR75–1 and MM-231 cells with DICER1 knockdown. Our research revealed the mechanisms through which miR-208a functioned in breast cancer and BrCSCs, and identified the miR-208a-SOX2/β-catenin-LIN28-let-7a-DICER1 regulatory feedback loop in regulations of stem cells renewal.
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