title: 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.
abstract: 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.
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325027, China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Huangzhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia, 30912, United States.|Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Tang
authors.affiliation: Neurosurgery Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Jichang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Du
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Chongwen
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Radiation Medicine, the Chinese Academy of Medical Sciences, Nankai District, Tianjing 300192, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Sida
authors.initials: S
authors.lastname: Qin
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 201204, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Tianjin Cancer Institute and Hospital Affiliated to Tianjin Medical University, Tianjin, 300060, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Breast Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, 510182, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C000715187:Lin28A protein, human; C550906:MIRN208 microRNA, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051176:beta Catenin; C487931:mirnlet7 microRNA, human; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: breast tumor; cancer stem cells; feedback loop; let-7a; miRNA-208a