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Theranostics 2018; 8(21):5801-5813. doi:10.7150/thno.29380 This issue Cite

Research Paper

miR-200c/141 Regulates Breast Cancer Stem Cell Heterogeneity via Targeting HIPK1/β-Catenin Axis

Bingjie Liu^1,2*, Ruikai Du^3*, Lei Zhou^1,2, Jiahui Xu¹, Song Chen^4,5, Ji Chen⁶, Xiaoli Yang¹, Dong-xu Liu⁷, Zhi-ming Shao^1,8, Lixing Zhang¹, Zuoren Yu⁹, Ni Xie^10✉, Jun-lin Guan^11✉, Suling Liu^1✉

1. Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institute, Key Laboratory of Breast Cancer in Shanghai, Key Laboratory of Medical Epigenetics and Metabolism, Innovation Center for Cell Signaling Network, Shanghai Medical College, Fudan University, Shanghai 200032, China;
2. School of Life Science, University of Science & Technology of China, Hefei, Anhui 230027, China;
3. State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China;
4. Institute of Medicinal Biotechnology, Jiangsu College of Nursing, Huaian, China
5. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
6. Department of Pathology, Suizhou Affiliated Hospital to Hubei University of Medicine, Suizhou, Hubei, 441300, China
7. The Centre for Biomedical and Chemical Sciences, School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 1010, New Zealand.
8. Department of Oncology, Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai 200032, China;
9. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Translational Medical Center for Stem Cell Therapy, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China;
10. Institute of translation medicine, Shenzhen Second People's Hospital, The first Affiliated Hospital of Shenzhen University Health Science Center
11. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267
^*These authors contributed equally to this article.

✉ Corresponding authors: Suling Liu, Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Tel/Fax: 086-21-34771023. Email: sulingedu.cn OR Jun-Lin Guan, Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Tel: 1-513-558-5323; Fax: 1-513-558-5061; Email: guanjledu OR Ni Xie, Institute of translation medicine, Shenzhen Second People's Hospital, The first Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China; Tel: +86-13501580802; Fax: +86-755-83003435; Email: xn100edu.cn More

Abstract

Increasing evidence demonstrates the existence of two inter-convertible states of breast cancer stem cells (BCSCs) with distinct behaviors in proliferation and mobility, and the BCSC heterogeneity is accurately regulated by sophisticated mechanisms including microRNAs. The microRNA-200 family including miR-200c/141 cluster was reported to affect cancer cell invasion and metastasis by regulating epithelial to mesenchymal transition (EMT). However, the effect of miR-200 family on BCSC heterogeneity is uncertain. Thus, we investigated whether the miR-200c/141 cluster had different effects on breast tumor growth and metastasis by switching the two states of BCSC.

Methods: The spontaneous mammary tumor mouse model with miR-200c/141 conditional knockout was utilized for analyzing the role of miR-200c/141 cluster in vivo. The effect of miR-200c/141 cluster on BCSCs was performed by CD24/CD29 staining and ALDEFLUOR assay. miR-200c/141 target expression and EMT-related marker expression were verified in tumor sections, primary cells and breast cancer cell lines by qRT-PCR or western blotting. Statistical analysis was determined using two-way ANOVA and Student's t-test. All values were presented as the mean ± s.e.m.

Results: The deletion of miR-200c/141 cluster regulated BCSC heterogeneity and promoted the EMT-like BCSC generation, which resulted in increased tumor metastasis and inhibited tumor growth by directly upregulating the target gene homeodomain-interacting protein kinase 1 (HIPK1) and sequential β-catenin activation.

Conclusions: Our results indicated that miR-200c/141 played biphasic roles in breast tumor progression via affecting the BCSC heterogeneity, suggesting targeting BCSC heterogeneity to simultaneously restrict breast cancer initiation and metastasis could be a promising therapeutic strategy for breast cancer.

Keywords: miR-200c/141, breast cancer, cancer stem cell, heterogeneity, HIPK1

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