Journal
THERANOSTICS
Volume 8, Issue 21, Pages 5801-5813Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.29380
Keywords
miR-200c/141; breast cancer; cancer stem cell; heterogeneity; HIPK1
Categories
Funding
- National Key Research and Development Program of China [Stem Cell and Translational Research] [2016YFA0101202]
- NSFC [81472741, 81772799, 81572877, 81773155, 31800708, 81530075]
- MOST [2015CB553800]
- Fudan-SIMM Joint Research Fund [FU-SIMM 20172007]
- Fudan University Research Foundation [IDH 1340042]
- Research Foundation of the Fudan University Shanghai Cancer Center grant [YJRC1603]
- Science & Technology Program of Jiangsu Province [BK20151287]
- Natural Science Foundation of Guangdong [2016A030313029, 2017A030313668]
- Sanming Project of Medicine in Shenzhen [SZSM201612031]
- Shenzhen Municipal Government of China [GJHZ20160301163138685, JCYJ20170817171808368, JCYJ20170818085657917]
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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 beta-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.
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