Journal
JOURNAL OF CANCER
Volume 12, Issue 16, Pages 5053-5065Publisher
IVYSPRING INT PUBL
DOI: 10.7150/jca.57752
Keywords
breast cancer; epithelial-mesenchymal transition; cancer stem cell; miR-30a; SOX4
Categories
Funding
- National Natural Science Foundation of China [81672940]
- Clinical Research Physician Program of Tongji Medical College, Huazhong University of Science and Technology [5001530053]
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miR-30a inhibits EMT and CSC phenotypes in breast cancer cells by targeting SOX4 and forming a double-negative feedback loop. Knockdown of SOX4 suppresses EMT and CSC phenotypes through the TGF-beta/SMAD pathway, consistent with the effects of miR-30a overexpression. High expression of miR-30a is associated with a good prognosis in breast cancer patients.
Background: Both epithelial-to-mesenchymal transition (EMT) and cancer stem cells play important roles in development and progression of breast cancer. MicroRNA (miR)-30 family members have been reported to be associated with the regulation of EMT and stem cell phenotypes, however, the underlying molecular mechanisms are not well understood. Methods: miR-30a stable transfectants of breast cancer cell lines were created using a lentiviral system. Bioinformatics analysis was performed to explore miR-30a target genes and SOX4 was selected and identified by dual luciferase reporter assay. The effects of miR-30a and target gene SOX4 on EMT and CSC phenotypes in breast cancer were explored in vitro and in vivo. Results: Overexpression of miR-30a in breast cancer cells inhibited EMT and CSC phenotypes by targeting SOX4. Luciferase reporter assay confirmed that miR-30a directly targeted 3'UTR of SOX4, and formed a double-negative feedback loop with SOX4. Functional experiments demonstrated that knockdown of SOX4 suppressed EMT and CSC phenotypes of breast cancer cells through TGF-beta/SMAD pathway, which was consistent with the inhibitory effects by overexpression of miR-30a. Additionally, we found disulfiram can upregulate miR-30a expression, and high miR-30a expression was associated with a good prognosis in breast cancer patients through TCGA database. Conclusion: Our findings suggest a novel double-negative loop between miR-30a and SOX4 mediated regulation of EMT and CSC features in breast cancer through TGF-B/SMAD pathway, highlighting a novel therapeutic target for breast cancer.
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