제1저자 김백길(병리학, BK21 2012.08졸)
Cell Death Dis. 2017 Mar 2ɖ(3):e2646. doi: 10.1038/cddis.2017.73.
Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation.
Kim BG1,2, Gao MQ3, Kang S1,4, Choi YP2, Lee JH2, Kim JE2, Han HH2, Mun SG2, Cho NH1,2,4,5.
1Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea.
2Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
3College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
4Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, South Korea.
5Global 5-5-10 System Biology, Yonsei University, Seoul, South Korea.
Tumor growth generates mechanical compression, which may trigger mechanotransduction in cancer and stromal cells and promote tumor progression. However, very little is known about how compression stimulates signal transduction and contributes to tumor progression. In the present study, we demonstrated that compression enhances a tumor progression phenotype using an in vitro compression model, and validated the results from the in vitro model with high- and low-compressed breast cancer tissues. Mechanical compression induced miR-9 downregulation by DNMT3A-dependent promoter methylation in the MDA-MB-231 and BT-474 breast cancer cell lines and in cancer-associated fibroblasts. The overexpression of miR-9 target genes (LAMC2, ITGA6, and EIF4E) was induced by miR-9 downregulation, which eventually enhanced vascular endothelial growth factors production. Demethylation and decompression could reverse compression-induced miR-9 downregulation and following overexpression of miR-9 target genes and VEGFA.