Transcriptome-wide analysis of compression-induced microRNA expression alteration in breast cancer for mining therapeutic targets

// Baek Gil Kim 1, 2 , Suki Kang 1, 3 , Hyun Ho Han 2 , Joo Hyun Lee 2 , Ji Eun Kim 2 , Sung Hwan Lee 4 , Nam Hoon Cho 1, 2, 3, 5 1 Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea 2 Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea 3 Severance Biomedical Science Institute (SBSI), Yonsei University College of Medicine, Seoul, South Korea 4 Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea 5 Global 5-5-10 System Biology, Yonsei University, Seoul, South Korea Correspondence to: Nam Hoon Cho, e-mail: cho1988@yuhs.ac Keywords: compression, microRNA, transcriptome, breast cancer, incurable cancer therapy Received: November 23, 2015 Accepted: March 14, 2016 Published: March 24, 2016 ABSTRACT Tumor growth–generated mechanical compression may increase or decrease expression of microRNAs, leading to tumor progression. However, little is known about whether mechanical compression induces aberrant expression of microRNAs in cancer and stromal cells. To investigate the relationship between compression and microRNA expression, microRNA array analysis was performed with breast cancer cell lines and cancer-associated fibroblasts (CAFs) exposed to different compressive conditions. In our study, mechanical compression induced alteration of microRNA expression level in breast cancer cells and CAFs. The alteration was greater in the breast cancer cells than CAFs. Mechanical compression mainly induced upregulation of microRNAs rather than downregulation. In a parallel mRNA array analysis, more than 25% of downregulated target genes were functionally involved in tumor suppression (apoptosis, cell adhesion, and cell cycle arrest), whereas generally less than 15% were associated with tumor progression (epithelial-mesenchymal transition, migration, invasion, and angiogenesis). Of all cells examined, MDA-MB-231 cells showed the largest number of compression-upregulated microRNAs. miR-4769-5p and miR-4446-3p were upregulated by compression in both MDA-MB-231 cells and CAFs. Our results suggest that mechanical compression induces changes in microRNA expression level, which contribute to tumor progression. In addition, miR-4769-5p and miR-4446-3p may be potential therapeutic targets for incurable cancers, such as triple negative breast cancer, in that this would reduce or prevent downregulation of tumor-suppressing genes in both the tumor and its microenvironment simultaneously.