MiR-129 blocks estrogen induction of NOTCH signaling activity in breast cancer stem-like cells

// Guodong Xiao 1, * , Xiang Li 1, * , Gang Li 1, * , Boxiang Zhang 1 , Chongwen Xu 2 , Sida Qin 1 , Ning Du 1 , Jichang Wang 3 , Shou-Ching Tang 4, 5 , Jing Zhang 1 , Hong Ren 1 , Ke Chen 6 and Xin Sun 1 1 Department of Thoracic Surgery and Oncology, The Second Department of Thoracic Surgery, Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 2 Department of Otorhinolaryngology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 3 Department of Vascular and Endovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, China 4 Breast Cancer Program and Interdisciplinary Translational Research Team, Georgia Regents University Cancer Center, Augusta, Georgia 30912, United States 5 Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China 6 Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China * These authors are considered as co-first authors Correspondence to: Xin Sun, email: endeavour.sun@gmail.com Ke Chen, email: shenke@hust.edu.cn Keywords: miR-129, ESR1, DICER1, Let-7, NOTCH signaling Received: March 24, 2017 Accepted: August 08, 2017 Published: September 21, 2017 ABSTRACT Stem-like cells in tumor group featured the major role in the chemotherapy resistance of breast cancer, and the reduction of stem-like cells helped to perish the tumor when receiving chemotherapy. Smaller stem cells number indicated better therapeutic effect in vitro and in clinics, but how did miR-129 and Notch signaling function in breast cancer stem-like cells (BrCSCs) were unclear yet. Through using sphere forming assay and FACS sorting, we found that miR-129 decreased the proportion of stem-like cells in breast cancer cells. Results further indicated that miR-129 degraded the Estrogen Receptor 1 (ESR1) mRNA through a post-translational manner and contributed to the decline of stem-like cells number, preventing tumor regeneration. Cyclin d1 and DICER 1 were proved to promote Let-7 maturation, and in present study, we proved that miR-129 exhibited inhibition on ESR1 and halted the cyclin d1/DICER 1 sustaining of Let-7, which consequently released the Let-7 degradation of NUMB. The restoration of suppressive NUMB by upregulating miR-129 resulted in NOTCH signaling inhibition. In conclusion, we demonstrated the negative regulation of miR-129 on NOTCH signaling activation in BrCSCs’ renewal, which was achieved via continuous suppression on cyclin d1/DICER1 sustaining of Let-7 level, and eventually rescued the targeted inhibition of NUMB. The miR-129/ESR1 signaling played pivotal role in controlling DICER1/Let-7/NOTCH cascade via cyclin d1, revealing the novel mechanism of dual Let-7 in non-coding genes network.