Placenta-Specific miRNA <i>miR-515-3p</i> Suppresses <i>HMGB3</i> Expression in the Breast Cancer Cell Line MCF-7

BACKGROUND: Pregnancy-related breast cancer is relatively rare, but its incidence is increasing as the age of childbearing advances. The impact of placenta-specific microRNAs (miRNAs) derived from the chromosome 19 miRNA cluster (C19MC) on pregnancy-associated breast cancer is unclear. Nuclear protein high mobility group box 3 (HMGB3) plays a role in cancer progression. This study examined the effects of placenta-specific C19MC miRNAs on the cancer-related gene HMGB3 in the human breast cancer cell line MCF-7. METHODS: We used target gene prediction programs to identify C19MC miRNAs that modulate HMGB3 and then validated them using analytical procedures (i.e., quantitative PCR, Western blot, and luciferase reporter assay). We investigated how inhibition of HMGB3 by C19MC miRNAs affects the invasive and proliferative ability of MCF-7 cells and explored the downstream effectors of this axis. RESULTS: C19MC miRNA miR-515-3p targeted HMGB3. In MCF-7 cells, reduction of HMGB3 expression by miR-515-3p increased cell invasion and proliferation. Furthermore, miR-515-3p-mediated HMGB3 inhibition led to the upregulation of CTNNB1 and GRB2, implicating invasion- and proliferation-related signaling pathways (e.g., WNT/β-catenin, Ras/MAPK, and PI3K/AKT/mTOR) in MCF-7 cells. CONCLUSIONS: The impact of C19MC miRNA miR-515-3p on the cancer-related gene HMGB3 in MCF-7 cells suggests a potential tumor-suppressive role for HMGB3 that contrasts with previous reports of oncogenic activity. The present findings raise the possibility that placenta-specific C19MC miRNAs play a role in pregnancy-related breast cancer during pregnancy.