miRNA-489 Induces Immunogenic Cell Death in Triple Negative Breast Cancer Cells

It has been well established that microRNAs (miRNAs) play an important role in the regulation of gene expression and consequently promoting or downregulating molecular pathways. When dysregulated, miRNAs have been found to serve as important biomarkers for cancer diagnosis and influence tumor initiation and progression. It has been previously established that miRNA-489 is a tumor suppressor microRNA, and it directly targets cell proliferative pathways like the HER2-SHP2-MAPK pathway. In this study, we focus on the role of miRNA-489, in the induction of immunogenic cell death (ICD) in triple-negative breast cancer cell lines. We first examined the effects of miRNA-489 on two main ICD hallmarks and showed that overexpression of miRNA-489 triggered the extracellular release of ATP and the relocalization of calreticulin (CRT) to the surface of the tumor cells. It was shown for the first time that miRNA- 489 induces ER stress through the upregulation of markers like PERK, IRE1 alpha, and eIF2 alpha, which triggers the release of damage-associated molecular patterns (DAMPs), leading to CRT exposure on the tumor cell surface and ATP release. Lastly, miRNA-489-induced ICD was further confirmed by the promotion of tumor cell phagocytosis by macrophages. Overall, our results suggested that miRNA-489 overexpression, without any corresponding ICD inducer, was able to elevate a phagocytotic and immunogenic response, through the trigger of DAMPS, relocalization of CRT on the cellular surface, and release of ATP