MiRNAs have been thoroughly studied for their vast roles in oncology, however, recent immune-related miRNAs have been recognized as prospective modulators in the tumor immune surveillance process. The high immunogenicity of TNBC along with its stubbornness towards effective targeted therapy shifted therapeutic interests towards immunotherapy. Accordingly, a promising approach would be targeting the immune suppressive tumor microenvironment (TME). Such an approach could be manifested in a dual manner through blocking prominent checkpoint proteins and regulating Natural Killer (NK) cells and thus modifying the TME. MiR-939-5p is a scarcely explored miRNA especially in TNBC. Therefore, our aim is to identify the expression profile of miR-939-5p in BC tissues and the role it plays in tumor suppression as well as the immunomodulatory role on checkpoint proteins and NKG2D ligands in TNBC.
Breast biopsies were collected from 40 BC patients. MDA-MB-231 cells were cultured and transfected with different oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, colony forming ability and migration were measured using MTT, colony forming and scratch assays, respectively.
MiR-939-5p was down-regulated in TNBC tissues compared to normal tissues and other BC subtypes. Functionally, forced expression of miR-939-5p ensued a decline in cellular viability, colony forming ability and migration capacity of MDA-MB-231 cells thus highlighting miR-939-5p as a tumor suppressive miRNA in TNBC. Immunomodulation wise, miR-939-5p overexpression resulted in down-regulation of the checkpoint protein PD-L1 as well as upregulation of the shedded NKG2D ligands MICA/B in TNBC cells. Lastly, drastic repression of the immune inhibitory cytokines, TNF-α and IL-10 was detected upon miR-939-5p upregulation.
The present study categorized miR-939-5p as a tumor suppressing miRNA under expressed in TNBC patients and cell lines. Furthermore, it institutes the first major stride in unraveling the immunomodulatory role of miR-939-5p in advancing NK cells cytotoxicity and trimming TME in favor of TNBC eradication, thus proposing miR-939-5p as a novel therapeutic module in TNBC.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.