TNBC is the most immunogenic tumor compared to other BC subtypes. Thus, clinicians shifted the treatment among TNBC patients to immunotherapeutic alternatives such as immune checkpoint inhibitors (ICB). Despite the success of ICB, resistance in some TNBC cases had recently appeared. Thus, adding a new factor in the immunotherpeutic equation which could be the tumor microenvironment (TME); TME includes an array of immune-modulatory cytokines such as Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) that acts as a barrier in eradicating the tumor cells by the cytotoxic immune cells. Recently, our group has reported a novel crosstalk between non-coding RNAs (ncRNAs). MALAT1, an oncogenic long ncRNA, is recently reported to directly bind to microRNA-17-92 cluster. However, miR-17-5p role in TNBC is still controversial. Moreover, the impact of miR-17-5p, MALAT1 and their interplay in the TME has never been investigated. The aim of this study is to investigate the crosstalk between ncRNAs and their impact on cytokines in TME of TNBC cells.
Twenty BC patients were recruited. Bioinformatic analysis was performed using more than 5 softwares. MDA-MB-231 cells were cultured and transfected with miR-17-5p oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability and Colony forming ability were measured using MTT and colony forming assay.
MALAT-1, miR-17-5p and IL-10 were down-regulated while TNF-α was upregulated in BC tissues compared to its counterparts. In-silico analysis showed that miR-17-5p binds to MALAT-1, IL-10 and TNF-α. Experimentally, ectopic expression of miR-17-5p (>5000 folds) resulted in a marked reduction in cellular viability and colony forming ability of TNBC cells. On top of that, miR-17-5p mimics resulted in a significant repression of MALAT1. Consequently, a marked increase in IL-10 and TNF-α levels was shown. While anti-miR-17-5p resulted in a marked repression of IL-10 and TNF-α.
miR-17-5p is an upstream orchestrator of MALAT-1/IL-10/TNF-α shaping the TME in TNBC patients. Therefore, this study provides a novel combination therapeutic approach of Anti-miR-17-5p and ICB with decreased chance of resistance in TNBC patients.
German University in Cairo.
Has not received any funding.
All authors have declared no conflicts of interest.