LncRNA HEIH/miR-939-5p interplay modulates triple-negative breast cancer progression through NOS2-induced nitric oxide production.

This study aimed to unravel the regulatory role of noncoding RNAs (ncRNA) on the nitric oxide (NO) machinery system in triple-negative breast cancer (TNBC) patients and to further assess the influence of NO-modulating ncRNAs on TNBC progression, immunogenic profile, and the tumor microenvironment (TME). The results revealed miR-939-5p and lncRNA HEIH as novel ncRNAs modulating NO machinery in TNBC. MiR-939-5p, an underexpressed microRNA (miRNA) in BC patients, showed an inhibitory effect on NOS2 and NOS3 transcript levels on TNBC cells. In contrast, HEIH was found to be markedly upregulated in TNBC patients and showed a modulatory role on miR-939-5p/NOS2/NO axis. Functionally, miR-939-5p was characterized as a tumor suppressor miRNA while HEIH was categorized as a novel oncogenic lncRNA in TNBC. Finally, knocking down of HEIH resulted in improvement of immunogenic profile of TNBC cells through inducing MICA/B and suppressing the immune checkpoint inhibitor PDL1. In the same context, knockdown of HEIH resulted in the alleviation of the immune-suppressive TME by repressing interleukin-10 and tumor necrosis factor-α levels. In conclusion, this study identifies miR-939-5p as a tumor suppressor miRNA while HEIH as an oncogenic lncRNA exhibiting its effect through miR-939-5p/NOS2/NO axis. Therefore, repressing BC hallmarks, improving TNBC immunogenic profile, and trimming TME.