Abstract 2280P
Background
Hydrogen sulfide (H2S) is an endogenous gaseous mediator implicated in breast cancer (BC) progression. The 3 principle enzymes responsible for H2S production in mammals are cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST), whose overexpression was correlated with poor prognosis in BC patients. Besides, H2Swas linked to the suppression of tumor immune microenvironment in BC. Our group recently reported that upon single or dual inhibition of any of H2S-synthesizing enzymes, the other untargeted enzyme(s) is/are upregulated/activated as a compensatory mechanism for maintaining the level of H2Sin cancer cells. Thus, the aim of this work is to find a pan-repressor of all 3 enzymes to skip the above compensatory/escape mechanism and to investigate its impact on oncogenic and immunogenic profiles of BC cells.
Methods
BC female patients (n=20) were recruited. In-silico analysis was used to identify microRNAs (miRNAs) that target CBS, CSE, and 3MST. MDA-MB-231 TNBC cells were cultured and transfected by oligonucleotides. Total RNA was extracted using Biazol, reverse transcribed and quantified using qRT-PCR. Western blot analysis was performed. H2S levels were measured by AzMc. BC hallmarks were assessed by MTT, transwell migration, and clonogenic assays.
Results
MiRNA-193a was validated to regulate the expression of H2S enzymes by 8 different bioinformatics software, and was found to be significantly downregulated in BC tissues. Further, miR-193a was negatively correlated with CBS, CSE and 3MST levels in BC patients. Ectopic expression of miR-193a resulted in a marked repression of CBS, CSE, and 3MST expression, inducing a significant decrease in cellular H2S production. in TNBC cells overexpressing miRNA-193a, not only the cancer hallmarks were markedly suppressed but also the immune-suppressor proteins Galectin (GAL) 3 and GAL 9 were decreased significantly.
Conclusions
This study identifies miRNA-193a as a pan-repressor of the 3 principle H2S-synthesizing enzymes in BC, bypassing the compensatory behavior observed at single or dual inhibition of H2S enzymes. Thus, miR-193a emerges as a novel tumor suppressor and immunomodulatory miRNA in TNBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Swiss National Science Foundation (SNSF) grant SNF IZSTZ0_198887.
Disclosure
All authors have declared no conflicts of interest.
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