Direct and indirect modulation of STAT3/CSE/H2S axis in triple negative breast cancer by non-coding RNAs: MALAT-1 lncRNA, miR-486–5p and miR-30a-5p

Recently, our research group reported an upregulated expression profile of cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), key enzymes involved in hydrogen sulfide (H₂S) production, in triple-negative breast cancer (TNBC) patients. However, the regulatory mechanisms underlying such altered expression patterns are not yet fully understood. In this study, we focused on the role of the STAT3/CSE/H₂S axis and the potential involvement of non-coding RNAs (ncRNAs), including long and short ncRNAs, in modulating this pivotal pathway. The results revealed that STAT3 was upregulated and positively correlated with CSE expression in BC patients. Additionally, the lncRNA MALAT-1 was found to regulate STAT3 expression, indirectly influencing CSE levels. Furthermore, we explored the interplay between the IGF-1R as a gatekeeper for JAK/STAT pathway and accordingly its impact on the STAT3/CSE/H₂S axis in TNBC cell lines. Our results demonstrated that miR-486–5p, a tumor suppressor miRNA, directly targets IGF-1R, leading to the downstream suppression of STAT3 and CSE in MDA-MB-231 cells. To identify a direct upstream repressor of CSE and CBS, we conducted an in silico analysis and identified miR-30a-5p as a promising candidate. When ectopically expressed, miR-30a-5p was downregulated in BC tissues and effectively suppressed CSE and CBS expression. In conclusion, this study revealed novel regulatory mechanisms involved in CSE and CBS expression in TNBC patients and cell lines. Abolishing H₂S-synthesizing machinery, particularly via miR-30a-5p, may represent a promising therapeutic strategy for TNBC patients.