miR-205-3p induces pyroptosis in triple-negative breast cancer by targeting HSP90AB1 and antagonizing MELK

Abstract

Pyroptosis, a form of inflammatory programmed cell death, has emerged as a significant pathway in cancer biology, yet its regulatory mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. Integrated bioinformatics analysis of GEO datasets identified key differentially expressed genes in breast cancer. MELK and miR-205-3p expression was validated in clinical TNBC specimens. Functional roles were assessed in TNBC cell lines through functional experiments. The targeting relationship between miR-205-3p and HSP90AB1 was confirmed by dual-luciferase reporter assay. Pyroptosis was evaluated by measuring caspase-1 activation, GSDMD/GSDME cleavage, and IL-1β/IL-18 release via Western blot and ELISA. MELK was identified as a hub gene significantly upregulated in TNBC, associated with advanced disease and poor prognosis. Functionally, MELK promoted TNBC cell proliferation, migration, and invasion. Conversely, miR-205-3p was frequently downregulated in TNBC and exerted tumor-suppressive effects by inducing caspase-1-dependent pyroptosis, as evidenced by cleavage of GSDMD and GSDME. Although miR-205-3p did not directly target MELK, overexpression of MELK partially reversed miR-205-3p–mediated suppression of malignancy. Mechanistically, HSP90AB1 was identified as a direct target of miR-205-3p and was positively regulated by MELK. miR-205-3p promotes pyroptosis by repressing HSP90AB1, whereas MELK enhanced HSP90AB1 expression, thereby inhibiting the pyroptotic pathway. Therefore, in TNBC, miR-205-3p promotes caspase-1-mediated pyroptosis by targeting HSP90AB1, which subsequently activates the GSDMD/GSDME pyroptotic pathway. Conversely, MELK functions as a critical upstream regulator, enhancing HSP90AB1 expression and thus inhibiting the miR-205-3p/HSP90AB1/GSDMD axis. This interplay between miR-205-3p and MELK through their shared target HSP90AB1 ultimately determines cellular fate.