miR-195-5p controls apoptotic cascade by regulating the XIAP/BCL2/Survivin network in colorectal cancer

Abstract Colorectal cancer (CRC) progression and therapeutic resistance are strongly associated with the ability of tumor cells to evade apoptosis through the dysregulation of key anti-apoptotic pathways. Among the molecular mechanisms involved in CRC progression, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of pathways controlling tumor growth, invasion, therapeutic response, and cell survival. We previously demonstrated that miR-195-5p acts as a tumor suppressor in CRC by impairing proliferation, migration, invasion, and cell-cycle progression. However, its contribution to the regulation of apoptotic signaling remains incompletely understood. In this study, we aimed to investigate the role of miR-195-5p as a regulator of apoptotic signaling in CRC. Using membrane-based apoptosis arrays in CRC cell lines, we identified a miR-195-5p–dependent modulation of multiple apoptotic mediators, with XIAP, BCL2, and BIRC5 (Survivin) emerging as common targets across independent prediction tools. Functional validation demonstrated that miR-195-5p overexpression significantly reduced the transcript and protein levels of these anti-apoptotic factors. This molecular modulation resulted in enhanced apoptotic activity, as evidenced by increased caspase-3/7 activation, DNA fragmentation, and Annexin V-positive cell populations. Importantly, in vivo administration of miR-195-5p in an AOM/DSS mouse model confirmed the downregulation of XIAP, BCL2, and BIRC5 (Survivin) in colonic tissues, supporting its translational relevance. Overall, our findings identified miR-195-5p as a key upstream regulator of apoptosis in CRC and highlighted its potential as a promising therapeutic strategy to overcome apoptosis resistance and improve treatment outcomes.