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

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.