miR-4652-5p targets GFPT1 to suppress ATF6-mediated unfolded protein response (UPR) and UPR-driven apoptosis to drive gastric tumor progression

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The equilibrium of the endoplasmic reticulum (ER) is vital for ensuring regular cellular operations. However, diverse pathological stimuli can disrupt ER proteostasis, leading to ER stress and ultimately triggering programmed cell death. Ongoing stress in the ER activates the unfolded protein response (UPR), an adaptive signaling mechanism aimed at reestablishing ER protein stability and aiding tumor cell survival in harsh microenvironmental conditions. Yet, the mechanisms through which key UPR regulators operate in this adaptive process are still not fully known. We investigated the role of miR-4652-5p in gastric cancer (GC) by quantifying its expression in clinical GC tissue samples. This was followed by modulating miR-4652-5p expression in GC cell lines via knockdown and overexpression. The effects on malignant phenotypes were evaluated via various methods, such as Cell Counting Kit 8 (CCK-8) proliferation assays, colony formation assays, wound healing assays, and Transwell migration assays. Transcriptome sequencing analysis suggested that miR-4652-5p plays a role in controlling the UPR and apoptosis. Experimental validation through qPCR, dual-luciferase reporter assays, and western blotting confirmed that miR-4652-5p aids in GC tumor progression by modulating UPR and apoptosis via a GFPT1-dependent mechanism affecting ATF6. We identified elevated expression of miR-4652-5p in GC, which correlated with unfavorable patient prognosis. Studies conducted with GC cell lines and clinical tissue specimens revealed that miR-4652-5p acts as an oncogene in GC by enhancing tumor cell growth and migration while also suppressing cell death. Transcriptome sequencing performed on miR-4652-5p–overexpressing cells revealed a pronounced association with the UPR. Mechanistically, miR-4652-5p attenuates ATF6 expression, thereby restraining excessive UPR activation and subsequent apoptosis—an effect likely mediated through its interaction with GFPT1. For the first time, we identified a novel regulatory axis in the UPR in which miR-4652-5p reduces both ATF6 expression and its proapoptotic effects by targeting GFPT1. This investigation identified miR-4652-5p as a novel and promising target for GC treatment.

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