BPS2026 – Impaired Mrs2/miR-132-3p/AGO2 axis inhibits HCC progression

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related mortality. Processing bodies (P-bodies, PBs) are dynamic cytoplasmic granules that regulate post-transcriptional gene expression by mediating mRNA decay, storage, and RNA interference (RNAi). Dysregulation of PBs contributes to tumor progression by altering oncogenic and tumor suppressor RNA networks. Although PB formation and function have been studied extensively, the influence of mitochondrial ion signaling on PB regulation remains poorly understood. The mitochondrial RNA splicing 2 protein (Mrs2), initially identified for its putative role in RNA processing, is now recognized as the primary mitochondrial Mg 2+ transporter. While Mrs2 has not been directly implicated in RNA regulatory pathways, PBs often localize near mitochondria. Argonaute 2 (AGO2) has been reported to shuttle between these compartments, suggesting that mitochondrial status may influence PB dynamics. Given the critical role of AGO2 in PB integrity and miRNA-mediated silencing, we hypothesized that mitochondrial Mg 2+ homeostasis regulates AGO2 function and PB stability in HCC. RNA sequencing and immunoblotting were performed in Mrs2 knockdown HepG2 cells to assess PB protein expression. The regulation of AGO2 and its mitochondrial translocation was analyzed. Downstream signaling pathways were examined to define the mechanistic basis of Mrs2-dependent regulation of PB integrity. Mrs2 KD markedly reduced PB protein transcripts, with AGO2 showing the most significant decrease. Mrs2 KD impaired mitochondrial translocation of AGO2, disrupting PB integrity and compromising cytosolic mRNA repression and turnover. Mechanistically, Mrs2 KD increased pCREB expression, which enhanced transcription of miR-132-3p, a negative regulator of AGO2. Mrs2 deficiency disrupts AGO2-mediated PB regulation by altering mitochondrial-PB crosstalk, impairing mRNA silencing and turnover in HCC cells. These findings identify a novel Mrs2-AGO2 axis controlling PB function and highlight a potential therapeutic vulnerability in HCC.