MEX3A Modulates PPARγ Pathway Activity and Colorectal Cancer Growth

RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of Mex-3 RNA binding family member A (MEX3A) in maintaining leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)+ intestinal stem cells identity and epithelial renewal. This work aimed to study MEX3A functional impact in colorectal cancer (CRC).

We characterized MEX3A expression profile in CRC mouse models and a cohort of CRC cases (n = 172). Mouse CRC tissues were used for the establishment of tumoroids and CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids to further understand its biological and therapeutic relevance. Simultaneously, we implemented the high-throughput technique HyperTRIBE to uncover MEX3A RNA targets.

Intestinal adenomas from Apc^+/fl mice have increased Mex3a expression, and Apc^+/fl;Mex3a^+/- animals presented a significant reduction in tumor burden. Apc^+/fl;Kras^+/G12D;Mex3a^+/- compound mice exhibited reduced tumor area, whereas corresponding tumoroids had reduced growth ability and enhanced differentiation potential associated with increased peroxisome proliferator-activated receptor gamma (PPARγ) signaling. MEX3A overexpression was observed in 85% of human CRC cases, whereas 72% presented PPARγ downregulation, with a significant inverse correlation (P = .039). Accordingly, MEX3A-depleted patient-derived CRC tumoroids showed decreased LGR5 expression, accompanied by increased PPARγ expression and higher sensitivity to 5-fluorouracil/oxaliplatin (FOLFOX)-based chemotherapy. HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts.

MEX3A contributes to colorectal carcinogenesis, in association with PPARγ signaling modulation, impacting tumor development and therapeutic response.