Intestinal stem cell marker MEX3A regulates PPARγ expression with functional impact in colorectal carcinogenesis
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RNA-binding proteins (RBPs) are major effectors of post-transcriptional regulation. Recently, we described the role of MEX3A in maintaining intestinal stem cell identity and epithelial renewal by repressing the PPARγ pathway. This work aimed to study MEX3A functional impact in colorectal cancer (CRC). MEX3A and PPARγ expression profiles were characterized in murine and human models. CRISPR/Cas9-mediated MEX3A knockout was performed in patient-derived CRC tumoroids (PDCTs) and MEX3A RNA targets identified through the HyperTRIBE technique. Apc +/fl ; Mex3a +/− mice presented a significant reduction in tumor burden. Apc +/fl ; Kras +/G12D ; Mex3a +/− mice presented a reduced tumor area, while corresponding tumoroids exhibited reduced growth and enhanced differentiation potential mediated by PPARγ signalling. MEX3A overexpression (85% of human CRC cases) was inversely correlated with PPARγ downregulation (72% of cases). Accordingly, MEX3A-depleted PDCTs showed decreased LGR5 expression, accompanied by increased PPARγ expression and higher sensitivity to 5-Fluorouracil/Oxaliplatin (FOLFOX)-based chemotherapy. The HyperTRIBE results revealed a direct interaction between MEX3A and PPARG transcripts.
STATEMENT OF SIGNIFICANCE
These results emphasize that MEX3A plays a crucial role in colorectal carcinogenesis, partially through regulation of the PPARG pathway, mediating tumour development and response to therapy, thus constituting a potential therapeutic target.
