RNA-based therapies for colorectal cancer: targeting the β-catenin pathway via microbiota -modulated miRNAs

Colorectal cancer (CRC) is a significant problem with worldwide public health consequences. One key factor in the genesis and progression of CRC is the aberrant upregulation of the Wnt/β-catenin signaling pathway. Inhibitors designed to target β-catenin directly have not been effective in clinical trials, whereas miRNAs have been shown to regulate post-transcriptional components of the Wnt/β-catenin signaling pathway. Microorganisms in the gut also produce miRNAs that regulate CRC-related genes at the post-transcriptional level, including those involved in the Wnt pathway. An example is <i>Fusobacterium nucleatum</i>, which increases expression of the oncogenic miR-135b/miR-21, thereby inhibiting the expression of the tumor suppressors APC/PTEN and stabilizing β-catenin. This results in increased MYC expression. Another example is <i>Bacteroides fragilis</i>, which reduces miR-200c expression, thereby promoting epithelial-mesenchymal transition (EMT). However, this increase in EMT is countered by miR-145 and miR-203, which are upregulated by probiotic treatment, and these miRNAs inhibit the oncogenes <i>CTNNB1</i> and <i>LEF1</i>. There are currently several reviews that address subsets of the pathways involved in the dysregulation of β-catenin, as well as the therapeutic potential of miRNAs, and reviews that address microbiota interaction with CRC, but none that combine these elements within the framework of a mechanistic axis for the CRC microbe-miRNA-β-catenin-tumor phenotype, nor therapies based upon that axis/mechanism<i>.</i> This review examines the β-catenin signaling pathway in CRC and its regulation by miRNAs. It summarizes the roles of miRNAs in CRC, highlights oncogenic and tumor-suppressive miRNAs, and outlines specific miRNAs that are targets of the β-catenin pathway. It also covers microbiota-host interactions, including bidirectional links between gut microbes and miRNAs, effects on intestinal homeostasis, and microbial metabolites that alter miRNA expression. Recent advances in RNA-based therapeutic strategies and progress in clinical trials are included to frame the current translational relevance.