Regulation of let-7 microRNAs by a two-step turnover pathway is of critical pathophysiological significance in humans

MicroRNAs (miRNAs) are critical regulators of diverse developmental and physiological processes, and they themselves get regulated both at the level of biogenesis and turnover. We demonstrate that the ribonuclease XRN2 can degrade the mature forms of certain let-7 family members in multiple human cancer cell lines, without affecting their precursors. XRN2 also affects the accumulation of several other tumor suppressor miRNAs known to play important roles in cancer metabolism. XRN2 depletion results in a reduction in the expression of many oncogenes and diminishes the proliferative and metastatic potential of cancer cells in vitro. These experimental cancer cells also show reduced capacity to form tumors in mice and regress over time. The clinical relevance of these observations is further verified in tumour transcriptomics data from public RNA-sequencing datasets, where XRN2 mRNA expression is inversely correlated with the levels of a large number of miRNAs, including let-7 members, and high XRN2 mRNA levels are associated with poor survival in hepatocellular carcinoma, lung adenocarcinoma, and glioblastoma. We demonstrate that the miRNA is released by an as-yet unidentified proteinaceous miRNA release factor from the grasp of Argonaute before its degradation, which is more abundant in the nuclear fraction. Our analyses of the patient-derived transcriptomics data also show that XRN2, via its regulation of let-7, affects multiple pathways in a consistent manner across epithelial and glial cell lineages, and thus, is of critical pathophysiological significance.