Differential TGFβ pathway targeting by miR-122 in humans and mice affects liver cancer metastasis

Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. Here we show a functional conservation of miR-122 in the TGF beta pathway: miR-122 target site is present in the mouse but not human TGF beta R1, whereas a noncanonical target site is present in the TGF beta 1 5'UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGF beta R1 and the ligand TGF beta 1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGF beta 1 in human primary liver tumours is associated with poor survival. We identify over 50 other miRNAs orthogonally targeting ligand/receptor pairs in humans and mice, suggesting that these are evolutionarily common events. These results reveal an evolutionary mechanism for miRNA-mediated gene regulation underlying species-specific physiological or pathological phenotype and provide a potentially valuable strategy for treating liver-associated diseases.