Abstract
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 TGFβ pathway: miR-122 target site is present in the mouse but not human TGFβR1, whereas a noncanonical target site is present in the TGFβ1 5′UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGFβR1 and the ligand TGFβ1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGFβ1 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.
Highlights
Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function
The expression of TGFb receptor 1 (TGFbR1) remained unchanged in response to miR122 or its sponge in human liver cancer cells (Fig. 1a)
We investigated the change of TGFb1 or TGFbR1 messenger RNAs when miR-122 was increased or decreased in human or mouse cell lines, and found the similar pattern to their protein one (Fig. 1b)
Summary
Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. 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. A single miRNA regulates a group of functionally related genes, acting more like a function regulating molecule[3,4] These small endogenous RNAs have been implicated in a wide range of important biological processes, such as cell growth and differentiation as well as development[2]. We report a new species-dependent miRNA signalling mechanism and propose that switch of miR-122 target from TGFbR1 to TGFb1 underlies the different patterns of liver cancer metastasis between the two species
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