Peking University, Mar. 25, 2016: Recently, the group of Professor Xi Jianzhong from the College of Engineering, Peking University and collaborators reported a functional conservation of miR122 in the TGFβ pathway.

They found that miR-122 targets TGFβR1 in mice but TGFβ1 in humans, that swapping this specificity affects metastasis, and that many other receptor-ligand pairs are differentially targeted by miRNAs across species.

These findings have been published in a research article entitled “Differential TGFβ Pathway Targeting by miR-122 in Humans and Mice affects Liver Cancer Metastasis” in journal Nature Communications.

Primary liver cancer is the fifth most frequently diagnosed cancer globally and the second leading cause of cancer death. A plethora of evidence has shown that miR-122, accounting for 70% of the total amount of liver miRNA, is associated with human liver cancer metastasis and reduced survival time.

However, mice with miR-122 silenced did not develop hepatocellular carcinoma (HCC). Even miR-122 knockout mice only developed liver fibrosis and HCC in most cases, with a few of them developing metastatic nodules as the animals aged.

In this work, they report three novel and important results.

First of all, they reported a novel species-dependent miRNA signaling mechanism. They demonstrate that miR-122 targets different components in the TGFβ1 pathway, namely TGFβ1 in humans and TGFβR1 in mice. This species-dependent miRNA regulation of a ligand/receptor convergent on the same signaling pathway is a new type of functionally conservation mechanism.

Under normal conditions, the inhibition of either the ligand or the receptor in the presence of miRNA results in a similar regulatory effect on downstream signaling molecules. However, this type of regulation might have dramatically different consequences across species in the case of miRNA dysregulation, such as occurs in pathological and/or stressful conditions.

Their results clearly prove that a loss of miR-122 exerts markedly different effects on metastatic liver cancer in humans and mice.

This finding provides not only a rational explanation for the observed paradoxical phenotypes in humans and mice, but also the insight provided into liver dysfunction and associated diseases, as well as potential therapeutics.

Furthermore, Xi and collaborators proved that miR-122 target switching between TGFβ1 and TGFβR1 is evolutionary conservation in vertebrates.

A conserved miR-122 target site was found in a vertebrate TGFβR1 coding sequence (CDS), not in the 3’UTR as would be expected. The loss of this conserved site in humans is accomplished by nucleotide mutation, mainly a G->A mutation (11th) that is conserved in humans and other primate species.

Interestingly, the functional inhibitory effect of miR-122 on the downstream components of the TGFβ pathway is guaranteed by the gain of a new, non-canonical target site in the TGFβ1 5’UTR in humans as well as other primate species, a site which forms a noncanonical base-pairing with the 3’ terminal sequence of miR-122.

Finally, this work also found that species-dependent switch of miRNA target is of general relevance.

The authors performed a genome-wide screening of the miRNA target sites in three ligand/receptor pairs using a self-assembled cell microarray (SAMcell). In total, over 50 miRNAs were identified orthogonally target HGF/HGFR, TGFβ1/TGFβR1 or FGF/FGFR in humans and mice, indicating a universal species-dependent miRNA signaling mechanism.

This finding is becoming dramatically important when rethinking the paradox related to miRNA functions across species. For example, the genetic knockout of individual miRNAs in mice were reported to have not resulted in any obvious phenotypic difference in most cases. In contrast, miRNA globally deregulates in human carcinoma and actively participates in the regulation of tumor development.

Thus, they conclude that the biological outs of these miRNAs need to be re-examined in species-dependent and global context.

The author includes Yin Shenyi (first author), Fan Yu , Zhang Hanshuo, Zhao Zhihua, Hao Yang, Li Juan, Sun Changhong, Yang Junyu, Yang Zhengjun, Yang Xiao, Lu Jian and Xi Jianzhong (corresponding author).

This research was supported by projects of State Key Laboratory of Natural and Biomimetic Drugs, State Key Laboratory of Biomembrane and Membrane Biotechnology, MOST and NSFC.

Edited by: Zhang Jiang
Source: College of Engineering