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The liver-specific microRNA-122*, the complementary strand of microRNA-122, acts as a tumor suppressor by modulating the p53/mouse double minute 2 homolog circuitry

Lookup NU author(s): Dr Olivier Govaere

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Abstract

© 2016 by the American Association for the Study of Liver Diseases.The tumor suppressor p53 is a central regulator of signaling pathways that controls the cell cycle and maintains the integrity of the human genome. p53 level is regulated by mouse double minute 2 homolog (Mdm2), which marks p53 for proteasomal degradation. The p53-Mdm2 circuitry is subjected to complex regulation by a variety of mechanisms, including microRNAs (miRNAs). We found a novel effector of this regulatory circuit, namely, miR-122*, the passenger strand of the abundantly expressed liver-specific miR-122. Here, we demonstrate that miR-122* levels are reduced in human hepatocellular carcinoma (HCC). We found that miR-122* targets Mdm2, thus participating as an important player in the p53-Mdm2 circuitry. Moreover, we observed significant negative correlation between levels of miR-122* and Mdm2 in a large set of human HCC samples. In vivo tumorigenicity assays demonstrate that miR-122* is capable of inhibiting tumor growth, emphasizing the tumor-suppressor characteristics of this miRNA. Furthermore, we show that blocking miR-122 in murine livers with an antagomiR-122 (miRNA inhibitor) results in miR-122* accumulation, leading to Mdm2 repression followed by elevated p53 protein levels. Conclusion: miR-122*, the passenger strand of miR-122, regulates the activity of p53 by targeting Mdm2. Importantly, similarly to miR-122, miR-122* is significantly down-regulated in human HCC. We therefore propose that miR-122* is an important contributor to the tumor suppression activity previously attributed solely to miR-122. (Hepatology 2016;64:1623-1636).


Publication metadata

Author(s): Simerzin A, Zorde-Khvalevsky E, Rivkin M, Adar R, Zucman-Rossi J, Couchy G, Roskams T, Govaere O, Oren M, Giladi H, Galun E

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2016

Volume: 64

Issue: 5

Pages: 1623-1636

Print publication date: 01/11/2016

Online publication date: 15/06/2015

Acceptance date: 27/05/2016

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/hep.28679

DOI: 10.1002/hep.28679

PubMed id: 27302319


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