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

Alina Simerzin, Elina Zorde-Khvalevsky, Mila Rivkin, Revital Adar, Jessica Zucman-Rossi, Gabrielle Couchy, Tania Roskams, Olivier Govaere, Moshe Oren, Hilla Giladi, Eithan Galun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

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).

Original languageAmerican English
Pages (from-to)1623-1636
Number of pages14
JournalHepatology
Volume64
Issue number5
DOIs
StatePublished - 1 Nov 2016

Bibliographical note

Funding Information:
We thank Dr. Daniel Goldenberg and Dr. Ezra Ella for providing us with frozen liver samples from the MDR2-KO mice for the microRNA analysis. We thank Dr. Hoffman Yonit (Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel) for assistance with the pull-down experiment and Dr. Reba Condiotti (Department of Developmental Biology and Cancer Research, The Hebrew University of Jerusalem, Israel) for critical reading of the manuscript.

Publisher Copyright:
© 2016 by the American Association for the Study of Liver Diseases.

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