Alina Simerzin1, Elina Zorde-Khvalevsky1, Mila Rivkin1, Revital Adar1, Jessica Zucman-Rossi2,3,4,5, Gabrielle Couchy2,3,4,5, Tania Roskams6, Olivier Govaere6, Moshe Oren7, Hilla Giladi1, Eithan Galun8. 1. The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel. 2. Inserm, UMR-1162, Functional Genomic of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Paris, France. 3. Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France. 4. Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France. 5. Université Paris Diderot, IUH, Paris, France. 6. Department of Pathology and the Laboratory of Morphology and Molecular Pathology, University Hospitals, University of Leuven, Leuven, Belgium. 7. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. 8. The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel. EithanG@hadassah.org.il.
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).
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).
Authors: Yateng Tie; Chong Chen; Yanli Yang; Zhen Qian; Hang Yuan; Huan Wang; Haili Tang; Yao Peng; Xilin Du; Bin Liu Journal: Oncol Lett Date: 2018-04-02 Impact factor: 2.967
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