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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.

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          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.

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          Author and article information

          Journal
          Hepatology
          Hepatology (Baltimore, Md.)
          Wiley-Blackwell
          1527-3350
          0270-9139
          Nov 2016
          : 64
          : 5
          Affiliations
          [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.
          Article
          10.1002/hep.28679
          27302319

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