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.
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.



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 Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
Alina
A
Simerzin
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
Elina
E
Zorde-Khvalevsky
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
Mila
M
Rivkin
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
Revital
R
Adar
Inserm, UMR-1162, Functional Genomic of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Paris, France.|Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France.|Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.|Université Paris Diderot, IUH, Paris, France.
Jessica
0000-0002-5687-0334
J
Zucman-Rossi
Inserm, UMR-1162, Functional Genomic of Solid Tumors, Equipe Labellisée Ligue Contre le Cancer, Paris, France.|Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Paris, France.|Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.|Université Paris Diderot, IUH, Paris, France.
Gabrielle
G
Couchy
Department of Pathology and the Laboratory of Morphology and Molecular Pathology, University Hospitals, University of Leuven, Leuven, Belgium.
Tania
T
Roskams
Department of Pathology and the Laboratory of Morphology and Molecular Pathology, University Hospitals, University of Leuven, Leuven, Belgium.
Olivier
O
Govaere
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Moshe
M
Oren
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel.
Hilla
H
Giladi
The Goldyne Savad Institute of Gene and Cell Therapy, Hadassah Hebrew University Hospital, Ein Karem, Jerusalem, Israel. EithanG@hadassah.org.il.
Eithan
E
Galun
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology
C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C544354:Mirn122 microRNA, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2