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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
Author(s) -
Simerzin Alina,
ZordeKhvalevsky Elina,
Rivkin Mila,
Adar Revital,
ZucmanRossi Jessica,
Couchy Gabrielle,
Roskams Tania,
Govaere Olivier,
Oren Moshe,
Giladi Hilla,
Galun Eithan
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28679
Subject(s) - mir 122 , mdm2 , microrna , antagomir , suppressor , biology , cancer research , regulator , microbiology and biotechnology , cancer , cell culture , gene , genetics
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. (H epatology 2016;64:1623‐1636)