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. Issue 5 (25th July 2016)

• Record Type: Journal Article
• Authors: Simerzin, Alina; Zorde‐Khvalevsky, Elina; Rivkin, Mila; Adar, Revital; Zucman‐Rossi, Jessica; Couchy, Gabrielle; Roskams, Tania; Govaere, Olivier; Oren, Moshe; Giladi, Hilla; Galun, Eithan
• Is Part Of: Hepatology. Volume 64:Issue 5(2016:Nov.)
• Page Start: 1623
• Page End: 1636
• Publication Date: 2016-07-25
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.28679
• Languages: English
• ISSNs: 0270-9139

Abstract

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)