Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma
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Francesca Rizzo1,*, Antonio Rinaldi1,*, Giovanna Marchese2, Elena Coviello1, Assunta Sellitto1, Angela Cordella3, Giorgio Giurato1,2, Giovanni Nassa1,2, Maria Ravo1, Roberta Tarallo1, Luciano Milanesi4, Anna Destro5, Guido Torzilli6,7, Massimo Roncalli5,6, Luca Di Tommaso5,6, Alessandro Weisz1
1Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry ‘Schola Medica Salernitana’, University of Salerno, Baronissi (SA), Italy
2Genomix4life, University of Salerno, Baronissi (SA), Italy
3Fondazione IRCCS SDN, Napoli, Italy
4Institute for Biomedical Technologies, National Research Council, Milano, Italy
5Pathology Unit, Humanitas Clinical and Research Center, Rozzano-Milan, Italy
6Department of Biomedical Sciences, Humanitas University, Rozzano-Milan, Italy
7Hepatobiliary and General Surgery Division, Humanitas Clinical and Research Center, Rozzano-Milan, Italy
*These authors contributed equally to this work
Alessandro Weisz, email: [email protected]
Keywords: hepatocarcinogenesis, hepatocellular carcinoma, piRNAs, small non-coding RNA, smallRNA-seq
Received: April 08, 2016 Accepted: June 06, 2016 Published: July 13, 2016
Hepatocellular carcinoma (HCC) is the result of a stepwise process, often beginning with development within a cirrhotic liver of premalignant lesions, morphologically characterized by low- (LGDN) and high-grade (HGDN) dysplastic nodules. PIWI-interacting RNAs (piRNAs) are small noncoding RNAs (sncRNAs), 23–35 nucleotide-long, exerting epigenetic and post-transcriptional regulation of gene expression. Recently the PIWI-piRNA pathway, best characterized in germline cells, has been identified also in somatic tissues, including stem and cancer cells, where it influences key cellular processes.
Small RNA sequencing was applied to search for liver piRNAs and to profile their expression patterns in cirrhotic nodules (CNs), LGDN, HGDN, early HCC and progressed HCC (pHCC), analyzing 55 samples (14 CN, 9 LGDN, 6 HGDN, 6 eHCC and 20 pHCC) from 17 patients, aiming at identifying possible relationships between these sncRNAs and liver carcinogenesis. We identified a 125 piRNA expression signature that characterize HCC from matched CNs, correlating also to microvascular invasion in HCC. Functional analysis of the predicted RNA targets of deregulated piRNAs indicates that these can target key signaling pathways involved in hepatocarcinogenesis and HCC progression, thereby affecting their activity. Interestingly, 24 piRNAs showed specific expression patterns in dysplastic nodules, respect to cirrhotic liver and/or pHCC.
The results demonstrate that the PIWI-piRNA pathway is active in human liver, where it represents a new player in the molecular events that characterize hepatocarcinogenesis, from early stages to pHCC. Furthermore, they suggest that piRNAs might be new disease biomarkers, useful for differential diagnosis of dysplastic and neoplastic liver lesions.
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