Abstract
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.
Highlights
Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer death [1]
We investigated in detail the behavior of a new family of regulatory RNAs, PIWI-interacting RNAs (piRNAs), in 14 cirrhotic and 20 matched Hepatocellular carcinoma (HCC) samples and thereby identified > 700 known piRNAs and 900 novel piRNA-likes expressed in human liver, indicating that PIWI-piRNAs system is active in benign and neoplastic tissues of this organ
Stringent analyses revealed a well-defined molecular signature, comprising 125 piRNAs, that discriminates HCCs from to cirrhotic liver (Figures 1C and 2D), providing a clear demonstration of piRNA deregulation in liver carcinogenesis. These results are supported by results obtained from a large TCGA cohort, demonstrating that many genes of piRNAs pathways are dys-regulated in HCC (Supplementary Figure S1)
Summary
Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer death [1]. Human hepatocarcinogenesis is a multi-step process characterized by different nodular lesions, currently classified as low- (LGDN) and highgrade (HGDN) dysplastic nodules, early HCC (eHCC) and progressed HCC (pHCC), depending on the degree of cytological or architectural atypia [3]. The multistep nature of human hepatocarcinogenesis has long been suggested, and convincingly demonstrated by a recent molecular study showing a progressive increase in the rate of mutations of the telomerase reverse transcriptase (TERT) gene promoter from cirrhosis (no mutation) to LGDN (6%), HGDN (19%), eHCC (61%), small pHCC (42%) to advanced HCC (64%) [4]. Many factors, including chromosomal anomalies, genetic and epigenetic alterations contribute to HCC onset and progression [6], the relevant molecular mechanisms remain largely unclear
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