Unknown,Transcriptomics,Genomics,Proteomics

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Specific patterns of PIWI-interacting small noncoding RNA expression changes in dysplastic liver nodules and hepatocellular carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is considered the result of a stepwise carcinogenic process, more often beginning with development of premalignant lesions within a cirrhotic liver, morphologically characterized by low- (LGDN) and high-grade (HGDN) dysplastic nodules. Piwi-interacting RNAs (piRNAs) represent a large family of small noncoding (snc) RNAs, 23-35 nucleotide-long, first identified in fruitfly germline cells by their ability to interact with PIWI proteins and thereby exert epigenetic and post-transcriptional regulation of gene expression. The PIWI-piRNAs pathway is active also in human somatic tissues, including stem and cancer cells, where piRNAs and piRNA-like molecules have been shown to influence key cellular processes. We applied small RNA sequencing to search for human liver piRNAs and to profile their expression patterns in cirrhotic nodules (CNs), LGDN, HGDN, early HCC (eHCC) and progressed HCC (pHCC), aiming at identifying possible relationships between these sncRNAs and liver carcinogenesis. Analyzing 54 nodules (14 CN, 8 LGDN, 6 HGDN, 6 eHCC and 20 pHCC) from 17 patients, we identified a 125 piRNA expression signature that clearly discriminates HCC from matched CNs, correlating also to clinicopathological characteristics of HCC. This result was confirmed by functional analysis of predicted piRNA target mRNAs. Interestingly, 24 piRNAs showed specific expression patterns in dysplastic nodules, respect to cirrhotic liver and/or pHCC. These results demonstrate that the piRNA pathway is active in human liver, where it is likely to represent a new player in the molecular events that characterize hepatocellular carcinogenesis, from early stages to pHCC. Furthermore, they suggest that piRNAs might represent new disease biomarkers, potentially useful for differential diagnosis of dysplastic and neoplastic liver lesions.

INSTRUMENT(S): Illumina HiSeq 2500

ORGANISM(S): Homo sapiens

SUBMITTER: Antonio Rinaldi

PROVIDER: E-MTAB-3973 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Hepatocarcinogenesis is a multi-stage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN) as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, clear differences were detected between DN and eHCC which included 460 differentially expressed genes. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the dysplastic nodules. In addition, gene set enrichment analysis (GSEA) revealed a remarkable enrichment of MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5 as well as with the higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high- and low-grade dysplastic nodules. In conclusion, our study identified unique expression patterns associated with the transition of high-grade dysplastic nodules to early HCC and demonstrated that activation of the MYC transcription signature is critical for the malignant conversion of pre-neoplastic liver lesions. Samples from forty-nine nodular liver lesions including 24 regenerative (cirrhotic) nodules (CN), 3 low-grade (LGDN), 12 high-grade dysplastic nodules (HGDN) and 10 early hepatocellular carcinomas (Early HCC) were used. The Human Operon V2 oligonucleotide library containing 22K features representing expressed sequences was printed to glass arrays in the Advanced Technology Center (National Cancer Institute, Gaithersburg, MD). The aRNA probes were fragmented and hybridized to the microarray slides following the standard procedures. All samples were hybridized against a common amplified reference RNA pooled from normal liver samples. Experimental duplicates were prepared following a reverse-flour design.

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Specific patterns of PIWI-interacting small noncoding RNA expression changes in dysplastic liver nodules and hepatocellular carcinoma

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