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Expression profiles dysplastic and neoplastic rat liver lesions

ABSTRACT: Predisposition to hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DN) and hepatocellular carcinoma (HCC) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis, to evaluate effector mechanisms of predisposition genes, and commonalties between transcription signatures of rat and human liver lesions. Gene expression profiles were determined by microarray analysis and validated by quantitative RT-PCR and Western blot. Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of F344 and BN rats and BN rat nodules, and the second one F344 nodules and HCC of both strains. Expression of 91 and 55 genes of DN and HCC, respectively, showed significant interstrain differences. Considering genes mostly associated with cell proliferation we identified a signature predicting DN evolution to HCC. Notably, expression of oncosuppressors Csmd1, Dmbt, Dusp1, and Gnmt ,in DN, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13, in HCC, was higher in BN than F344 rats. Comparative genomics approach, using gene expression data from rat lesions, and human HCC with different prognosis (based on survival length), revealed expression patterns of BN and F344 lesions close to those of human HCCs with better and poorer prognosis, respectively, suggesting that similar molecular events contribute to create a phenotype prone to progression in rats and human lesions. In conclusion, we identified a molecular signature of DN prone to progress to HCC and suggest that oncosuppressor genes are determinants of the genetically transmitted resistance to hepatocarcinogenesis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE24600 | GEO | 2010/10/09

SECONDARY ACCESSION(S): PRJNA132391

REPOSITORIES: GEO

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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.

Project description:Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions in humans. Experimental models recapitulating human hepatocellular carcinoma (HCC) are then entailed to perform this analysis. We performed miRNA and gene expression profiling to characterize the molecular events involved in the multistep process of hepatocarcinogenesis in the Resistant-Hepatocyte rat model. A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in early preneoplastic lesions positive for the stem/progenitor cell marker cytokeratin-19, indicating that several HCC-associated alterations occur from the very beginning of the carcinogenic process. Our analysis also identified miRNA/gene-target networks aberrantly activated at the initial stage of hepatocarcinogenesis. Activation of the NRF2 pathway and up-regulation of the miR-200 family were among the most prominent changes. The relevance of these alterations in the development of HCC was confirmed by the observation that NRF2 silencing impaired while miR-200a overexpression promoted HCC cell proliferation in vitro. Moreover, T3-induced in vivo inhibition of the NRF2 pathway accompanied the regression of cytokeratin-19 positive nodules, suggesting that activation of this transcription factor contributes to the onset and progression of preneoplastic lesions towards malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat HCC have been previously associated to human HCC as well underlines the translational value of our results. Conclusions: this study indicates that most of the molecular changes found in HCC occur in the very early stages of hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may represent a new therapeutic target. 20 nodules (10 weeks after initiation with DENA), 4 adenomas (10 months), 5 eHCCs (10 months) and 9 aHCCs (14 months) were dissected. 10 controls also included.

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Expression profiles dysplastic and neoplastic rat liver lesions

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