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Le carcinome hépatocellulaire est la deuxième cause de décès par cancer au monde. L’une des raisons est le diagnostic tardif des patients à un stade où seulement l’ablation de la tumeur n’est plus un traitement efficace. Dans l’objectif d’identifier de nouveaux biomarqueurs pour améliorer le dépistage précoce de l’hépatocarcinome, les données de séquençage de l’ARN de tissus d’hépatocarcinomes, générées par The Cancer Genome Atlas, ont été comparées à celles de tissus de foie sains. Il a ainsi été possible d’identifier plus de 4000 gènes dont l’expression est significativement dérégulée dans les tissus tumoraux, dont plusieurs appartiennent à la famille des cytochromes P450 (CYP450). L’analyse des niveaux d’expression des gènes de chacun des patients a permis d’identifier 8 CYP450 candidats. Le changement d’expression de 6 d’entre eux a été validé par qPCR sur des échantillons d’ADN complémentaire de tissus sains et cancéreux. Du côté des caractéristiques diagnostiques de ces CYP450, la répression de CYP1A2, CYP2B6 ou CYP2C19, au niveau de l’ARNm, sous leur seuil respectif, permet l’identification des tissus cancéreux avec une sensibilité et une spécificité de 90% à 100%. Une répression de leur niveau d’expression en protéine est également observable dans les tissus cancéreux par immunohistochimie. Finalement, ce changement d’expression est identifiable peu importe la présence ou non d’une infection aux virus de l’hépatite B et/ou C chez les patients et dès le stade 1 des tumeurs. En conclusion, il semblerait que les cytochromes P450, particulièrement CYP1A2, CYP2B6 et CYP2C19, soient des biomarqueurs potentiels pour le carcinome hépatocellulaire permettant un diagnostic plus précoce et l’amélioration du traitement des patients.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths around the world. Recent advances in genomic technologies have allowed the identification of various molecular signatures in HCC tissues. For instance, differential gene expression levels of various cytochrome P450 genes (CYP450) have been reported in studies performed on limited numbers of HCC tissue samples, or focused on a small subset on CYP450s. In the present study, we monitored the expression landscape of all the members of the CYP450 family (57 genes) in more than 200 HCC tissues using RNA-Seq data from The Cancer Genome Atlas. Using stringent statistical filters and data from paired tissues, we identified significantly dysregulated CYP450 genes in HCC. Moreover, the expression level of selected CYP450s was validated by qPCR on cDNA samples from an independent cohort. Threshold values (sensitivity and specificity) based on dysregulated gene expression were also determined to allow for confident identification of HCC tissues. Finally, a global look at expression levels of the 57 members of the CYP450 family across ten different cancer types revealed specific expression signatures. Overall, this study provides useful information on the transcriptomic landscape of CYP450 genes in HCC and on new potential HCC biomarkers.

Background: Dysregulations in alternative splicing (AS) patterns have been associated with many human diseases including cancer. In the present study, alterations to the global RNA splicing landscape of cellular genes were investigated in a large-scale screen from 377 liver tissue samples using high-throughput RNA sequencing data. Results: Our study identifies modifications in the AS patterns of transcripts encoded by more than 2500 genes such as tumor suppressor genes, transcription factors, and kinases. These findings provide insights into the molecular differences between various types of hepatocellular carcinoma (HCC). Our analysis allowed the identification of 761 unique transcripts for which AS is misregulated in HBV-associated HCC, while 68 are unique to HCV-associated HCC, 54 to HBV&HCV-associated HCC, and 299 to virus-free HCC. Moreover, we demonstrate that the expression pattern of the RNA splicing factor hnRNPC in HCC tissues significantly correlates with patient survival. We also show that the expression of the HBx protein from HBV leads to modifications in the AS profiles of cellular genes. Finally, using RNA interference and a reverse transcription-PCR screening platform, we examined the implications of cellular proteins involved in the splicing of transcripts involved in apoptosis and demonstrate the potential contribution of these proteins in AS control. Conclusions: This study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in hepatocellular carcinoma. Moreover, these data allowed us to identify unique signatures of genes for which AS is misregulated in the different types of HCC.

Alternative splicing (AS) is a central mechanism of genetic regulation which modifies the sequence of RNA transcripts in higher eukaryotes. AS has been shown to increase both the variability and diversity of the cellular proteome by changing the composition of resulting proteins through differential choice of exons to be included in mature mRNAs. In the present study, alterations to the global RNA splicing landscape of cellular genes upon viral infection were investigated using mammalian reovirus as a model. Our study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in eukaryotic cells following infection with a human virus. We identify 240 modified alternative splicing events upon infection which belong to transcripts frequently involved in the regulation of gene expression and RNA metabolism. Using mass spectrometry, we also confirm modifications to transcript-specific peptides resulting from AS in virus-infected cells. These findings provide additional insights into the complexity of virus-host interactions as these splice variants expand proteome diversity and function during viral infection.