Global profiling of alternative RNA splicing events provides insights into molecular differences between various types of hepatocellular carcinoma

Abstract

BackgroundDysregulations 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.ResultsOur 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3029-z) contains supplementary material, which is available to authorized users.

Transcriptome‐Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer

“…Compared to a previous study that focused on HBV-and HCV-associated HCC, (42) we identified many more ASEs (280,000 vs. 45,000) and include not only protein-coding, but noncoding and unannotated genes. By comparing paired tumor and adjacent normal samples, we demonstrated that a significant number of differential ASEs affected genes involved in metabolic processes and found that some genes showed transcripts switch in liver cancer, such as UGP2.…”

Epigenetic events involved in organic cation transporter 1‐dependent impaired response of hepatocellular carcinoma to sorafenib

“…Dysregulation in splicing patterns have been associated with many human diseases, including cancer. Indeed, aberrant splicing of many genes, including SLC22A1 , has been reported to be increased in HCC (Tremblay et al, 2016). Changes in the profile of alternative splicing have been suggested to play a role in the high variability existing among individual tumours.…”

Peer Review #1 of "Systematic analysis and prediction model construction of alternative splicing events in hepatocellular carcinoma: a study on the basis of large-scale spliceseq data from The Cancer Genome Atlas (v0.2)"

“…The prognostic value of AS events has a great potential for development. Tremblay et al (Tremblay et al, 2016) firstly investigated differential AS events between HCC sample and normal liver sample based on TCGA database, and they provided an overview of misregulated AS events in different types of HCC (e.g., HBV-related HCC, HCV-related HCC, HBV&HCV-associated HCC and virus-free HCC). But they did not explore the association between the AS events and the prognosis of HCC patients.…”