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RNA-Binding Protein Trx regulates alternative splicing and promotes metastasis of HCC via interacting with LINC00152

ABSTRACT: RNA-binding proteins (RBPs) were reported to be the key regulator of epithelial-mesenchymal transition (EMT)-related post-transcriptional in tumor diseases.To explore the role of RBPs in metastasis of hepatocellular To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcription sequencing was conducted to identify differential RBPs between HCC with metastasis or without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. Interaction of RBPs with non-coding RNAs was evaluated by RNA immune-precipitation and pull-down assay. RNA-seq whole genome sequencing and alternative splicing analysis were further performed to clarify post-transcription regulation mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245587 | GEO | 2023/10/24

REPOSITORIES: GEO

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Project description:Global transcriptomic alterations of both coding and non-coding RNA species are a ubiquitous feature associated with human cancers including hepatocellular carcinoma (HCC). Dysregulation of RNA-binding proteins (RBPs), the key regulators of RNA processing, is one mechanism in which cancer cells select to promote tumorigenesis. We analyzed genomic alterations amongst a family of more than 800 mRNA RBPs (mRBPs) in 1,225 clinical specimens from HCC patients and found that RBPs are significantly activated through gene amplification in a subset of tumors with poor prognosis, suggesting their potential oncogenic roles in HCC progression. Amongst the top candidates, RD binding protein (RDBP) was further characterized for its oncogenic role and effects on the HCC transcriptome. While the activation of RDBP induced an oncogenic phenotype, the abrogation of RDBP in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further microarray analyses revealed that RDBP-dependent genes were tumor-related with a significant enrichment for c-Myc targets, suggesting interplay between RDBP and c-Myc signaling. Similar data were also found in HCC clinical specimens where c-Myc amplification was uncommon. Consistently, the RDBP-dependent c-Myc target gene signature was able to predict HCC patient survival in two independent cohorts of more than 400 patients. Taken together, our results suggest that oncogenic activation of RDBP is a novel mechanism that contributes to global transcriptome imbalance that is selective for the activation of c-Myc oncogenic signaling in HCC. We used microarray analysis to determine the affects of siRNA mediated RDBP knockdown in HCC transcriptome in cell lines. Hep3b and Huh1 cells were transfected with RDBP or scramble control siRNA for 48 hours in quadruplicates. Quality control using Spearman or Pearson correlation removes outliers resulting in triplicates for each group