Dataset Information

CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma.

ABSTRACT: CircRNAs are crucial in tumorigenesis and metastasis, and are comprehensively downregulated in hepatocellular carcinoma (HCC). Previous studies demonstrated that the back-splicing of circRNAs was closely related to 3'-end splicing. As a core executor of 3'-end cleavage, we hypothesized that CPSF3 modulated circRNA circularization. Clinical data were analyzed to establish the prognostic correlations. Cytological experiments were performed to determine the role of CPSF3 in HCC. A fluorescent reporter was employed to explore the back-splicing mechanism. The circRNAs regulated by CPSF3 were screened by RNA-seq and validated by PCR, and changes in downstream pathways were explored by molecular experiments. Finally, the safety and efficacy of the CPSF3 inhibitor JTE-607 were verified both in vitro and in vivo. The results showed that CPSF3 was highly expressed in HCC cells, promoting their proliferation and migration, and that a high CPSF3 level was predictive of a poor prognosis. A mechanistic study revealed that CPSF3 enhanced RNA cleavage, thereby reducing circRNAs, and increasing linear mRNAs. Furthermore, inhibition of CPSF3 by JET-607 suppressed the proliferation of HCC cells. Our findings indicate that the increase of CPSF3 in HCC promotes the shift of pre-mRNA from circRNA to linear mRNA, leading to uncontrolled cell proliferation. JTE-607 exerted a therapeutic effect on HCC by blocking CPSF3.

SUBMITTER: Huang Y

PROVIDER: S-EPMC10452738 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma.

Huang Ying Y Ji Haofei H Dong Jiani J Wang Xueying X He Zhilin Z Cheng Zeneng Z Zhu Qubo Q

Cancers 20230811 16

CircRNAs are crucial in tumorigenesis and metastasis, and are comprehensively downregulated in hepatocellular carcinoma (HCC). Previous studies demonstrated that the back-splicing of circRNAs was closely related to 3'-end splicing. As a core executor of 3'-end cleavage, we hypothesized that CPSF3 modulated circRNA circularization. Clinical data were analyzed to establish the prognostic correlations. Cytological experiments were performed to determine the role of CPSF3 in HCC. A fluorescent repor ...[more]

PMID: 37627085

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Project description:Background: Hepatocellular carcinoma (HCC) accounts for the majority of liver cancer, with the incidence and mortality rates increasing every year. Despite the improvement of clinical management, substantial challenges remain due to its high recurrence rates and short survival period. This study aimed to identify potential diagnostic and prognostic biomarkers in HCC through bioinformatic analysis. Methods: Datasets from GEO and TCGA databases were used for the bioinformatic analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out by WebGestalt website and clusterProfiler package of R. The STRING database and Cytoscape software were used to establish the protein-protein interaction (PPI) network. The GEPIA website was used to perform expression analyses of the genes. The miRDB, miRWalk, and TargetScan were employed to predict miRNAs and the expression levels of the predicted miRNAs were explored via OncomiR database. LncRNAs were predicted in the StarBase and LncBase while circRNA prediction was performed by the circBank. ROC curve analysis and Kaplan-Meier (KM) survival analysis were performed to evaluate the diagnostic and prognostic value of the gene expression, respectively. Results: A total of 327 upregulated and 422 downregulated overlapping DEGs were identified between HCC tissues and noncancerous liver tissues. The PPI network was constructed with 89 nodes and 178 edges and eight hub genes were selected to predict upstream miRNAs and ceRNAs. A lncRNA/circRNA-miRNA-mRNA network was successfully constructed based on the ceRNA hypothesis, including five lncRNAs (DLGAP1-AS1, GAS5, LINC00665, TYMSOS, and ZFAS1), six circRNAs (hsa_circ_0003209, hsa_circ_0008128, hsa_circ_0020396, hsa_circ_0030051, hsa_circ_0034049, and hsa_circ_0082333), eight miRNAs (hsa-miR-150-5p, hsa-miR-19b-3p, hsa-miR-23b-3p, hsa-miR-26a-5p, hsa-miR-651-5p, hsa-miR-10a-5p, hsa-miR-214-5p and hsa-miR-486-5p), and five mRNAs (CDC6, GINS1, MCM4, MCM6, and MCM7). The ceRNA network can promote HCC progression via cell cycle, DNA replication, and other pathways. Clinical diagnostic and survival analyses demonstrated that the ZFAS1/hsa-miR-150-5p/GINS1 ceRNA regulatory axis had a high diagnostic and prognostic value. Conclusion: These results revealed that cell cycle and DNA replication pathway could be potential pathways to participate in HCC development. The ceRNA network is expected to provide potential biomarkers and therapeutic targets for HCC management, especially the ZFAS1/hsa-miR-150-5p/GINS1 regulatory axis.

Dataset Information

CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma.

Publications

CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma.

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