Cleavage and Polyadenylation Specific Factor 1 Promotes Tumor Progression via Alternative Polyadenylation and Splicing in Hepatocellular Carcinoma.

Shi-Lu Chen,Xin Wang,Xin-Yuan Guan,Ming-Ming Yang,Xia Yang,Zhong-Xu Zhu,Yang-Fan He,Jing-Ping Yun,Li-Li Liu

doi:10.3389/fcell.2021.616835

Abstract

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism required for cleavage and polyadenylation (CPA) of the 3′ untranslated region (3′ UTR) of mRNAs. Several aberrant APA events have been reported in hepatocellular carcinoma (HCC). However, the regulatory mechanisms underlying APA remain unclear. In this study, we found that the expression of cleavage and polyadenylation specific factor 1 (CPSF1), a major component of the CPA complex, was significantly increased in HCC tissues and correlated with unfavorable survival outcomes. Knockdown of CPSF1 inhibited HCC cell proliferation and migration, whereas overexpression of CPSF1 caused the opposite effect. Based on integrative analysis of Iso-Seq and RNA-seq data from HepG2.2.15 cells, we identified a series of transcripts with differential 3′ UTR lengths following the knockdown of CPSF1. These transcripts were related to the biological functions of gene transcription, cytoskeleton maintenance, and endomembrane system transportation. Moreover, knockdown of CPSF1 induced an increase in alternative splicing (AS) events in addition to APA. Taken together, this study provides new insights into our understanding of the post-transcriptional regulatory mechanisms in HCC and implies that CPSF1 may be a potential prognostic biomarker and therapeutic target for HCC.

Highlights

Liver cancer is one of the most aggressive malignancies worldwide, with 841,080 new cases and 781,631 cancer-related deaths reported in 2018 (Bray et al, 2018)
As indicated by the hepatocellular carcinoma (HCC) patient dataset from The Cancer Genome Atlas (TCGA), cleavage and polyadenylation specific factor 1 (CPSF1) mRNA was significantly increased in HCC compared to that in normal liver tissues (Figure 1A)
In 50 paired HCC tissues from the TCGA database, CPSF1 mRNA was relatively elevated in tumor tissues compared to the paired non-tumor tissues (Figure 1C)

Summary

Introduction

Liver cancer is one of the most aggressive malignancies worldwide, with 841,080 new cases and 781,631 cancer-related deaths reported in 2018 (Bray et al, 2018). According to GLOBOCAN statistics, the incidence and mortality rate of liver cancer were 905,677 and 830,180, respectively, in 2020. Hepatocellular carcinoma (HCC) constitutes approximately 80% of primary liver cancer cases and has extremely poor prognosis. Recent studies have identified many liver-specific oncogenes and CPSF1 Promotes HCC Progression tumor suppressor genes that control HCC growth and metastasis, that have been driving research in targeted therapies (Chen et al, 2020). The improvement in HCC survival rate is still not acceptable; HCC ranked fourth as a leading cause of cancerrelated deaths in 2018 because of poor response to systemic therapies. It is necessary to continue searching for potential prognostic and therapeutic targets for HCC through enhancing our understanding of its cellular biological processes

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Conclusion