CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma
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 mo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/16/4057 |
| _version_ | 1797585278180786176 |
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| author | Ying Huang Haofei Ji Jiani Dong Xueying Wang Zhilin He Zeneng Cheng Qubo Zhu |
| author_facet | Ying Huang Haofei Ji Jiani Dong Xueying Wang Zhilin He Zeneng Cheng Qubo Zhu |
| author_sort | Ying Huang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T00:03:49Z |
| format | Article |
| id | doaj.art-dac1b4d704394180a8219c57264988f0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:03:49Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-dac1b4d704394180a8219c57264988f02023-11-19T00:32:34ZengMDPI AGCancers2072-66942023-08-011516405710.3390/cancers15164057CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular CarcinomaYing Huang0Haofei Ji1Jiani Dong2Xueying Wang3Zhilin He4Zeneng Cheng5Qubo Zhu6Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaXiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaXiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaChina National Intellectual Property Administration, Beijing 100088, ChinaXiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaXiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaXiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaCircRNAs 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.https://www.mdpi.com/2072-6694/15/16/4057competing endogenous RNA (ceRNA)circular RNAs (circRNAs)cleavage and polyadenylation specificity factor (CPSF)hepatocellular carcinoma (HCC)JTE-607 |
| spellingShingle | Ying Huang Haofei Ji Jiani Dong Xueying Wang Zhilin He Zeneng Cheng Qubo Zhu CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma Cancers competing endogenous RNA (ceRNA) circular RNAs (circRNAs) cleavage and polyadenylation specificity factor (CPSF) hepatocellular carcinoma (HCC) JTE-607 |
| title | CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma |
| title_full | CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma |
| title_fullStr | CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma |
| title_full_unstemmed | CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma |
| title_short | CPSF3 Promotes Pre-mRNA Splicing and Prevents CircRNA Cyclization in Hepatocellular Carcinoma |
| title_sort | cpsf3 promotes pre mrna splicing and prevents circrna cyclization in hepatocellular carcinoma |
| topic | competing endogenous RNA (ceRNA) circular RNAs (circRNAs) cleavage and polyadenylation specificity factor (CPSF) hepatocellular carcinoma (HCC) JTE-607 |
| url | https://www.mdpi.com/2072-6694/15/16/4057 |
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