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CPSF4 regulates circRNA formation and microRNA mediated gene silencing in hepatocellular carcinoma

Abstract

CircRNAs play essential roles in various physiological processes and involves in many diseases, in particular cancer. Global downregulation of circRNA expression has been observed in hepatocellular carcinoma (HCC) in many studies. Previous studies revealed that the pre-mRNA 3′ end processing complex participates in circRNA cyclization and plays an important role in HCC tumorigenesis. Therefore, we explored the role of CPSF4, for 3′ end formation and cleavage, in circRNA formation. Clinical research has shown that CPSF4 expression is upregulated in HCC and that high expression of CPSF4 is associated with poor prognosis in HCC patients. Mechanistic studies have demonstrated that CPSF4 reduces the levels of circRNAs, which possess a polyadenylation signal sequence and this decrease in circRNAs reduces the accumulation of miRNA and disrupts the miRNA-mediated gene silencing in HCC. Experiments in cell culture and xenograft mouse models showed that CPSF4 promotes the proliferation of HCC cells and enhances tumorigenicity. Moreover, CPSF4 antagonizes the tumor suppressor effect of its downstream circRNA in HCC. In summary, CPSF4 acts as an oncogene in HCC through circRNA inhibition and disruption of miRNA-mediated gene silencing.

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Fig. 1: CPSF4 is highly expressed in HCC tissues and higher expression of CPSF4 indicates a poor prognosis for HCC patients.
Fig. 2: CPSF4 reduces the circRNA biogenesis in HCC cells.
Fig. 3: The PAS sequence is critical for CPSF4-mediated RNA cyclization.
Fig. 4: CPSF4 reduced the accumulation of miRNA and gene silencing.
Fig. 5: CPSF4 promotes the proliferation and tumorigenicity of HCC cells.
Fig. 6: CPSF4 antagonizes the tumor suppression effect of hsa_circ_0004913.
Fig. 7: Schematic diagram of how CPSF4 regulates circRNA biogenesis in HCC.

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Acknowledgements

We thank Biomarker Technologies (Beijing, China) for providing RNA sequencing and data analysis and the Molecular Medical Center in the Xiangya Hospital (Changsha, China) for the confocal microscopy. This research is supported by the National Natural Science Foundation of China (C0709-31201056) and the Hunan Provincial Natural Science Foundation of China (2018JJ2493)

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This work was supported by the National Natural Science Foundation of China (C0709- 31201056) and the Hunan Provincial Natural Science Foundation of China (2018JJ2493).

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Correspondence to Qubo Zhu.

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Wang, X., Dong, J., Li, X. et al. CPSF4 regulates circRNA formation and microRNA mediated gene silencing in hepatocellular carcinoma. Oncogene 40, 4338–4351 (2021). https://doi.org/10.1038/s41388-021-01867-6

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