PTBP1通过调控FGFR2的可变剪接促进肝癌的发展

doi:10.16288/j.yczz.23-224

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Hereditas(Beijing) ›› 2024, Vol. 46 ›› Issue (1): 46-62.doi: 10.16288/j.yczz.23-224

• Research Article • Previous Articles Next Articles

PTBP1 promotes the progression of hepatocellular carcinoma by enhancing the oncogenic splicing switch of FGFR2

Yuying Chen^1,²(), Qian Zhang³(), Menghui Gui⁴, Lan Feng², Pengbo Cao², Gangqiao Zhou^1,^2,⁴()

1. Hengyang Medical College, University of South China, Hengyang 421001, China
2. State Key Lab of Medical Proteomics, National Center for Protein Sciences at Beijing, Institute of Radiation Medicine, Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, China
3. National Facility for Translational Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
4. School of Public Health, Nanjing Medical University, Nanjing 211166, China

Received:2023-08-23 Revised:2023-11-08 Online:2024-01-20 Published:2023-12-05
Contact: Gangqiao Zhou E-mail:529897537@qq.com;15111174004@163.com;zhougq114@126.com
Supported by:
National Natural Science Foundation of China(82002573);National Natural Science Foundation of China(82172707);National Key Research and Development Program of China(2017YFA0504301)

Abstract

Abstract:

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer accounting for 90% of cases. It is a highly invasive and deadly cancer with a gradual onset. Polypyrimidine tract-binding protein 1 (PTBP1) is an important RNA-binding protein involved in RNA metabolism and has been linked to oncogenic splicing events. While the oncogenic role of PTBP1 in HCC cells has been established, the exact mechanism of action remains unclear. This study aimed to investigate the functional connection between PTBP1 and dysregulated splicing events in HCC. Through immunoprecipitation-mass spectrometry analyses, we discovered that the proteins bound to PTBP1 were significantly enriched in the complex responsible for the alternative splicing of FGFR2 (fibroblast growth factor receptor 2). Further RNA immunoprecipitation and quantitative PCR assays confirmed that PTBP1 down-regulated the FGFR2-IIIb isoform levels and up-regulated the FGFR2-IIIc isoform levels in HCC cells, leading to a switch from FGFR2-IIIb to FGFR2-IIIc isoforms. Subsequent functional evaluations using CCK-8, transwell, and plate clone formation assays in HCC cell lines HepG2 and Huh7 demonstrated that FGFR2-IIIb exhibited tumor-suppressive effects, while FGFR2-IIIc displayed tumor-promoting effects. In conclusion, this study provides insights into the PTBP1-mediated alternative splicing mechanism in HCC progression, offering a new theoretical basis for the prevention and treatment of this malignancy. Mechanistically, the isoform switch from FGFR2-IIIb to FGFR2-IIIc promoted epithelial-mesenchymal transformation (EMT) of HCC cells and activated the FGFR cascades ERK and AKT pathways.

Key words: hepatocellular carcinoma, PTBP1, alternative splicing, FGFR2, epithelial-mesenchymal

Yuying Chen, Qian Zhang, Menghui Gui, Lan Feng, Pengbo Cao, Gangqiao Zhou. PTBP1 promotes the progression of hepatocellular carcinoma by enhancing the oncogenic splicing switch of FGFR2[J]. Hereditas(Beijing), 2024, 46(1): 46-62.

Figures/Tables 8

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显著富集的信号通路及生物学过程	富集的蛋白质数量	错误发现率	信号通路显著富集的蛋白质
mRNA splicing-major pathway	23	9.12E-20	CPSF7、CSTF1、EIF4A3、FUS、HNRNPA1、HNRNPC、HNRNPD、HNRNPH2、HSPA8、NUDT21、PCBP1、PCBP2、POLR2A、POLR2B、PRPF19、PTBP1、PUF60、SF1、SF3B4、SNRNP40、SNW1、U2AF2、YBX1
Processing of capped intron- containing pre-mRNA	25	9.12E-20	CPSF7、CSTF1、EIF4A3、FUS、HNRNPA1、HNRNPC、HNRNPD、HNRNPH2、HSPA8、NUDT21、NXF1、PCBP1、PCBP2、POLDIP3、POLR2A、POLR2B、PRPF19、PTBP1、PUF60、SF1、SF3B4、SNRNP40SNW1、U2AF2、YBX1
rRNA processing in the nucleus and cytosol	15	6.05E-10	DDX21、EBNA1BP2、FBL、GNL3、NOP2、PES1、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0、RRP1
Major pathway of rRNA processing in the nucleolus and cytosol	14	2.71E-09	DDX21、EBNA1BP2、FBL、GNL3、PES1、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0、RRP1
FGFR2 alternative splicing	7	1.02E-07	HNRNPA1、POLR2A、POLR2B、PTBP1、RBFOX2、TIA1、TIAL1
L13a-mediated translational silencing of ceruloplasmin expression	10	2.93E-07	EIF2S2、EIF2S3、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0
GTP hydrolysis and joining of the 60S ribosomal subunit	10	2.93E-07	EIF2S2、EIF2S3、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0
Influenza infection	11	3.79E-07	EIF2AK2、POLR2A、POLR2B、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0
Influenza viral RNA transcription and replication	10	9.28E-07	POLR2A、POLR2B、RPL10、RPL18、RPL28、RPL3、RPL36A、RPL4、RPL6、RPLP0

PTBP1 promotes the progression of hepatocellular carcinoma by enhancing the oncogenic splicing switch of FGFR2

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