Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression

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Abstract: Tumors usually display fetal‐like characteristics, and many oncofetal proteins have been identified. However, fetal‐like reprogramming of RNA splicing in hepatocellular carcinoma (HCC) is poorly understood. Here, it is demonstrated that the expression of epithelial splicing regulatory protein 2 (ESRP2), an RNA splicing factor, is suppressed in fetal hepatocytes and HCC, in parallel with tumor progression. By combining RNA‐Seq with splicing analysis, it is identified that ESRP2 controls the fetal‐to‐adult switch of multiple splice isoforms in HCC. Functionally, ESRP2 suppressed cell proliferation and migration by specifically switching the alternative splicing (AS) of the TAK1 gene and restraining the expression of the fetal and oncogenic isoform, TAK1_ΔE12. Notably, aberrant TAK1 splicing led to the activation of p38MAPK signaling and predicted poor prognosis in HCC patients. Further investigation revealed that TAK1_ΔE12 protein interacted closely with TAB3 and formed liquid condensation in HCC cells, resulting in p38MAPK activation, enhanced cell migration, and accelerated tumorigenesis. Loss of ESRP2 sensitized HCC cells to TAK1 kinase inhibitor (TAK1i), promoting pyroptotic cell death and CD8+ T cell infiltration. Combining TAK1i with immune checkpoint therapy achieved potent tumor regression in mice. Overall, the findings reveal a previously unexplored onco‐fetal reprogramming of RNA splicing and provide novel therapeutic avenues for HCC.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression ; day:20 ; month:11 ; year:2023 ; extent:17
Advanced science ; (20.11.2023) (gesamt 17)

Creator: Yan, Qian
Fang, Xiaona
Liu, Xiaoxia
Guo, Sai
Chen, Siqi
Luo, Min
Lan, Ping
Guan, Xin‐Yuan

DOI: 10.1002/advs.202305653

URN: urn:nbn:de:101:1-2023112114440705430739

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:31 AM CEST

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Yan, Qian
Fang, Xiaona
Liu, Xiaoxia
Guo, Sai
Chen, Siqi
Luo, Min
Lan, Ping
Guan, Xin‐Yuan

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Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression

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Other Objects (12)

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