Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression
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 prote...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202305653 |
| _version_ | 1797365328650436608 |
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| author | Qian Yan Xiaona Fang Xiaoxia Liu Sai Guo Siqi Chen Min Luo Ping Lan Xin‐Yuan Guan |
| author_facet | Qian Yan Xiaona Fang Xiaoxia Liu Sai Guo Siqi Chen Min Luo Ping Lan Xin‐Yuan Guan |
| author_sort | Qian Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:48:33Z |
| format | Article |
| id | doaj.art-ec9bd40c9781487180b5d28982afd811 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T16:48:33Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-ec9bd40c9781487180b5d28982afd8112024-01-05T08:26:58ZengWileyAdvanced Science2198-38442024-01-01111n/an/a10.1002/advs.202305653Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma ProgressionQian Yan0Xiaona Fang1Xiaoxia Liu2Sai Guo3Siqi Chen4Min Luo5Ping Lan6Xin‐Yuan Guan7Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases Guangdong Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 ChinaSun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine Guangzhou 510060 ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases Guangdong Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 ChinaShenzhen Traditional Chinese Medicine Hospital Shenzhen ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases Guangdong Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases Guangdong Institute of Gastroenterology The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 ChinaDepartment of Clinical Oncology The University of Hong Kong‐Shenzhen Hospital Shenzhen ChinaAbstract 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.https://doi.org/10.1002/advs.202305653epithelial splicing regulatory protein 2fetal reprogramminghepatocellular carcinomaRNA splicingTAK1/MAPK activation |
| spellingShingle | Qian Yan Xiaona Fang Xiaoxia Liu Sai Guo Siqi Chen Min Luo Ping Lan Xin‐Yuan Guan Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression Advanced Science epithelial splicing regulatory protein 2 fetal reprogramming hepatocellular carcinoma RNA splicing TAK1/MAPK activation |
| title | Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression |
| title_full | Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression |
| title_fullStr | Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression |
| title_full_unstemmed | Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression |
| title_short | Loss of ESRP2 Activates TAK1‐MAPK Signaling through the Fetal RNA‐Splicing Program to Promote Hepatocellular Carcinoma Progression |
| title_sort | loss of esrp2 activates tak1 mapk signaling through the fetal rna splicing program to promote hepatocellular carcinoma progression |
| topic | epithelial splicing regulatory protein 2 fetal reprogramming hepatocellular carcinoma RNA splicing TAK1/MAPK activation |
| url | https://doi.org/10.1002/advs.202305653 |
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