HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis
Introduction: Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC). Objectives: This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice var...
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Elsevier
2025-02-01
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| Series: | Journal of Advanced Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123224000729 |
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| author | Hong Wang Dong Qian Jiabei Wang Yao Liu Wenguang Luo Hongyan Zhang Jingjing Cheng Heng Li Yang Wu Wuhan Li Jing Wang Xia Yang Tianzhi Zhang Dong Han Qinyao Wang Chris Zhiyi Zhang Lianxin Liu |
| author_facet | Hong Wang Dong Qian Jiabei Wang Yao Liu Wenguang Luo Hongyan Zhang Jingjing Cheng Heng Li Yang Wu Wuhan Li Jing Wang Xia Yang Tianzhi Zhang Dong Han Qinyao Wang Chris Zhiyi Zhang Lianxin Liu |
| author_sort | Hong Wang |
| collection | DOAJ |
| description | Introduction: Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC). Objectives: This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis. Methods: Basescope assay was performed to analyze the expression of UPF3B-S mRNA in tissues and cells. RNA immunoprecipitation, and in vitro and in vivo models were used to explore the role of UPF3B-S and the underlying mechanisms. Results: We show that splicing factor HnRNPR binds to the pre-mRNA of UPF3B via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. High expression of UPF3B-S is correlated with tumor metastasis and unfavorable overall survival in patients with HCC. The knockdown of UPF3B-S markedly suppresses the invasive and migratory capacities of HCC cells in vitro and in vivo. Mechanistically, UPF3B-S protein targets the 3′-UTR of CDH1 mRNA to enhance the degradation of CDH1 mRNA, which results in the downregulation of E-cadherin and the activation of epithelial–mesenchymal transition. Overexpression of UPF3B-S enhances the dephosphorylation of LATS1 and the nuclear accumulation of YAP1 to trigger the Hippo signaling pathway. Conclusion: Our findings suggest that HnRNPR-induced UPF3B-S promotes HCC invasion and metastasis by exhausting CDH1 mRNA and modulating YAP1-Hippo signaling. UPF3B-S could potentially serve as a promising biomarker for the clinical management of invasive HCC. |
| format | Article |
| id | doaj-art-9f080af83dcf4177a0b10934045cc1d1 |
| institution | Kabale University |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj-art-9f080af83dcf4177a0b10934045cc1d12025-01-18T05:04:18ZengElsevierJournal of Advanced Research2090-12322025-02-0168257270HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasisHong Wang0Dong Qian1Jiabei Wang2Yao Liu3Wenguang Luo4Hongyan Zhang5Jingjing Cheng6Heng Li7Yang Wu8Wuhan Li9Jing Wang10Xia Yang11Tianzhi Zhang12Dong Han13Qinyao Wang14Chris Zhiyi Zhang15Lianxin Liu16Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Comprehensive Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC) West District/Anhui Provincial Cancer Hospital, Hefei, Anhui, ChinaAnhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of General Surgery, Division of Life Science and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Emergency Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaDepartment of Pathology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, ChinaState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, ChinaDepartment of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, ChinaTianjin Medical University Cancer Institute and Hospital, Department of Radiation Oncology, Tianjin, ChinaAnhui Chest Hospital, Department of Radiation Oncology, Hefei, Anhui, ChinaMOE Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; Corresponding authors at: Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (L.L.).Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Corresponding authors at: Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (L.L.).Introduction: Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC). Objectives: This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis. Methods: Basescope assay was performed to analyze the expression of UPF3B-S mRNA in tissues and cells. RNA immunoprecipitation, and in vitro and in vivo models were used to explore the role of UPF3B-S and the underlying mechanisms. Results: We show that splicing factor HnRNPR binds to the pre-mRNA of UPF3B via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. High expression of UPF3B-S is correlated with tumor metastasis and unfavorable overall survival in patients with HCC. The knockdown of UPF3B-S markedly suppresses the invasive and migratory capacities of HCC cells in vitro and in vivo. Mechanistically, UPF3B-S protein targets the 3′-UTR of CDH1 mRNA to enhance the degradation of CDH1 mRNA, which results in the downregulation of E-cadherin and the activation of epithelial–mesenchymal transition. Overexpression of UPF3B-S enhances the dephosphorylation of LATS1 and the nuclear accumulation of YAP1 to trigger the Hippo signaling pathway. Conclusion: Our findings suggest that HnRNPR-induced UPF3B-S promotes HCC invasion and metastasis by exhausting CDH1 mRNA and modulating YAP1-Hippo signaling. UPF3B-S could potentially serve as a promising biomarker for the clinical management of invasive HCC.http://www.sciencedirect.com/science/article/pii/S2090123224000729Alternative splicingHepatocellular carcinomaInvasion and metastasisUPF3B-SHnRNPR |
| spellingShingle | Hong Wang Dong Qian Jiabei Wang Yao Liu Wenguang Luo Hongyan Zhang Jingjing Cheng Heng Li Yang Wu Wuhan Li Jing Wang Xia Yang Tianzhi Zhang Dong Han Qinyao Wang Chris Zhiyi Zhang Lianxin Liu HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis Journal of Advanced Research Alternative splicing Hepatocellular carcinoma Invasion and metastasis UPF3B-S HnRNPR |
| title | HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis |
| title_full | HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis |
| title_fullStr | HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis |
| title_full_unstemmed | HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis |
| title_short | HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis |
| title_sort | hnrnpr mediated upf3b mrna splicing drives hepatocellular carcinoma metastasis |
| topic | Alternative splicing Hepatocellular carcinoma Invasion and metastasis UPF3B-S HnRNPR |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224000729 |
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