HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis

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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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:Journal of Advanced Research
Subjects:
Alternative splicing
Hepatocellular carcinoma
Invasion and metastasis
UPF3B-S
HnRNPR
Online Access:http://www.sciencedirect.com/science/article/pii/S2090123224000729
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Summary: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.
ISSN:2090-1232

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