%0 Journal Article
%T HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis.
%A Wang H
%A Qian D
%A Wang J
%A Liu Y
%A Luo W
%A Zhang H
%A Cheng J
%A Li H
%A Wu Y
%A Li W
%A Wang J
%A Yang X
%A Zhang T
%A Han D
%A Wang Q
%A Zhang CZ
%A Liu L
%J J Adv Res
%V 0
%N 0
%D 2024 Feb 24
%M 38402949
%F 12.822
%R 10.1016/j.jare.2024.02.010
%X <B>BACKGROUND: </B>Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC).<BR><B>OBJECTIVE: </B>This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.