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Abstract
Hepatic ischemia-reperfusion injury (IRI) disrupts cellular signaling pathways and contributes to early allograft dysfunction (EAD) in orthotopic liver transplantation (OLT). In this study, we found that the hepatic RNA binding protein Human Antigen R (HuR) regulated the 3′ untranslated region (UTR) of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (Ceacam1) following ischemic stress. Hepatocyte-specific preinjury HuR-null mice exhibited elevated LDH-5 isoenzyme activity and reduced Ceacam1-S expression, reflecting tissue-specific injury. In situ hybridization demonstrated that the stability of Ceacam1 mRNA depended on HuR. Luciferase assays identified Ceacam1 3′UTR cis-elements responsive to high oxygen tension. HuR-targeting short-activating RNAs (saRNAs) preferentially induced the alternative splicing of Ceacam1-S. Antisense oligos directed to the Ceacam1 3′UTR protected WT mice against acute liver injury. In the clinical arm, increased HuR and CEACAM1 expression were associated with reduced proinflammatory phenotype and a lower incidence of EAD in patients with OLT (n = 164). Human discarded livers with elevated ELAVL1/CEACAM1 levels correlated with improved tissue homeostasis. These findings suggest that HuR regulation of Ceacam1 represents a key determinant of donor tissue quality and offers a potential target for future therapeutic strategies in OLT recipients.
Authors
Brian Cheng, Tristan D. Tibbe, Siyuan Yao, Megan Wei, Zeriel Y. Wong, Taylor Torgerson, Richard Chiu, Aanchal S. Kasargod, Kojiro Nakamura, Monica Cappelletti, Myung Sim, Douglas G. Farmer, Fady Kaldas, Jerzy W. Kupiec-Weglinski, Kenneth J. Dery
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