Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J Fitzgerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green
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SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.
End-stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia-lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.
期刊介绍:
JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.