SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
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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引用次数: 0

Abstract

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.

SLC4A11介导氨的输入并促进肝细胞癌的癌干性。
肝病晚期的特征是门静脉高压、全身氨升高和肝细胞癌(HCC)的发展。虽然肝硬化的这些临床后果已被充分描述,但人们对肝功能不全和随之而来的氨升高是否会导致 HCC 癌变仍然知之甚少。利用临床前模型,我们发现氨通过转运体 SLC4A11 进入细胞,并作为氨基酸和核苷酸生物合成的氮源。氨的升高在体外促进了癌症干细胞的特性,在体内促进了肿瘤的发生。提高氨的清除率可减少 HCC 干细胞和肿瘤的生长。在患者中,血清氨的升高与HCC发病率的增加有关。综上所述,这项研究为使用降氨剂作为潜在疗法来降低HCC发病率和侵袭性的临床研究奠定了基础。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
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.
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