Department of Radiation Oncology and.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
JCI Insight. 2024 Nov 8;9(21):e184826. doi: 10.1172/jci.insight.184826.
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.
终末期肝病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有详细描述，但仍不清楚肝衰竭和随之而来的氨升高是否会促进 HCC 的发生。我们使用临床前模型发现，氨通过转运蛋白 SLC4A11 进入细胞，并作为氨基酸和核苷酸生物合成的氮源。升高的氨促进了体外癌症干细胞特性和体内肿瘤起始。增强氨清除可降低 HCC 干性和肿瘤生长。在患者中，血清氨升高与 HCC 发生率增加相关。总之，这项研究为使用降低氨的药物作为潜在疗法来减轻 HCC 的发生率和侵袭性的临床研究奠定了基础。
