Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. While ammonia is a toxic metabolic byproduct, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin-driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid (TIF) and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC.

中文翻译：

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β-连环蛋白激活重新编程氨代谢以促进肝细胞癌的衰老抵抗

肝细胞癌（HCC）是一种典型的代谢重编程肿瘤，其葡萄糖、脂质、核酸和氨基酸代谢与正常肝组织不同。虽然氨是一种有毒的代谢副产物，但它最近也被认为是激活脂质代谢的信号分子，并且它可以作为生物合成的氮源以支持肿瘤发生。在这项研究中，我们发现β-连环蛋白活化主要通过刺激谷氨酰胺分解来增加肝癌中氨的产生。β-catenin/LEF1 激活谷氨酸脱氢酶 GLUD1 的转录，然后促进氨利用，从而增强谷氨酸、天冬氨酸和脯氨酸的产生，如 15NH4Cl 代谢流所证明的那样。β-连环蛋白/TCF4 诱导氨转运蛋白 SLC4A11 的转录，以排出多余的氨。SLC4A11 在 HCC 肿瘤组织中表达上调，高 SLC4A11 表达与不良预后和晚期疾病阶段相关。SLC4A11 的缺失可通过阻断氨排泄来诱导体外肝癌细胞衰老，并减少体内β-连环蛋白驱动的肿瘤生长。此外，血浆氨水平升高促进了 β-catenin 突变型 HCC 的进展，而 SLC4A11 缺陷则阻碍了这种进展。SLC4A11 的下调导致肿瘤间质液 (TIF) 中氨积累，并降低激活 β-连环蛋白的 HCC 血浆氨水平。总而言之，这项研究表明，β-连环蛋白激活会重新编程氨代谢，并且通过靶向 SLC4A11 阻断氨排泄可能是诱导 β-连环蛋白突变型 HCC 衰老的有前途的方法。