Cell. 2023 Oct 6
Dirk Mossmann, Christoph Müller, Sujin Park, Brendan Ryback, Marco Colombi, Nathalie Ritter, Diana Weißenberger, Eva Dazert, Mairene Coto-Llerena, Sandro Nuciforo, Lauriane Blukacz, Caner Ercan, Veronica Jimenez, Salvatore Piscuoglio, Fatima Bosch, Luigi M. Terracciano, Uwe Sauer, Markus H. Heim, Michael N. Hall
Products used in the paper Details Operation
AAV vector packaging For knockdown of Asns and Rbm39 following AAV particles were purchased from Packgene (USA): AAV-DJ[ssAAV.ALB.EGFP.miR30shRNA(mScramble). WPRE.SV40pA] (AAV-shCtrl), AAV-DJ[ssAAV.ALB.EGFP.miR30shRNA(mASNS).WPRE.SV40pA] (AAV-shAsns), AAV-DJ[ssAAV. ALB.EGFP.miR30shRNA(mRBM39).WPRE.SV40pA] (AAV-shRbm39). 5×10^11 GC in PBS were injected per mouse. Request Quote

Research Field: Liver Cancer

Keywords: hepatocellular carcinoma, metabolism, arginine, ARG1,
AGMAT, ASNS, RBM39, indisulam

AAV Serotype: AAV.DJ

Dose: 5E11/mouse

Routes of Administration: tail vein injection

Targeted organ: Liver

Animal or cell line strain: Mouse


Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

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