4.7 Article

Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers

Journal

BIOMOLECULES
Volume 11, Issue 8, Pages -

Publisher

MDPI
DOI: 10.3390/biom11081086

Keywords

metabolic reprogramming; arginine auxotrophy; argininosuccinate lyase; dimethylarginine dimethylaminohydrolase; protein arginine methyltransferase; nitric oxide synthase; dimethylarginine; ornithine decarboxylase; ornithine translocase; argininosuccinate synthase

Funding

  1. Wroclaw Medical University [SUB.A040.19.016]

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The study identified aberrations in L-arginine metabolism in gastric cancer, reflecting different subtypes and pathology. A metabolite diagnostic panel showed high accuracy in detecting and differentiating gastric cancer from benign disorders, while enzyme gene expression was related to tumor advancement and metastasis. Further functional studies on ASL, PRMT2, and ORNT1 in gastric cancer are warranted.
There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes' gene expression was quantified in 29 paired tumor-normal samples using qPCR and referred to cancer pathology and molecular landscape. Patients with cancer or benign disorders had reduced systemic arginine, citrulline, and ornithine and elevated symmetric dimethylarginine and dimethylamine. Citrulline and ornithine depletion was accentuated in metastasizing cancers. Metabolite diagnostic panel had 91% accuracy in detecting cancer and 70% accuracy in differentiating cancer from benign disorders. Gastric tumors had upregulated NOS2 and downregulated ASL, PRMT2, ORNT1, and DDAH1 expression. NOS2 upregulation was less and ASL downregulation was more pronounced in metastatic cancers. Tumor ASL and PRMT2 expression was inversely related to local advancement. Enzyme up- or downregulation was greater or significant solely in cardia subtype. Metabolic reprogramming in GC includes aberrant L-arginine metabolism, reflecting GC subtype and pathology, and is manifested by altered interplay of its intermediates and enzymes. Exploiting L-arginine metabolic pathways for diagnostic and therapeutic purposes is warranted. Functional studies on ASL, PRMT2, and ORNT1 in GC are needed.

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