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Open AccessArticle

Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway

1
Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland
2
Department of Gastrointestinal and General Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland
3
Department of Nervous System Diseases, Wroclaw Medical University, 51-618 Wroclaw, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6282; https://doi.org/10.3390/ijms21176282
Received: 5 August 2020 / Revised: 26 August 2020 / Accepted: 28 August 2020 / Published: 30 August 2020
(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)
The L-arginine/NO pathway holds promise as a source of potential therapy target and biomarker; yet, its status and utility in esophageal squamous cell carcinoma (ESCC) is unclear. We aimed at quantifying pathway metabolites in sera from patients with ESCC (n = 61) and benign conditions (n = 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples (n = 40) using real-time PCR with reference to ESCC pathology and circulating immune/inflammatory mediators, quantified using Luminex xMAP technology. ESCC was associated with elevated systemic arginine and asymmetric dimethylarginine. Citrulline decreased and arginine bioavailability increased along with increasing ESCC advancement. Compared to adjacent tissue, tumors overexpressed ODC1, NOS2, PRMT1, and PRMT5 but had downregulated ARG1, ARG2, and DDAH1. Except for markedly higher NOS2 and lower ODC1 in tumors from M1 patients, the pathology-associated changes in enzyme expression were subtle and present also in noncancerous tissue. Both the local enzyme expression level and systemic metabolite concentration were related to circulating inflammatory and immune mediators, particularly those associated with eosinophils and those promoting viability and self-renewal of cancer stem cells. Metabolic reprogramming in ESCC manifests itself by the altered L-arginine/NO pathway. Upregulation of PRMTs in addition to NOS2 and ODC1 and the pathway link with stemness-promoting cytokines warrants further investigation. View Full-Text
Keywords: asymmetric dimethylarginine (ADMA); symmetric dimethylarginine (SDMA); ornithine; citrulline; dimethylamine (DMA); arginase (ARG); nitric oxide synthase (NOS); protein arginine N-methyltransferase (PRMT); dimethylarginine dimethylaminohydrolase (DDAH); ornithine decarboxylase (ODC) asymmetric dimethylarginine (ADMA); symmetric dimethylarginine (SDMA); ornithine; citrulline; dimethylamine (DMA); arginase (ARG); nitric oxide synthase (NOS); protein arginine N-methyltransferase (PRMT); dimethylarginine dimethylaminohydrolase (DDAH); ornithine decarboxylase (ODC)
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Bednarz-Misa, I.; Fortuna, P.; Fleszar, M.G.; Lewandowski, Ł.; Diakowska, D.; Rosińczuk, J.; Krzystek-Korpacka, M. Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway. Int. J. Mol. Sci. 2020, 21, 6282.

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