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

• Published in: International journal of molecular sciences Vol. 21; no. 17; p. 6282
• Main Authors: Bednarz-Misa, Iwona, Fortuna, Paulina, Fleszar, Mariusz G, Lewandowski, Łukasz, Diakowska, Dorota, Rosińczuk, Joanna, Krzystek-Korpacka, Małgorzata
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30-08-2020; MDPI
• Subjects: Adult; arginase (ARG); Arginine; Arginine - metabolism; asymmetric dimethylarginine (ADMA); Bioavailability; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell self-renewal; Citrulline; Cytokines; dimethylamine (DMA); Dimethylargininase; Enzymes; Eosinophils; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; Female; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Leukocytes (eosinophilic); Lymphatic system; Male; Metabolism; Metabolites; Metabolome; Metastasis; Nitric oxide; Nitric Oxide - metabolism; ornithine; Pathology; Polyamines; Prognosis; Squamous cell carcinoma; Stem cells; symmetric dimethylarginine (SDMA); Transcriptome; Tumors; protein arginine N-methyltransferase (PRMT); symmetric dimethylarginine (SDMA); asymmetric dimethylarginine (ADMA); ornithine; dimethylamine (DMA); dimethylarginine dimethylaminohydrolase (DDAH); ornithine decarboxylase (ODC); nitric oxide synthase (NOS); arginase (ARG); citrulline
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21176282

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 (
= 61) and benign conditions (
= 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples (
= 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
,
,
, and
but had downregulated
,
, and
. Except for markedly higher
and lower
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
s in addition to
and
and the pathway link with stemness-promoting cytokines warrants further investigation.