We have previously shown that ARG2 expression was increased in most malignant thyroid tumors, but absent in benign lesions and normal tissues. Small interfering RNA knockdown was used to investigate the role of ARG2 in a thyroid carcinoma cell line. ARG2 knockdown decreased eNOS expression as well as the expression of eNOS-related genes (p21, Akt1, HIF-1, VEGF, and CAV1). ARG2 silencing changed tumor properties of thyroid cancer cells promoting apoptosis and reduced expression of cell proliferation markers. These results, coupled with enhanced nitric oxide production and elevated reactive oxygen species (ROS) levels, account for the altered intracellular redox environment. Genes related to either production (DUOX1 and NOX4) or catabolism (SODs) of ROS and reactive nitrogen species were negatively modulated by ARG2 knockdown. Additionally, a positive correlation of ARG2 with eNOS and related genes was investigated in thyroid tumors, further substantiating our in vitro findings. Our results suggest that ARG2 and eNOS may work in a coordinated manner and the underlying mechanism might be of major significance for thyroid tumorigenesis and/or tumor progression pathways. Fine modulation of ARG2, eNOS, and related genes may represent a potential source for targeted therapy of several cancer types.
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