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. 2021 Jun 10;22(12):6264. doi: 10.3390/ijms22126264

Figure 3.

Figure 3

Implications of micro RNAs (A) and long non-coding RNAs (B) in carcinogenesis induced by NO. Inducible NOS (NOS2) positively regulates migration and invasion in cancer cells and negatively regulates phosphatase and tensin homolog (PTEN) suppressor gene and apoptosis through microRNA miR-29b/c expression induction. Furthermore, miR-29b/c represses DNA demethylase DNMT3A in a negative feedback loop (A1). Endothelial NOS (NOS3) also promotes proliferation, migration and invasion, which constitutes a shared target of miR-335 and miR-543 (A2). Activity of NOS2 is also controlled by miRNA expression. In particular, miR-193b targets dimethylarginine dimethylaminohydrolase 1 (DDAH1) enzyme, which removes asymmetric dimethylarginine (ADMA), a nitric oxide synthase (NOS) inhibitor (A3). miR-16 promotes NOS2 activity, increasing NO production, necessary for maintaining an anti-tumoral microenvironment. Moreover, miR-16 targets PD-L1, reducing immunosuppression (A4). miR-155 controls proliferation, migration, invasion and angiogenesis by negatively targeting FGF-2 in esophageal adenocarcinoma cells (EACs) and promoting NOS2 in tumor-associated macrophages (TAMs) (A5). Arginine availability also controls proliferation induced by NO-derived NOS2. SLC7A1 is an arginine transporter, which is negatively regulated by miR-122 (A6). Long non-coding RNA (lncRNAs) (HCC upregulated EZH2-associated or HEIH, urothelial carcinoma-associated 1 or UCA1, and H19) reduce miRNAs expression (miR-939-5p, miR-204 and miR-148b-3p, respectively) (B). miR-939-5p inhibits NOS2, which increments NO production, leading to tumor promotion (B1). miR-204 inhibits sirtuin 1 (SIRT1), cyclooxygenase-2 (COX-2) and NOS2 expression causing cell proliferation boost and apoptosis reduction (B2). miR-148b-3p upregulates NOS3 and enhances NO production leading to a negative participation in hypoxia stress and, on the other hand, this miRNA also downregulates NADPH oxidase 4 (NOX4) and increases superoxide anion production, which has a positive participation in hypoxic stress (B3).