Efeitos da enzima óxido nítrico sintase induzível (iNOS) no desenvolvimento e progressão do carcinoma de células escamosas bucal experimental e humano

Abstract

Inducible nitric oxide synthase (iNOS) is most important protein of nitric oxide synthases family, which is capable to produce huge amounts of nitric oxide. Permanent induction of iNOS has been raised as potentially mutagenic; presenting pivotal roles in tumor biology. The aim of this study is to investigate the role of iNOS in the development of oral squamous cells carcinomas (OSCC), using a mouse model of oral carcinogenesis in NOS2 knockout animals and human samples derived from normal mucosa, leukoplakia and OSCC. Wild-type (iNOS+/+) and NOS2-knockout (iNOS-/-) mices, were challenged with 4- nitroquinoline- 1-oxide (4NQO) in drinking water for 16 weeks and killed after 0, 8 and 16 weeks of after treatment. Tongues were removed and the number of dysplasias and carcinomas was counted. Mice’s peripheral blood were analyzed by flux cytometry in search of circulating tumor cells. Human samples derived from normal mucosa, leukoplakia and OSCC, were utilized to relative quantify the amount of NOS2-mRNA. The human samples were also immune-stained with anti-iNOS and anti- Nitrotyrosine antibodies. In both groups, a reduction of dysplasias and an increase of carcinomas from week 16 to week 32 were observed. iNOS-/- mices had shown a small number of dysplastic and neoplastic lesion in all evaluated periods, moreover these lesions were usually smaller and less invasive when compared to wild type animals. Apparently, there is a rising tendency in the iNOS mRNA and protein levels during human oral carcinogenesis. Similar findings were obtained in the nitrotyrosine staining. Furthermore, iNOS and nitrotyrosine imuno-stained is associated with several clinic-pathological features of OSCC (site, presence of metastasis, staging and recidive). Our results shows that, iNOS affects the process of experimental and human oral carcinogenesis, being associated with OSCC genesis and progression. More studies should be done to provide us a deep understanding of the iNOS functions in oral cancer development.