Invasão perineural no carcinoma epidermóide de cabeça e pescoço: Impacto de genes relacionados ao ritmo circadiano

Abstract

During the processes of tumor formation and progression there is the involvement of the action of cells that create a favorable microenvironment for cancer development. Among the mechanisms involved in these events are circadian rhythm alterations and perineural invasion. Both events have been described, separately, as active in tumor aggressiveness. It is important to identify events related to circadian rhythm alterations that are associated with cancer that may directly impact the invasion of this tissue into the peripheral nervous system. The aim of this study was to evaluate perineural invasion in head and neck cancer, associating it with genes related to the peripheral nervous system and circadian rhythm. The data showed that the circadian rhythm and axon guidance pathways were deregulated in head and neck squamous cell carcinoma with positive perineural invasion. Differential expression analyses identified that genes associated with Schwann cell response in injured nerves that are positively regulated activate the circadian rhythm pathway. Negative correlation was identified between expression and methylation of PER3 and RORC genes when analyzed separately in both tumor groups. Positive correlations between expression of PER2 and RORC, as well as of RORC with MPZ, S100A8 and NUF2 genes were identified only in the groups of patients who did not present perineural invasion. Circadian rhythm genes are dysregulated in neoplastic tissues, with increased expression of oncogenes and decreased expression of tumor suppressors. Increased expression of mTOR protein was identified in patients presenting with perineural invasion. The data suggest that dedifferentiation and proliferation of Schwann cells may be associated with downregulation of circadian rhythm genes; consequently, Schwann cells produce different factors that participate in various processes of tumor progression and invasion of adjacent tissues, including activation of the mTOR pathway. These processes may also be involved in tumor invasion into the perineural tissue in head and neck cancer.