Papel das protocaderinas na carcinogênese humana: revisão sistemática com meta-análise e estudo imunomolecular em carcinoma de células escamosas oral

Abstract

Introduction: Understanding the participation and real role of protocadherins (PCDH) is essential for a better understanding of carcinogenesis, especially oral carcinogenesis, and possibly to identify new predictive markers for Oral Epithelial Dysplasia (OED) and Oral Squamous Cell Carcinoma (OSCC), providing a better understanding of the clinical course of these injuries. So far, there are no works that have carried out similar research. Objective: This thesis has two chapters, whose main objectives are: to summarize the scientific evidence on the methylation profile of PCDHs in the carcinogenesis of human malignancies (chapter 1) and to investigate the immunomolecular profile of PCDH10 in oral carcinogenesis (chapter 2). Methods: In chapter 1, a Systematic Review (SR) with meta-analysis was conducted according to the PRISMA checklist and the search was performed in LILACS, PubMed, Science Direct, Scopus and Web of Science databases, from manually and without restriction of date or language. In chapter 2, an immunomolecular study was performed by means of immunohistochemical evaluation, with antibodies to PCDH10, 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in OSCC, OED and Normal Oral Mucosa (NOM). The immunoexpression analysis was performed quantitatively, counting the number of immunomarked cells and then categorized by the score of the percentage of immunomarked cells (0 to 3), and qualitatively through subjective assessment based on staining intensity (0 = absent; 1 = mild; 2 = moderate; 3 = intense). A histoscore was obtained and immunoexpression levels were categorized as negative (0), low (1 to 4), and high (histoscore 5 to 12). The methylation analysis of PCDH10 was performed using digested (HpaII and MspI) and undigested genomic DNA amplified in the real-time polymerase chain reaction system (RTPCR) in cases of OSCC, OED and NOM. Results: In SR, 41 articles were selected, of which 26 were used in the meta-analysis. The most studied PCDH in the literature were: PCDH10, PCDH17 and PCDH8, with an association between methylation and studied cancers of 26.08 (95%CI 15.42 – 44.13). In the immunomolecular study, a total of 48 cases (18 of CCEO, 20 of DEO and 10 of MON) were submitted to immunohistochemical analysis. Loss of PCDH10 membrane marking was observed in OSCC; low nuclear and cytoplasmic immunoexpression in OSCC, OED and NOM (p<0.001). There was also greater immunopositivity for 5-mC compared to 5-hmC, with a reduction in the intensity of NOM labeling for OED and OSCC. The immunoexpression of 5-mC was high (p<0.001), showing cells marked in the OSCC (p<0.001). On the other hand, for 5-hmC, there was greater immunostaining in OED (p=0.001). The methylation profile of PCDH10 was different between groups, with the OED having a higher methylation status (p<0.001). Conclusion: PCDH methylation is an important epigenetic event in the carcinogenesis of different malignant neoplasms and PCDH10 methylation can act as a regulatory mechanism in oral carcinogenesis. Furthermore, it can be suggested that the loss of 5-hmC may be a predictor of progression in OED.