الملخص الإنجليزي
The expression of Neuropilin-1 (NRP-1) has been related to more advanced stages of malignancy in several types of cancer including Epithelial Ovarian Cancer (EOC). Epithelial to Mesenchymal Transition (EMT) is an active process in EOC, which is responsible for cancer cells invasion and metastasis. Therefore, we hypothesized that NRP-1 can be a potential biomarker for EOC and might be involved in the EMT process. In the first part of my thesis, we used immunohistochemical staining for tissue arrays containing 150 tissues of 75 cases (two core per case), among the 75 cases there were 2 normal, 3 benign and 70 EOC cases of different pathologies mainly endometrioid adenocarcinoma (27 cases), serous cystadenocarcinoma (24 cases) and mucinous cystadenocarcinoma (12 cases). In this work we noticed that NRP-1 was only expressed in tumors epithelium. Spearman's rank correlation coefficient showed a positive relationship between NRP-1 expression and two strong EMT markers, E-Cadherin and Slug ((=0. 258, p-value= 0.025) and (o =0.519, p-value <0.001) respectively). Fisher's Exact Test revealing that NRP-1 expression was tumor subtype dependent and was proportionally related with tumor grade (p=0.05). Another interesting finding was that Vimentin as a stromal protein was expressed by the epithelium of many tumors indicating their transformation. Mucinous carcinomas showed no Vimentin expression, higher expression level of E-cadherin as well as less NRP-1 and Slug expression, which supports its previous classification to be less aggressive than the other two types of EOC. In an attempt to investigate what regulates NRP-1 in EOC we assessed the pattern of NRP-1 promoter methylation in two ovarian cancer cell variants; OVCAR-3 parental and OVCAR-3-KDR1-1 derivative (VEGFR2 knockdown) and investigated the role of glycemic microenvironment on modulating this pattern. Our study was carried out on the downstream region of the transcription start site of the NRP-1 promoter. We found that NRP-1 promoter DNA methylation and demethylation are both responsible for its mode of expression in the two cell variants and that was modulated upon hypoglycemia. These results indicate that the available drugs which modulate DNA methylation can hold a promise to treat EOC subtypes depending on their expressed levels of this interesting protein.
