Down-regulation of FA-BRCA Pathway in Cervical Carcinoma Gradually Reversed During the Development of Chemo-tolerance: Clinical Implications.

Abstract

Cervical cancer is one of the leading causes of cancer death among females, worldwide. The contributory role of different cellular pathways in the process of carcinogenesis is still poorly understood. Our study was focused here to understand the functional evaluation of key regulatory genes of FA-BRCA pathway in the development of CACX and their role in chemo-tolerance of the disease by analyzing the molecular profile of the genes both in normal and tumour tissue of our sample pool, also validated in in silico datasets. Later on, prognostic importance of the genes was further evaluated in plasma DNA and cisplatin-treated in vitro system. We found that expression profile of FA-BRCA pathway genes was gradually reduced from undifferentiated basal-parabasal layers of normal tissue towards the progression of the disease. Further analysis revealed that frequent promoter methylation [32-55%] and deletion [34-52%] events were the plausible reasons for their reduced expression in CACX. Noticeably, invasion of promoter methylation of the genes [11-17%] in plasma CTCs of CACX patients was positively correlated [p < 0.001] with poor prognosis among patients. On the other hand, functional upregulation of these genes at higher concentrations [IC50-70] of cisplatin was a predictor for the development of drug tolerance, as evaluated in our in vitro study. This finding was supported further by low prevalence of γ-H2X foci formation and reduced expression of DNMT1 at higher concentrations of cisplatin. In totality, we discovered that the FA-BRCA pathway must be inactivated for cancer formation. In contrast, elevated gene expression played a substantial role in building of chemo-tolerance and might be associated with developing increased risk of disease recurrence among patients.