Clear cell carcinoma of the ovary: potential pathogenic mechanisms (Review)

Epithelial ovarian cancer (EOC) is the most common cause of gynecological cancer-related mortality. Clear cell EOC (cEOC) has a number of clinical features distinguishing it from other EOC because of frequent concurrence of endometriosis and highly chemoresistant nature resulting in a poor prognosis. Recent biochemical studies based on genome-wide expression analysis technology have noted specific expression of a transcription factor, hepatocyte nuclear factor-1beta (HNF-1beta), in cEOC and genetic alteration may be involved in oxidative stress. We describe the HNF-1beta-dependent pathophysiology of cEOC and discuss its role in oxidative stress-induced carcinogenesis. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2009, combining the keywords, genome-wide, microarray, epithelial ovarian cancer, clear cell carcinoma, oxidative stress, and detoxification, with specific expression profiles of genes. The catalog of cEOC-specificity might be a manifestation of six essential alterations in cell physiology: oxidative stress and detoxification, proteases, signal transduction, adhesion, transcription, and metabolism. Among 54 genes highly upregulated in cEOC, 47 genes (87.0%) were associated with the redox-related genes. Several important cEOC-related genes overlap with those known to be regulated by HNF-1beta. Twenty-two (40.7%) of the 54 genes predominantly identified in cEOC were involved in downstream targets of HNF-1beta. The HNF-1beta-dependent pathway might provide new insights into regulation of glycogen synthesis, detoxification and resistance to anticancer agents. This review summarizes recent advances in the understanding of oxidative stress and antioxidant mechanisms in pathogenesis of cEOC. A redox-sensitive subset of cEOC genes linked to oxidative and detoxification pathways was identified and associated with HNF-1beta-specific downstream targets.