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

Abstract

Abstract. 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 genomewide expression analysis technology have noted specific expression of a transcription factor, hepatocyte nuclear factor-1ß (HNF-1ß), in cEOC and genetic alteration may be involved in oxidative stress. We describe the HNF-1ß-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-1ß. Twenty-two (40.7%) of the 54 genes predominantly identified in cEOC were involved in downstream targets of HNF-1ß. The HNF-1ß-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-1ß-specific downstream targets.

Targeting DNA Damage Response Pathway in Ovarian Clear Cell Carcinoma

“…As a transcription factor HNF-1β assume several functional roles during the carcinogenesis of OCCC, such as metabolic reprogramming of the cancer cells ( 152 , 153 ), causing tumor-associated thrombosis ( 154 ), and conferring carboplatin resistance ( 155 ). More importantly, HNF1β appears to be integral to the transformation of endometriosis lesions, serving as the master regulator of an antioxidant detoxification system responsible for resisting the oxidative microenvironment caused by hemolysis during the development of endometriosis ( 156 ). In terms of DDR, HNF-1β takes part in the Chk1 regulated cell cycle checkpoint in endometriotic cells, contributing to their transformation ( 157 ).…”

Clinicopathological correlations of endometrioid and clear cell carcinomas in the uterus and ovary

“…HNF-1β is a transcription factor that protects cells from oxidative stress by inducing antioxidant protein expression. [ 24 ] Furthermore, HNF-1β upregulation activates STAT3 and nuclear factor kappa B signaling to promote IL-6 and IL-8 production. [ 25 ] Therefore, HNF-1β upregulation may activate IL-6–STAT3–HIF signaling, particularly in OCC.…”

New insights about endometriosis-associated ovarian cancer: pathogenesis, risk factors, prediction and diagnosis and treatment

“…A considerable percentage of the genes displaying elevated expression levels in ovarian clear cell carcinoma are linked to redox processes, including oxidative and detoxification enzymes ( 45 ). HNF-1β, acting as a transcription factor, exerts control over target genes responsible for encoding proteins involved in vital cellular processes such as proliferation, differentiation, glucose metabolism, dysplasia, and glycogen synthesis ( 46 ).…”