The Role of Hepatocyte Nuclear Factor-1Beta in the Pathogenesis of Endometriosi-Associated Ovarian Cancer

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Problem Clear cell carcinoma of the ovary (CCC) has a number of features distinguishing it from other epithelial ovarian carcinomas (EOC) because of its characteristic histology and biology, frequent concurrence with endometriotic lesion, and highly chemoresistant nature resulting in an extremely poor prognosis. The incidence of CCC has been steadily increasing in Japan. They comprise approximately 20% of all EOC. Understanding the mechanisms of CCC development and elucidating pathogenesis and pathophysiology are intrinsic to prevention and effective therapies for CCC. Method We have investigated the role of hepatocyte nuclear factor-1beta (HNF-1beta) for biology, pathogenesis, and pathophysiological studies on endometriosis-associated EOC. Several data are discussed in the context of endometriosis and CCC biology. Results Here, we show that 1) the expression of the genes involved in transcription, signaling, cell cycle, adhesion, matrix, proteinase, and detoxification was greatly incr … More eased in the CCC carcinogenesis ; 2) upregulation of HNF-1beta and Polo-like kinase (PLK)-Early mitotic inhibitor-1 (Emi1) as well as their downstream targets are specifically found in most CCC. The promising molecular targeting approach will emerge in the context of HNF-1beta and PLK-Emi1 biology ; and 3) several significant common pathways observed in CCC of the ovary overlap the datasets identified in CCC of the kidney. To improve the outcome in CCC therapy, we must learn various adaptive treatment strategies for renal CCC, although it is not supported by any preliminary clinical data. These studies based on genome-wide expression analysis technology have noted specific expression of transcription factor genes, HNF-1beta, in endometriosis and CCC, suggesting that early differentiation into the clear cell lineage takes place in the endometriosis. The HNF-1beta-dependent pathway of CCC will be discussed, which are providing new insights into regulation of apoptosis and glycogen synthesis and resistance of CCC to anticancer agents. Conclusion This study demonstrates recent advances in the HNF-1beta and its target genes, the potential challenges to the understanding of carcinogenesis, pathogenesis and pathophysiology of CCC, and a possible novel model is proposed. The inhibitors that target HNF-1beta and PLK-Emi1 and their downstream signaling molecules would be evaluated. The challenges accompanying the recent advance are described in this article. Less