Abstract
Ovarian clear cell carcinoma (OCCC) constitutes one of the subtypes of ovarian cancers, but it has unique clinical, histological and biological characteristics, one of which is chemo-resistance. It is also known to develop from endometriotic cyst, a benign ovarian tumor, at relatively high frequency. Recently, it is becoming well known that most of OCCCs express HNF1β, a transcription factor, which is closely associated with the development of liver, pancreas and kidney, as well as occurrence of familial forms of type 2 diabetes. Expression of HNF1β is now regarded as a hallmark of this tumor. Nevertheless, exact biological function of this gene in OCCC has not been clarified. We have shown in previous studies that microenvironment in endometriotic cysts contains severe oxidative stress and OCCC develops under such stressful environment as stress-resistant tumor, which may lead to chemo-resistance. We also showed that increased expression of HNF1β facilitates glucose uptake and glycolysis, which is known as Warburg effect. In the previous issue of this journal, by using comprehensive metabolome analysis, we report that HNF1β actually reduces and protects themselves from internal oxidative stress by dramatically changing cellular metabolism. In this article, we review the relevance and significance of cancer-specific metabolism and how they are associated with biological characteristics of OCCC via expression of HNF1β, along with future clinical implications of targeting cancer-specific metabolism.
Highlights
Ovarian clear cell carcinoma (OCCC) has recently been considered as a distinct entity among epithelial ovarian cancers
We provide an overview of cancer-specific metabolism, discuss how they play important roles in OCCC, and possible future direction of metabolism-targeted cancer therapy
Among the genes included in the OCCC signature, we focused on hepatocyte nuclear factor 1β (HNF1β) for the following reasons
Summary
Ovarian clear cell carcinoma (OCCC) has recently been considered as a distinct entity among epithelial ovarian cancers. We have shown that HNF1β overexpression significantly influences the metabolic activity of OCCC, which is distinct from that of other ovarian cancers [21]. The OCCC signature was induced when ovarian epithelial cells were exposed to the contents of endometriotic cysts, implying that it is originally driven by the unique microenvironment. Due to its sensitivity and specificity, HNF1β overexpression is regarded as a hallmark of OCCC among epithelial ovarian cancers. In comparison of methylation profiles between OCCC and non-clear cell ovarian cancers, a majority of the OCCC-specific hypomethylated genes were shown to have HNF1-binding sites. HNF1β is a multifunctional transcription factor that shares strong homology with HNF1α and regulates wide variety of gene expressions [40] It is especially associated with the developmental process of important organs. HNF1β was shown to play a crucial role in renal repair after ischemia/ reperfusion in the acute kidney injury model [49, 50]
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