Hepatocyte nuclear factor‐1β (HNF‐1β) promotes glucose uptake and glycolytic activity in ovarian clear cell carcinoma

Abstract

Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas that often arises in ovarian endometriosis. We previously reported that a unique carcinogenic environment, especially iron-induced oxidative stress in endometriotic cysts may promote development of OCCC. We also identified a gene expression profile characteristic of OCCC (the "OCCC signature"). This 320-gene OCCC signature is enriched in genes associated with stress response and sugar metabolism. However, the biological implication of this profile is unclear. In this study, we have focused on the biological role of the HNF-1β gene within the OCCC signature, which was previously shown to be overexpressed in OCCC. Suppression of HNF-1β in the HNF-1β-overexpressing human ovarian cancer cell line RMG2 using short hairpin RNA resulted in a significant increase in proliferation. It also facilitated glucose uptake, glycolytic activity, and lactate secretion along with increased expression of the glucose transporter-1 (GLUT-1) gene and several key enzymes in the glycolytic process. Conversely, forced expression of HNF-1β in the serous ovarian cancer cell line, Hey, resulted in slowed cellular growth and repressed glycolytic activity. These data suggest that HNF-1β represses cell growth, and at the same time, it promotes aerobic glycolysis which is known as the "Warburg effect." As the Warburg effect is regarded as a characteristic metabolic process in cancer which may contribute to cell survival under hypoxic conditions or in a stressful environment, overexpression of HNF-1β may play an inevitable role in the occurrence of OCCC in stressful environment.

Transcriptional upregulation of HNF-1β by NF-κB in ovarian clear cell carcinoma modulates susceptibility to apoptosis through alteration in bcl-2 expression

“…In this study, an unexpected finding was that transfection of HNF-1β was able to increase transcription of the Glut-1 gene, in line with a previous study, 27 but such an association was not observed in OCCCs. This may be owing to the presence of abundant and intricate signals that regulate glycolytic metabolism, such as HIF-1α pathways.…”

“…Given that HNF-1β acts as an inducer of potent cell cycle regulatory genes that inhibit G1 progression, including CDKNA1A and CDKN1B, 27 it was expected that HNF-1β may function as a suppressive effector of cell proliferation in OCCCs. Our results, however, demonstrated that HNF-1β expression did not alter during steady cell growth in OCCC cells, as well as in Hec251 cells stably overexpressing exogenous HNF-1β.…”

DNA methylation changes in epithelial ovarian cancer histotypes

“…It is hypothesized that these widespread changes in DNA methylation arise due to the oxidative stress and/or inflammation experienced in the unique CC-EOC tumor microenvironment (i.e. endometrial tissues exposed to the ovary surface or in the oxygen free and radical enriched environment of endometriotic cysts) [54,63,64]. …”

“…CIMP status and HNF1B expression levels are strongly positively correlated in EOC (P b 10 −16 ) [59], but a hypothesis for causation is not forthcoming. Plausibly, these two molecular features are a byproduct of the CC-EOC microenvironment, overexpression of HNF1B being a mechanism by which CC-EOC precursors manage and survive their stressful environment [64], and CIMP arising in that environment by mechanisms that are not yet known.…”

Urinary interleukin-1ß levels among gynecological patients

“…Increased metabolic activity and glucose concentrations driven by the Warburg effect [45] are associated with highly aggressive OC cell lines [46]. In cancer, the Warburg effect is regarded as a characteristic metabolic process that may contribute to cell survival in a stressful environment, such as the stress of chronic inflammation [47]. The Warburg effect suggests that cancer cells produce energy predominately by glycolysis and lactic acid production over oxidative phosphorylation [45].…”