PO-240 WWOX suppressor gene regulate glucose metabolism and warburg effect in case of gestational diabetes mellitusas well as breast cancer

Abstract

Introduction WWOX gene is a tumour suppressor which loss of expression is demonstrated in many cancers. WWOX is involved in the regulation of glucose metabolism by interaction with HIF1a. WWOX knockdown regulates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in breast cancer MCF7 cell line. This metabolic reprograming called the Warburg effect enhances glycolysis to generate energy over oxidative phosphorylation in aerobic conditions. We considered that aerobic glycolysis can be upregulated via changes in WWOX expression in case of women with gestational diabetes mellitus (GDM). We hypothesised that WWOX has a function in regulating glucose metabolism in GDM. Literature indicates that GDM may be associated with increased risk of breast cancer. Material and methods We analysed expression level of WWOX, HIF1A, glucose transporters SLC2A1, SLC2A4 and glycolytic genes HK2, PFK1, PKM2, LDHA by RT-qPCR in GDM and NGT blood samples. The expression of same genes, we analysed in normal/tumour pair of breast tissue from GEO database (GSE109169). The results, we referred to expression level of these genes in MCF7 and MCF7 sh WWOX cell line obtained by Abu-Remaileh et. al. Results and discussions Relative expression level of WWOX was lower in case of GDM than NGT. Opposite result we observed for HIF1A. Moreover, WWOX/HIF1A ratio is significantly lower in GDM than NGT. The increased level of HIF1A in GDM group is further associated with higher expression of glucose transporters and glycolytic genes. In GDM we observed negative correlation between WWOX/ HIF1A ratio and HIF1A, SLC2A1 as well as HK2, PFK and PKM2. WWOX knockout in MCF7 leads to increasing of HIF1a target glycolytic genes. Similar to GDM, WWOX expression level is lower and HIF1A is higher in breast cancer in comparison to normal breast tissue, which gives statistically lower WWOX/HIF1A ratio. Expression level of SLC2A1, HK2, PKM2, LDHA in breast cancer are higher than in normal. Conclusion We found elevated WWOX and HIF1A expression level, enhanced glycolysis, reduced WWOX/HIF1A ratio in GDM. Our results suggest that WWOX is responsible for Warburg effect occurrence in GDM via regulation of HIF1A, as like in breast cancer. Therefore, a hypothesis can be formed that elevated risk of breast cancer in diabetes mellitus patients could be associated with systemic WWOX function insufficiency.