Abstract
PurposeThere are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.MethodsWe evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).ResultsObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.ConclusionThese results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.Graphical abstract
Highlights
Leptin is a small (16 kDa) protein produced and secreted by adipose tissue, which is involved in appetite regulation, bone formation and reproductive function
Based on the fact that leptin exerts its activity through the leptin receptor (ObR), and through cross talk with other signalling systems implicated in tumour genesis [18, 19], in this study we focused our attention on the relationship between the leptin/ObR axis and oestrogen receptors (ERα/β)
Assuming the gene expression in HGrC1 cell to be 1, ObR gene expression in COV434 and KGN cells was 50% higher (Fig. 1a), while there were no differences in ObR protein expression (Fig. 1b)
Summary
Leptin is a small (16 kDa) protein produced and secreted by adipose tissue, which is involved in appetite regulation, bone formation and reproductive function. Epidemiological studies have indicated a positive correlation between obesity and an increased risk of several types of cancer [2]. Serum leptin levels have been reported to be higher in overweight and obese women than in women with normal weight. Leptin levels can reach 40 ng/mL, which is up to ten times higher than in normal weight people [3, 4]. Cancer risk is higher among overweight and obese people, with an increased risk of 16 and 30%, respectively [5]. Leptin and its receptors are over-expressed in different human cancers [1]. Leptin has been proposed as one of the six markers of ovarian cancer [6]. Uddin et al revealed a significant association between ObR overexpression and poor survival rates in 59.2% of epithelial ovarian cancer cases [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
