Reduced Gonadotrophin Receptor Expression Is Associated with a More Aggressive Ovarian Cancer Phenotype.

Janelle Cheung,Martin K. Oehler,Nicolae Ghinea,Anne M. Macpherson,Noor A. Lokman,Eunice Lee,Carmela Ricciardelli,Frank Grutzner,Riya D. Abraham

doi:10.3390/ijms22010071

Janelle Cheung, Martin K. Oehler + Show 7 more

Open Access

https://doi.org/10.3390/ijms22010071

Copy DOI

Abstract

Follicle-stimulating hormone (FSH) and luteinising hormone (LH) play important roles in regulating cell growth and proliferation in the ovary. However, few studies have explored the expression of FSH and LH receptors (FSHR and LHCGR) in ovarian cancer, and their functional roles in cancer progression remain inconclusive. This study investigated the potential impact of both mRNA (FSHR, LHCGR) and protein (FSHR, LHCGR) expression on ovarian cancer progression using publicly available online databases, qRT-PCR (high grade serous ovarian cancers, HGSOC, n = 29 and benign ovarian tumors, n = 17) and immunohistochemistry (HGSOC, n = 144). In addition, we investigated the effect of FSHR and LHCGR siRNA knockdown on the pro-metastatic behavior of serous ovarian cancer cells in vitro. High FSHR or high LHCGR expression in patients with all subtypes of high-grade ovarian cancer was significantly associated with longer progression-free survival (PFS) and overall survival (OS). High FSHR protein expression was associated with increased PFS (p = 0.050) and OS (p = 0.025). HGSOC patients with both high FSHR and high LHCGR protein levels had the best survival outcome, whilst both low FSHR and low LHCGR expression was associated with poorest survival (p = 0.019). Knockdown of FSHR significantly increased the invasion of serous ovarian cancer cells (OVCAR3 and COV362) in vitro. LHCGR knockdown also promoted invasion of COV362 cells. This study highlights that lower FSHR and LHCGR expression is associated with a more aggressive epithelial ovarian cancer phenotype and promotes pro-metastatic behaviour.

Highlights

Ovarian cancer is the leading cause of cancer-related mortality among gynaecological cancers in the Western world [1]
Using the publicly available CSIOVDB database, follicle-stimulating hormone receptor (FSHR) and LHCGR expression was increased in early-stage ovarian cancer compared to stage II, III or IV cancers (p < 0.01, Figure 1a,c)
FSHR and LHCGR expression was increased in lowgrade ovarian cancers, compared to high grade ovarian cancers

Summary

Introduction

Ovarian cancer is the leading cause of cancer-related mortality among gynaecological cancers in the Western world [1]. Clear cell, and endometrioid ovarian cancers [2]. The glycoprotein hormones follicle-stimulating hormone (FSH) and luteinising hormone (LH) are gonadotropins produced by gonadotrope cells in the anterior pituitary gland [4]. FSH and LH regulate the secretion of sex steroid hormones from the gonads by binding to their specific receptors, follicle-stimulating hormone receptor (FSHR) and luteinising hormone receptor (LHCGR), respectively [5,6]. FSHR is predominantly expressed on the granulosa and ovarian surface epithelium (OSE) and when activated induces follicular growth and development, as well as the secretion of estrogen and the conversion of androgen to estrogen [5,6,7]. In postmenopausal women, sex steroid hormone production is reduced and the lack of negative feedback on FSH and LH production can lead to a chronic elevation of these hormones [9].

Methods

Results

Conclusion