Towards understanding leydigioma: do G protein-coupled estrogen receptor and peroxisome proliferator–activated receptor regulate lipid metabolism and steroidogenesis in Leydig cell tumors?

Abstract

Leydig cell tumors (LCT) are the most common type of testicular stromal tumor. Herein, we investigate the G protein-coupled estrogen receptor (GPER) and peroxisome proliferator-activated receptor (PPAR) implication in regulation of lipid homeostasis including the expression of steroidogenesis-controlling molecules in clinical specimens of LCTs and tumor Leydig cells (MA-10). We showed the general structure and morphology of LCTs by scanning electron and light microscopy. In LCTs, mRNA and protein analyses revealed increased expression of GPER and decreased expression of PPARα, β, and γ. Concomitantly, changes in expression pattern of the lutropin receptor (LHR), protein kinase A (PKA), perilipin (PLIN), hormone sensitive lipase (HSL), steroidogenic acute regulatory protein (StAR), translocator protein (TSPO), HMG-CoA synthase, and reductase (HMGCS, HMGCR) were observed. Using MA-10 cells treated with GPER and PPAR antagonists (alone and in combination), we demonstrated GPER-PPAR-mediated control of estradiol secretion via GPER-PPARα and cyclic guanosine monophosphate (cGMP) concentration via GPER-PPARγ. It is assumed that GPER and PPAR can crosstalk, and this can be altered in LCT, resulting in a perturbed lipid balance and steroidogenesis. In LCTs, the phosphatidylinositol-3-kinase (PI3K)-Akt-mTOR pathway was disturbed. Thus, PI3K-Akt-mTOR with cGMP can play a role in LCT outcome and biology including lipid metabolism.

Interstitial Leydig Cell Tumorigenesis—Leptin and Adiponectin Signaling in Relation to Aromatase Expression in the Human Testis

“…Low expression of peroxisome-proliferator activated receptor α, β, and γ (PPAR α, β, and γ) was confirmed in the Leydig cell tumor [28] and its regulation by adiponectin was confirmed [48]. Our recent findings showed different morphological types of Leydig cells present in tumor mass [28]. Herein, on ultrathin sections of the tumor, we confirmed also the presence of adipocyte-like cells.…”

“…In addition, adipokine signaling proteins were examined to define the role these hormones play and whether there is a potential interaction between adipokines and aromatase. This study is a continuation of our prior reported data [28,29] and provides further knowledge on the biology of Leydig cell tumors.…”

“…It was demonstrated that in the testis, adipokines regulate metabolism through both paracrine and autocrine action [46,47]. Low expression of peroxisome-proliferator activated receptor α, β, and γ (PPAR α, β, and γ) was confirmed in the Leydig cell tumor [28] and its regulation by adiponectin was confirmed [48]. Our recent findings showed different morphological types of Leydig cells present in tumor mass [28].…”

Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

“…Consequently, it was also observed that there are alterations in lipid-and cholesterol-associated proteins such as LHR, PKA, PLIN, HSL, StAR, TSPO, HMGCS, and HMGCR, together with the cGMP and PI3K-Akt-mTOR pathways. These changes of expression could be primary disturbances in healthy Leydig cell, and the study of these alterations could be useful to design a new therapeutic approach for Leydig cell tumors [134].…”

“…Testicular Physiology Testicular Tumors SPG GPER activation induces proliferation [84][85][86] GPER is overexpressed in seminoma and embryonal carcinoma [119], (whereas ERα is missing [120]) GPER mediates estrogen and xenoestrogen-dependent proliferation in seminomas [123][124][125]128,129] SPT GPER activation induces apoptosis [31,32,88] RS GPER activation induces apoptosis [30] LC GPER is involved in: LC morphology and function [38] LCT [where ERα is overexpressed]: GPER activation decrease cell proliferation and induces apoptosis [130] Xenoestrogens decrease GPER expression favoring LCT progression [133] GPER is involved in LCT control of lipid metabolism and steroidogenesis (interaction with PPAR) [134] LC androgens production [40] LC lipophagy inhibition [43] LC miRNA biogenesis [49] LC development and function [PPAR crosstalk] [46] SC GPER activation induces proliferation in immature testis [65][66][67][68] Sertoli cell tumors: GPER is expressed but the role has been not identified. In interstitial compartment, GPER appears to play an important role in regulating estrogen-dependent lipid homeostasis and testosterone biosynthesis that occur in Leydig cells.…”