Involvement of Hormone Receptors, Membrane Receptors and Signaling Pathways in European Gastric Cancers Regarding Subtypes and Epigenetic Alterations: A Pilot Study

<b>Background</b>: Gastric cancer (GC) is a highly heterogeneous disease and remains one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including diffuse and intestinal GC that may differ in their incidence between Asian and non-Asian cohorts. The intestinal-subtype GC has declined over the past 50 years. In contrast to the intestinal-subtype adenocarcinoma, the incidence of diffuse-subtype GC, often associated with poor overall survival, has constantly increased in the USA and Europe. The aim of this study was to analyze the expression and clinical significance of steroid hormone receptors, two membrane-bound receptors (<i>ERRγ</i> and <i>GPER</i>), and several genes involved in epigenetic alterations. The findings may contribute to revealing events driving tumorigenesis and may aid prognosis. <b>Methods</b>: Using mRNA from diffuse and intestinal GC tumor samples, the expression level of 11 genes, including those coding for sex hormone receptors (estrogen receptors <i>ERα</i> and <i>ERβ</i>), progesterone receptor (<i>PR</i>) and androgen receptor (<i>AR</i>), and the putative relevant <i>ERRγ</i> and <i>GPER</i> receptor were determined by RT-qPCR. <b>Results</b>: In diffuse GC, the expression of <i>ERα</i>, <i>ERβ</i>, <i>PR</i> and <i>AR</i> differed from their expression in the intestinal subtype. The expression of <i>ERα</i> and <i>ERβ</i> was strongly increased in the diffuse subtype compared to the intestinal subtype (×1.90, <i>p</i> = 0.001 and ×2.68, <i>p</i> = 0.002, respectively). Overexpression of <i>ERα</i> and <i>ERβ</i> was observed in diffuse GC (15 and 42%, respectively). The expression levels of <i>PR</i> and <i>AR</i> were strongly decreased in the intestinal subtype as compared to diffuse GC (×0.48, <i>p =</i> 0.005 and ×0.25, <i>p</i> = 0.003, respectively; 37.5% and 56% underexpression). <i>ERα</i>, <i>ERβ</i>, <i>PR</i> and <i>AR</i> showed notable differences for clinicopathological correlation in the diffuse and intestinal GC. A significant decrease of <i>ERα</i>, <i>ERβ</i>, <i>PR</i> and <i>AR</i> in intestinal GC correlated with the absence of lymphatic invasion and lower TNM (I-II). In diffuse GC, among the hormone receptors, increases of <i>ERs</i> and <i>PR</i> mainly correlated with expression of growth factors and receptors (<i>IGF1</i>, <i>FGF7</i> and <i>FGFR1</i>), and with genes involved in epithelial-mesenchymal transition (<i>VIM</i> and <i>ZEB2</i>) or cell migration (<i>MMP2</i>). Our results also report the strong decreased expression of <i>ERRγ</i> and <i>GPER</i> (two receptors that bind estrogen or xenoestrogens) in diffuse and intestinal subtypes. <b>Conclusions</b>: Our study identified new target genes, namely hormone receptors and membrane receptors (<i>ERRγ</i> and <i>GPER</i>), whose expression is associated with an aggressive phenotype of diffuse GC, and revealed the importance of epigenetic factors (<i>EZH2</i>, <i>HOTAIR</i>, <i>H19</i> and <i>DNMT1</i>) in gastric cancers.