Perrot-Applanat Martine, Pimpie Cynthia, Vacher Sophie, Pocard Marc, Baud Véronique
INSERM U1275, Peritoneal Carcimomatosis Paris-Technologies, Hôpital Lariboisiere, Université Paris Cité, 75010 Paris, France.
Department of Genetics, Curie Institute, PSL Research University, 75005 Paris, France.
Biomedicines. 2024 Aug 20;12(8):1905. doi: 10.3390/biomedicines12081905.
The vast majority of gastric cancer (GC) cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GC, often associated with poor overall survival, has constantly increased in Western countries. Epidemiological studies have reported increased mortality from GC after occupational exposure to pro-carcinogens that are metabolically activated by cytochrome P450 enzymes through aryl hydrocarbon receptor (AhR). However, little is known about the role of AhR and environmental AhR ligands in diffuse GC as compared to intestinal GC in Western patients. In a cohort of 29, we demonstrated a significant increase in AhR protein and mRNA expression levels in GCs independently of their subtypes and clinical parameters. and mRNA expression were correlated in diffuse GC. Further, our study aimed to characterize in GC how AhR and the AhR-related genes cytochrome P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) affect the mRNA expression of a panel of genes involved in cancer development and progression. In diffuse GC, expression correlated with genes involved in IGF signaling, epithelial-mesenchymal transition (), and migration (). Using the poorly differentiated KATO III epithelial cell line, two well-known AhR pollutant ligands, namely 2-3-7-8 tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (BaP), strongly increased the expression of and (), and to a lesser extend , and (). Moreover, the increased expression of was seen in diffuse GC, and IHC staining indicated that CYP1B1 is mainly expressed in stromal cells. TCDD treatment increased expression in KATO III cells, although at lower levels as compared to . In intestinal GC, expression is inversely correlated with several cancer-related genes such as , a gene involved in the early steps of tryptophan metabolism that contributes to the endogenous AhR ligand kynurenine expression. Altogether, our data provide evidence for a major role of AhR in GC, as an environmental xenobiotic receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support the continued efforts to clarify the identity of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies.
绝大多数胃癌（GC）病例为腺癌，包括肠型和弥漫型GC。弥漫型GC的发病率在西方国家持续上升，且往往与总体生存率较低相关。流行病学研究报告称，职业性接触经细胞色素P450酶通过芳烃受体（AhR）代谢激活的致癌物后，GC死亡率有所上升。然而，与西方患者的肠型GC相比，AhR和环境AhR配体在弥漫型GC中的作用知之甚少。在一个29例的队列中，我们证明GC中AhR蛋白和mRNA表达水平显著增加，与它们的亚型和临床参数无关。并且在弥漫型GC中，mRNA表达是相关的。此外，我们的研究旨在表征在GC中AhR以及与AhR相关的基因细胞色素P450 1A1（CYP1A1）和P450 1B1（CYP1B1）如何影响一组参与癌症发生和进展的基因的mRNA表达。在弥漫型GC中，表达与参与胰岛素样生长因子信号传导、上皮-间质转化（）和迁移（）的基因相关。使用低分化的KATO III上皮细胞系，两种著名的AhR污染物配体，即2-3-7-8四氯二苯并对二恶英（TCDD）和苯并[a]芘（BaP），强烈增加了和（）的表达，并在较小程度上增加了、和（）的表达。此外，在弥漫型GC中观察到表达增加，免疫组化染色表明CYP1B1主要在基质细胞中表达。TCDD处理增加了KATO III细胞中的表达，尽管与相比水平较低。在肠型GC中，表达与几个癌症相关基因呈负相关，例如，该基因参与色氨酸代谢的早期步骤，有助于内源性AhR配体犬尿氨酸的表达。总之，我们的数据证明AhR在GC中作为环境异源生物受体通过不同机制和途径在弥漫型和肠型GC中发挥主要作用。我们的结果支持继续努力阐明弥漫型GC中外源性AhR配体的身份，以确定新的治疗策略。
