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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. AhR and RHOA 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, CYP1A1 expression correlated with genes involved in IGF signaling, epithelial–mesenchymal transition (Vimentin), and migration (MMP2). 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 CYP1A1 and Interleukin1β (IL1B), and to a lesser extend UGT1, NQO1, and AhR Repressor (AhRR). Moreover, the increased expression of CYP1B1 was seen in diffuse GC, and IHC staining indicated that CYP1B1 is mainly expressed in stromal cells. TCDD treatment increased CYP1B1 expression in KATO III cells, although at lower levels as compared to CYP1A1. In intestinal GC, CYP1B1 expression is inversely correlated with several cancer-related genes such as IDO1, 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.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults and reveals distinct genetic and metabolic signatures. NF-κB transcription factor family is involved in diverse biological processes enabling tumor development and resistance to anticancer-therapy through activation of its two main pathways, the canonical and the alternative NF-κB pathways, the main actor of the latter being the RelB NF-kB subunit. RelB DNA binding activity is frequently activated in DLBCL patients and cell lines. RelB activation defines a new DLBCL subgroup with dismal outcome upon immunochemotherapy, and RelB confers DLBCL cell resistance to DNA damage. However, whether RelB can impact on DLBCL cell metabolism and survival upon metabolic stress is unknown. Here, we reveal that RelB controls DLBCL oxidative energetic metabolism. Accordingly, RelB inhibition reduce DLBCL mitochondrial ATP production, and sensitizes DLBCL cells to apoptosis induced by Metformin and L-asparaginase (®Kidrolase), two FDA approved antimetabolic drugs targeting mitochondrial metabolism. RelB also confers DLBCL cell resistance to glutamine deprivation, an essential amino acid that feeds the TCA cycle. Taken together, our findings uncover a new role for RelB in the regulation of DLBCL cell metabolism and DLBCL cell survival upon metabolic stress.

Gastric cancer (GC) is one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GCs, often associated with poor overall survival, has constantly increased in USA and Europe The molecular basis of diffuse GC aggressivity remains unclear. Using mRNA from diffuse and intestinal GC tumor samples of a Western cohort, this study reports the expression level of the immunomodulatory aryl-hydrocarbon receptor (AhR), and genes involved in immune suppression (PD1, PD-L1, PD-L2) and the early steps of tryptophan metabolism (IDO1, IDO2, TDO2). Strongly increased expression of IDO1 (p < 0.001) and PD1 (p < 0.003) was observed in the intestinal sub-type. The highest expression of IDO1 and PDL1 correlated with early clinical stage and absence of lymphatic invasion (×25 p = 0.004, ×3 p = 0.04, respectively). Our results suggest that kynurenine, produced by tryptophan catabolism, and AhR activation play a central role in creating an immunosuppressive environment. Correspondingly, as compared to intestinal GCs, expression levels of IDO1-TDO2 and PD-L1 were less prominent in diffuse GCs which also had less infiltration of immune cells, suggesting an inactive immune response in the advanced diffuse GC. Confirmation of these patterns of gene expression will require a larger cohort of early and advanced stages of diffuse GC samples.