Cancer is a leading cause of death worldwide. Understanding the functional mechanisms associated with metabolic reprogramming, which is a typical feature of cancer cells, is key to effective therapy. CD38, primarily a NAD+glycohydrolase and ADPR cyclase, is a multifunctional transmembrane protein whose abnormal overexpression in a variety of tumor types is associated with cancer progression. It is linked to VEGFR2 mediated angiogenesis and immune suppression as it favors the recruitment of suppressive immune cells like Tregs and myeloid-derived suppressor cells, thus helping immune escape. CD38 is expressed in M1 macrophages and in neutrophil and T cell-mediated immune response and is associated with IFNγ-mediated suppressor activity of immune responses. Targeting CD38 with anti-CD38 monoclonal antibodies in hematological malignancies has shown excellent results. Bearing that in mind, targeting CD38 in other nonhematological cancer types, especially carcinomas, which are of epithelial origin with specific anti-CD38 antibodies alone or in combination with immunomodulatory drugs, is an interesting option that deserves profound consideration.

Vanadium is an air pollutant that imparts immunosuppressive effects on NK cell immune responses, in part, by dysregulating interleukin (IL)-2/IL-2R-mediated JAK signaling pathways and inducing apoptosis. The aim of the present study was to evaluate effects of vanadium pentoxide (V₂O₅) on other IL-2 receptor-mediated signaling pathways, i.e. PI3K-AKT-mTOR and Ras-MAPK. Here, IL-2-independent NK-92MI cells were exposed to different V₂O₅ doses for 24 h periods. Expression of PI3K, Akt, mTOR, ERK1/2, MEK1, PTEN, SHP1, BAD and phosphorylated forms, as well as caspases-3, -8, -9, BAX and BAK in/on the cells were then determined by flow cytometry. The results show that V₂O₅ was cytotoxic to NK cells in a dose-related manner. Exposure increased BAD and pBAD expression and decreased that of BAK and BAX, but cell death was not related to caspase activation. At 400 µM V₂O₅, expression of PI3K-p85 regulatory subunit increased 20% and pPI3K 50%, while that of the non-pPI3K 110α catalytic subunit decreased by 20%. At 200 μM, V₂O₅ showed significant decrease in non-pAkt expression (p < 0.05); the decrease in pAkt expression was significant at 100 μM. Non-pmTOR expression displayed a significant downward trend beginning at 100 μM. Expressions of pMEK-1/2 and pERK-1/2 increased substantially at 200 μM V₂O₅. No differences were found with non-phosphorylated ERK-1/2. PTEN expression increased significantly at 100 μM V₂O₅ exposure whereas pPTEN decreased by 18% at 25 μM V₂O₅ concentrations, but remained unchanged thereafter. Lastly, V₂O₅ at all doses decreased SHP1 expression and increased expression of its phosphorylated form. These results indicated a toxic effect of V₂O₅ on NK cells that was due in part to dysregulation of signaling pathways mediated by IL-2 via increased PTEN and decreased SHP1 expression. These results can help to explain some of the known deleterious effects of this particular form of vanadium on innate immune responses_.

(1) Abnormally increased expression of claudin-6 in gastric cancer is considered a prognostic marker of the chromosomal unstable molecular subtype. However, a detailed molecular profile analysis of differentially expressed genes and affected pathways associated with claudin-6 increased (Cldn6^high) expression has not been assessed. (2) The TCGA Stomach Adenocarcinoma Pan-Cancer Atlas Data was evaluated using Cytoscape’s Gene Mania, MCODE, and Cytohubba bioinformatic software. (3) 96.88% of Cldn6^high gastric cancer tumors belonging to the chromosomal unstable molecular subtype are associated with a worse prognosis. Cldn6expression coincided with higher mutations in TP53, MIEN1, STARD3, PGAP3, and CCNE1 genes compared to Cldn6^low expression. In Cldn6^high cancers, 1316 genes were highly expressed. Cholesterol metabolism was the most affected pathway as APOA1, APOA2, APOH, APOC2, APOC3, APOB-100, LDL receptor-related protein 1/2, Sterol O-acyltransferase, STARD3, MAGEA-2, -3, -4, -6, -9B, and -12 genes were overexpressed in Cldn6^high gastric cancers; interestingly, APOA2 and MAGEA9b were identified as top hub genes. Functional enrichment of DEGs linked HNF-4α and HNF-1α genes as highly expressed in Cldn6^high gastric cancer. (4) Our results suggest that APOA2 and MAGEA9b could be considered as prognostic markers for Cldn6^high gastric cancers.

Aberrant expression of the tight junction protein claudin 6 (CLDN6) is a hallmark of gastric cancer progression. Its expression is regulated by the cAMP response element-binding protein (CREB). In gastric cancer induced by Helicobacter pylori (H. pylori) there is no information regarding what transcription factors induce/upregulate the expression of CLDN6. We aimed to identify whether CREB and Yin Yang1 (YY1) regulate the expression of CLDN6 and the site where they bind to the promoter sequence. Bioinformatics analysis, H. pylori lipopolysaccharide (LPS), YY1 and CREB silencing, Western blot, luciferase assays, and chromatin immunoprecipitation experiments were performed using the stomach gastric adenocarcinoma cell line AGS. A gen reporter assay suggested that the initial 2000 bp contains the regulatory sequence associated with CLDN6 transcription; the luciferase assay demonstrated three different regions with transcriptional activity, but the −901 to −1421 bp region displayed the maximal transcriptional activity in response to LPS. Fragment 1279–1421 showed CREB and, surprisingly, YY1 occupancy. Sequential Chromatin Immunoprecipitation (ChIP) experiments confirmed that YY1 and CREB interact in the 1279–1421 region. Our results suggest that CLDN6 expression is regulated by the binding of YY1 and CREB in the 901–1421 enhancer, in which a non-described interaction of YY1 with CREB was established in the 1279–1421 region.