An Immunohistochemical Study of β-catenin Expression and Immune Cell Population in Metastatic Carcinoma to the Liver.
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ABSTRACT:
SUBMITTER: Au KY
PROVIDER: S-EPMC8262218 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As a key enzyme in de novo pyrimidine biosynthesis, the expression level of dihydroorotate dehydrogenase (DHODH) has been reported to be elevated in various types of malignant tumors and its tumor-promoting effect was considered to relate to its pyrimidine synthesis function. Here, we revealed one intriguing potential mechanism that DHODH modulated β-catenin signaling in esophageal squamous cell carcinoma (ESCC). We demonstrated that DHODH directly bound to the NH2 terminal of β-catenin, thereby, interrupting the interaction of GSK3β with β-catenin and leading to the abrogation of β-catenin degradation and accumulation of β-catenin in the nucleus, which in turn, resulted in the activation of β-catenin downstream genes, including CCND1, E2F3, Nanog, and OCT4. We further demonstrated that the regulation of β-catenin by DHODH was independent of DHODH catalyzing activity. Univariate and multivariate analyses suggested that DHODH expression might be an independent prognostic factor for ESCC patients. Collectively, our study highlights the pivotal role of DHODH mediated β-catenin signaling and indicates that DHODH may act as a multi-functional switcher from catalyzing pyrimidine metabolism to regulating tumor-related signaling pathways in ESCC.
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Project description:BackgroundInflammation is believed to influence human colorectal carcinogenesis and may have an impact on prognosis and survival. The mucosal immunophenotype in dogs with colorectal cancer is poorly described. The aim of this study was to investigate whether the density, distribution and grade of tumor-infiltrating immune cells (TIIs) are different in normal colonic tissue vs benign stages (adenomas) and malignant stages (adenocarcinomas) of canine colorectal carcinogenesis, and thus, whether they can be considered as prognostic factors in dogs. This retrospective case-control study was performed on formalin-fixed, paraffin-embedded tissue samples from dogs with histologically confirmed colorectal adenoma (n = 18) and adenocarcinoma (n = 13) collected from archived samples. The samples had been collected by colonoscopy, surgery or during postmortem examination. Healthy colonic tissue obtained post mortem from dogs euthanized for reasons not involving the gastrointestinal tract served as control tissue (n = 9).ResultsThe tumor samples had significantly lower numbers of CD3+ T-cells in the epithelium compared to controls (adenocarcinoma vs control, Kruskal-Wallis test, p = 0.0004, and adenoma vs control, p = 0.002). Adenomas had a significantly lower number of CD18+ cells in the lamina propria, compared to control samples (Kruskal-Wallis test, p = 0.008). Colonic samples from control dogs had uniform staining of β-catenin along the cell membrane of epithelial cells. Compared to normal colonic cells, the expression levels of cytoplasmic β-catenin were significantly higher in adenomas and adenocarcinomas (adenoma vs control Kruskal-Wallis test, p = 0.004, and adenocarcinoma vs control, p = 0.002). None of the control samples showed positive staining of β-catenin in the nucleus of colonic cells. In contrast, adenocarcinomas and adenomas showed moderate to strong staining of the cell nucleus. The nuclear β-catenin expression (signal strength and distribution) was significantly higher in adenomas compared to adenocarcinomas (Kruskal-Wallis test, p < 0.05).Conclusionsβ-catenin and Ki67 were not useful markers for demonstrating tumor progression from adenomas to adenocarcinomas. The lower presence of CD18 and CD3+ cells in colorectal tumors compared to controls indicates a reduced presence of histiocytes and T-cells, which may have implications for the pathogenesis and progression of colorectal cancer in dogs.
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