ABSTRACT
Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment (TME). Previous studies have shown that TAMs play a dual role in the development of colorectal cancer and promote the additional exploration of the immune escape of colorectal cancer. Studies have confirmed that macrophages utilize amino acid metabolism under the stimulation of some factors released by tumor cells, thus affecting the direction of polarization. Therefore, we investigated the effect of amino acid metabolism on macrophage function and the involved mechanism. Based on the comprehensive analysis of the GSE18804 GEO dataset and amino acid metabolism pathway, we identified the eight key enzymes of amino acid metabolism in colon TAMs, namely, ACADM, ACADS, GPX4, GSR, HADH, HMGCL, HMGCS1 and IDH1. We then evaluated the expression, survival analysis and relationship of clinicopathological features with these eight key enzymes. The results supported the critical role of these eight genes in colorectal cancer. Macrophages phagocytose tumor cells, and these eight key enzymes were identified in combination with GPX4, a critical protein of ferroptosis, suggesting that the change in the expression of these eight key enzymes in TAMs may be involved in the regulation of colorectal cancer through cell death. Correlation analysis of three programmed cell death (PCD) marker genes indicated that these eight key enzymes may cause macrophage death through pyroptosis, leading to immune escape of colorectal cancer. We also investigated the regulation of ACADS in CRC using flow cytometry, qPCR and ELISAs, which demonstrated that an ACADS deficiency polarizes TAMs to M2 macrophages. In summary, the present study revealed the relationship between amino acid metabolism and the cell death of macrophages, providing a new research direction for the molecular mechanism of macrophage polarization.
Subject(s)
Colorectal Neoplasms , Tumor-Associated Macrophages , Humans , Tumor-Associated Macrophages/pathology , Cell Line, Tumor , Macrophages/metabolism , Colorectal Neoplasms/pathology , Amino Acids/metabolism , Tumor MicroenvironmentABSTRACT
Tumor metastasis is a fundamental cause of the poor prognosis of gastric carcinoma (GC). In order to study the problems affecting metastasis and recurrence of gastric cancer, the paper expose that TNF alpha induced protein 6 (TNFAIP6) is aberrantly overexpressed in GC, and patients with high-TNFAIP6 levels exhibited inferior overall survival. Mechanistically, overexpression of TNFAIP6 raised ß-catenin ectopic nuclear distribution and activated the Wnt/ß-catenin signal pathway. The experimental results show that TNFAIP6 facilitates the aggressive potential of GC cells through modulating PTX3 expression.
Subject(s)
C-Reactive Protein , Carcinoma , Serum Amyloid P-Component , Stomach Neoplasms , Tumor Necrosis Factor-alpha , Wnt Signaling Pathway , C-Reactive Protein/metabolism , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , Cell Movement/physiology , Cell Proliferation/physiology , Humans , Neoplasm Metastasis , Serum Amyloid P-Component/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Tumor Necrosis Factor-alpha/metabolism , beta Catenin/metabolismABSTRACT
BACKGROUND: Emerging studies have indicated that circular RNAs (circRNAs) play important roles in the development of many tumors. CircRNA-scavenger receptor class B member 1 (Circ-SCARB1) was consistently reported as an elevated circRNA in RCC tissues. This study focused on examining the biological function and molecular mechanism of circSCARB1 in RCC progression. METHODS: Expressions of Circ-SCARB1, microRNA (miR)-510-5p, and syndecan 3 (SDC3) were detected using a quantitative real-time polymerase chain reaction (RT-PCR) and/or western blot. Cell proliferation and apoptosis were measured by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-diphenytetrazoliumromide and flow cytometry, respectively. Cell migration and invasion were measured using Transwell assays. The interaction between miR-510-5p and Circ-SCARB1 or SDC3 was verified using dual-luciferase reporter assays. RESULTS: Circ-SCARB1 was elevated in 30 pairs of RCC tissues and multiple RCC cell lines. Knockdown of Circ-SCARB1 inhibited cell proliferation, migration, and invasion while inducing cell apoptosis. MiR-510-5p was confirmed to be a target of Circ-SCARB1; inhibition of cell progression by silencing Circ-SCARB1 was mediated by a direct interaction between Circ-SCARB1 and miR-510-5p. SDC3 was verified to be a gene target of miR-510-5p; transfection of miR-510-5p mimic not only suppressed the expression of SDC3 but also the cell proliferation and an SDC3 cotransfection partially restored cell proliferation. Additionally, the genetic knockdown of Circ- SCARB1 reduced the expression SDC3, and the addition of anti-miR-510-5p could partially reelevate SDC3 expression. CONCLUSION: Circ-SCARB1 promotes RCC progression via sequestering miR-510-5p and indirectly up-regulating SDC3 expression. This provides a novel perspective for the pathogenesis of RCC and potential therapeutic targets for the treatment of RCC.
