Dataset Information

Gastric Cancer Cell-Derived Kynurenines Hyperactive Regulatory T Cells to Promote Chemoresistance via the IL-10/STAT3/BCL2 Signaling Pathway.

ABSTRACT: Chemotherapy resistance is frequently observed in gastric cancer patients and is associated with poor prognosis; tryptophan (Trp) catabolism has been recognized as a key metabolic regulator of many types of cancer progression. Regulatory T cells (Tregs) and Trp metabolite kynurenine (Kyn) were analyzed using tumor tissues. Chemotherapy resistance induced by IL-10 or Treg was detected by flow cytometry assay. The activation of STAT3/BCL2 signaling pathways in gastric cells cocultured by Treg was illustrated by western blotting. Patients' Treg and human gastric cancer organoid model were established to examine the anticancer effects of STAT3 inhibitor. We found that a higher level of IL-10 secreted by Kyn-induced Tregs was responsible for the 5-fluorouracil-induced resistance of gastric cancer cell lines. STAT3 and BCL2 knockout significantly abrogated Treg supernatant- or IL-10-induced chemoresistance in SGC7901 and BGC823 cell lines. Furthermore, STAT3 inhibitor significantly reduced the organoid and clonogenicity of organoids cocultured with Treg. Our data suggested that tumor-derived Kyn may hyperactivate Tregs and induce chemoresistance through the IL-10/STAT3/BCL2 signaling pathway.

SUBMITTER: Wu D

PROVIDER: S-EPMC9063152 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Gastric Cancer Cell-Derived Kynurenines Hyperactive Regulatory T Cells to Promote Chemoresistance via the <i>IL-10/STAT3/BCL2</i> Signaling Pathway.

Wu Dandan D Wang Zhongli Z

DNA and cell biology 20220329 4

Chemotherapy resistance is frequently observed in gastric cancer patients and is associated with poor prognosis; tryptophan (Trp) catabolism has been recognized as a key metabolic regulator of many types of cancer progression. Regulatory T cells (Tregs) and Trp metabolite kynurenine (Kyn) were analyzed using tumor tissues. Chemotherapy resistance induced by IL-10 or Treg was detected by flow cytometry assay. The activation of <i>STAT3/BCL2</i> signaling pathways in gastric cells cocultured by Tr ...[more]

PMID: 35353612

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Project description:Background: Recently, the molecular classification of gastric cancer (GC) promotes the advances of GC patients' precision therapy and prognosis prediction. According to the Asian Cancer Research Group (ACRG), GC is classified as microsatellite instable (MSI) subtype GC, microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT) subtype GC, MSS/TP53- subtype GC, and MSS/TP53+ subtype GC. Due to the easy metastasis of EMT-subtype GC, it has the worst prognosis, the highest recurrence rate, and the tendency to occur at a younger age. Therefore, it is curious and crucial for us to understand the molecular basis of EMT-subtype GC. Methods: The expression of RHOJ was detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in GC cells and tissues. Western blotting and immunofluorescence (IF) were conducted to examine the effects of RHOJ on the EMT markers' expression of GC cells. The GC cells' migration and invasion were investigated by transwell assay. The tumor growth and metastasis were demonstrated correspondingly in different xenograft models. Results: Firstly, it was noticed that RHOJ was significantly upregulated in EMT-subtype GC and RHOJ has close relationships with the EMT process of GC, based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Next, transwell assay and tail vein metastasis models were conducted to verify that RHOJ mediates the EMT to regulate the invasion and metastasis of GC in vitro and in vivo. In addition, weakened tumor angiogenesis was observed after RHOJ knockdown by the angiogenesis assay of HUVEC. RNA-seq and further study unveiled that RHOJ aggravates the malignant progression of GC by inducing EMT through IL-6/STAT3 to promote invasion and metastasis. Finally, blocking the IL-6/STAT3 signaling overcame RHOJ-mediated GC cells' growth and migration. Conclusions: These results indicate that the upregulation of RHOJ contributes to EMT-subtype GC invasion and metastasis via IL-6/STAT3 signaling, and RHOJ is expected to become a promising biomarker and therapeutic target for EMT-subtype GC patients.

Dataset Information

Gastric Cancer Cell-Derived Kynurenines Hyperactive Regulatory T Cells to Promote Chemoresistance via the IL-10/STAT3/BCL2 Signaling Pathway.

Publications

Gastric Cancer Cell-Derived Kynurenines Hyperactive Regulatory T Cells to Promote Chemoresistance via the <i>IL-10/STAT3/BCL2</i> Signaling Pathway.

Similar Datasets

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