STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells

Garrido‐Tapia, Macarena; Hernández, Carolina; Ascui, Gabriel; Kramm, Karina; Morales, Marcela; Gárate, Valentina; Zúñiga, Roberto Ariel Abeldaño; Bustamante, Marco; Aguillón, Juan Carlos; Catalán, Diego; Ribeiro, Carolina; Molina, Marı́a

doi:10.1016/j.imbio.2017.05.009

Cited by 16 publications

(13 citation statements)

References 38 publications

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“…Discrepancy effects of STAT‐3 inhibitors on MIC‐A and MIC‐B expression were previously reported in cancer cells; thus, Garrido‐Tapia et al. recently published that STAT3 inhibition by Stat21 increases the cell‐surface expression of MIC‐B, but had no effect on MIC‐A in gastric adenocarcinoma cells, whereas Stat21 affects MIC‐A and MIC‐B expression in colorectal adenocarcinoma cells , but with little or no effect on MIC‐B and myeloma cells . This suggests that the role of STAT3 inhibition on MIC‐A and/or MIC‐B expression perhaps could be dependent on the pathology.…”

Section: Discussionmentioning

confidence: 89%

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

et al. 2019

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Dengue virus (DENV) is the most widespread arbovirus worldwide and is responsible for major outbreaks. The host's immune response plays a crucial role in controlling this infection but might also contribute to the promotion of viral spread and immunopathology. In response to DENV infection, NK cells preferentially produce cytokines and are cytotoxic in the presence of specific antibodies. Here, we identified that DENV‐2 inhibits glycogen synthase kinase 3 (GSK‐3) activity to subsequently induce MHC class‐1‐related chain (MIC) A and MIC‐B expression and IL‐12 production in monocyte‐derived DCs, independently of the STAT‐3 pathway. The inhibition of GSK‐3 by DENV‐2 or small molecules induced MIC‐A/B expression on monocyte‐derived DCs, resulting in autologous NK cells of a specific increase in IFN‐γ and TNF‐α production, in the absence of direct cytotoxicity. Together, these findings identified GSK‐3 as a regulator of MIC‐A/B expression and suggested its role in DENV‐2 infection to specifically induce cytokine production by NK cells.

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Section: Discussionmentioning

confidence: 89%

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

et al. 2019

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“…Moreover, MFGE8, an anti-fibrotic protein which is secreted by mesenchymal stem cells, could strongly inhibit TGF-β signaling pathway and reduce deposition of extracellular matrix (35). Moreover, primary gastric adenocarcinoma tissue could release soluble MICB into the extracellular milieu and induce a significant decrease in the levels of NKG2D receptor on effector natural killer cells and CD8+ T cells, correlating with an impaired cytotoxic function (36,37). Furthermore, CXCL12/CXCR4 derived from cancer-associated fibroblasts (CAFs) can promote invasion of GC cells by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression (38), and cross-talk between CXCR4 and CXCR2 might contribute to epithelial-mesenchymal transition, migration and invasion of GC (39).…”

Section: Discussionmentioning

confidence: 99%

Immune signature profiling identified prognostic factors for gastric cancer

Yang

Lai

et al. 2019

Chinese Journal of Cancer Research

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Objective Tumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer (GC) has not been reported. Methods Expressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma (STAD) patients from The Cancer Genome Atlas (TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well. Results Survival analyses revealed 73 genes, which were significantly associated with patient’s overall survival (OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1 , C6 , CXCR4 , LBP , PNMA1 , TLR5 , ITGA6 , MICB , PBK and TNFRSF18 , with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1 , TGFβ2 and MFGE8 , were also significantly associated with patient’s OS by an independent validation achieved from Kaplan-Meier plotter database. Conclusions We profiled prognostic immune signature and established prognostic predictive model for GC, which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.

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“…STAT3 executes anti-autophagic functions by upregulating negative regulators of autophagy, such as MCL1, PIK3R1/ p55a, and PIK3R1/p50a [26], and by downregulating essential autophagy genes, such as BECN1 and PIK3C3 [57]. Moreover, STAT3 negatively regulates gene expression in MEFs and cancer lines to control type I IFN-mediated antiviral response [58][59][60]. In fact, a whole-transcriptome profiling study showed that STAT3 acts as a transcriptional activator and suppressor, with a comparable number of upregulated and downregulated genes in diffuse large B cell lymphoma (DLBCL) cells [61].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic effects of inhibition of mTORC1/STAT3 axis facilitates Staphylococcus aureus-induced pyroptosis in human macrophages

et al. 2020

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Background Pyroptosis is a recently identified pathway of caspase-mediated cell death in response to microbes, lipopolysaccharide, or chemotherapy in certain types of cells. However, the mechanism of how pyroptosis is regulated is not well-established. Methods Herein, the intracellular bacteria were detected by staining and laser confocal microscopy and TEM. Live/dead cell imaging assay was used to examine macrophage death. Western blot and immunohistochemical staining were used to examine the protein changes. IFA was used to identify typical budding vesicles of pyroptosis and the STAT3 nuclear localization. SEM was used to observe the morphological characteristics of pyroptosis. ELISA was used to detect the level of inflammatory cytokines. Pyroptosis was filmed in macrophages by LSCM. Results S. aureus was internalized by human macrophages. Intracellular S. aureus induced macrophage death. S. aureus invasion increased the expression of NLRP3, Caspase1 (Casp-1 p20) and the accumulation of GSDMD-NT, GSDMD-NT pore structures, and the release of IL-1β and IL-18 in macrophages. Macrophages pyroptosis induced by S. aureus can be abrogated by blockage of S. aureus phagocytosis. The pyroptosic effect by S. aureus infection was promoted by either rapamycin or Stattic, a specific inhibitor for mTORC1 or STAT3. Inhibition of mTORC1 or STAT3 induced pyroptosis. mTORC1 regulated the pyroptosic gene expression through governing the nuclear localization of STAT3. mTORC1/STAT3 axis may play a regulatory role in pyroptosis within macrophages. Conclusions S. aureus infection induces human macrophage pyroptosis, inhibition of mTORC1/STAT3 axis facilitates S. aureus-induced pyroptosis. mTORC1 and STAT3 are associated with pyroptosis. Our findings demonstrate a regulatory function of the mTORC1/STAT3 axis in macrophage pyroptosis, constituting a novel mechanism by which pyroptosis is regulated in macrophages.

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STAT3 inhibition by STA21 increases cell surface expression of MICB and the release of soluble MICB by gastric adenocarcinoma cells

Cited by 16 publications

References 38 publications

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Glycogen synthetase kinase 3 inhibition drives MIC‐A/B to promote cytokine production by human natural killer cells in Dengue virus type 2 infection

Immune signature profiling identified prognostic factors for gastric cancer

Pathogenic effects of inhibition of mTORC1/STAT3 axis facilitates Staphylococcus aureus-induced pyroptosis in human macrophages

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