Pharmacological inhibition of IRAK1 attenuates colitis‐induced tumorigenesis in mice by inhibiting the inflammatory response and epithelial–mesenchymal transition

2021 ◽  
Author(s):  
Zeyu Feng ◽  
Zhenglan Duan ◽  
Guoping Shi ◽  
Qiong Wang ◽  
Jinyong Zhou ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Pharmacological Inhibition

scholarly journals Epithelial Transcription Factor FOXA1 Regulates Prostate Cancer Immune Response

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1017-A1017
Author(s):  
Lourdes T Brea ◽  
Xiaohai Wang ◽  
Jindan Yu
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
Transcription Factor ◽  
Inflammatory Response ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Macrophage Infiltration ◽  
Dependent Manner ◽  
Rna Seq ◽  
Mesenchymal Transition

Abstract Background : While localized prostate cancer (PCa) can be mitigated by surgery and radiation, metastatic PCa remains a challenge to treat. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors are mainstay treatments for advanced PCa. Yet, resistance often develops leading to castration-resistant prostate cancer (CRPC). Forkhead Box A1 (FOXA1) is a pioneer transcription factor that plays pivotal roles in regulating AR activity and promoting epithelial differentiation. Studies have shown that FOXA1 is frequently downregulated in CRPC tumors. Congruently, FOXA1 loss is reported to induce aberrant AR signaling, epithelial-mesenchymal transition, and PCa de-differentiation. However, the role of FOXA1 in regulating PCa immune response, an area of much interest recently, has not been reported. CRPC has shown poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. A better understanding of the tumor intrinsic mechanisms regulating PCa tumor immunity will inform the design of better targeted immunotherapeutic approaches. Methods: We performed RNA-seq, ChIP-seq, qPCR, western blot, and ELISA analyses to evaluate how FOXA1 regulates inflammatory response genes. We utilized an in vitro macrophage infiltration transwell assay, in which M2-like macrophages were added to the upper chamber and PCa cells were plated in the lower chamber, to examine how perturbations to PCa cells affect macrophage migration. Finally, we performed bioinformatic analyses of patient datasets to confirm the clinical relevance of FOXA1 repression of inflammatory genes in PCa. Results: Through integration of RNA-seq and ChIP-seq data, we uncovered a novel function of FOXA1 in suppressing inflammatory response pathways. In accordance, patient data analyses revealed that inflammatory response genes were upregulated in FOXA1-low PCa tumors. Mechanistically, we showed that FOXA1 proteins bound an intragenic enhancer of Hypoxia-inducible factor 1-alpha (HIF1A) gene to directly repress its expression, such that FOXA1 loss induced HIF1A upregulation. We further showed that Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) became upregulated upon FOXA1 depletion in a HIF1A-dependent manner. This led to infiltration by immunosuppressive, tumor promoting M2-like macrophages. Inhibiting this HIF1A-CCL2 axis with a HIF1A inhibitor or CCL2 neutralizing antibody blocked macrophage infiltration. Future studies using immunocompetent mouse models are needed to confirm the effect of FOXA1 on macrophage infiltration in vivo and evaluate the preclinical potential of targeting the FOXA1-HIF1A-CCL2 axis in CRPC. Conclusion: This study proposes a novel role for FOXA1 loss in promoting macrophage infiltration via the HIF1A-CCL2 axis. Moreover, our findings suggest that targeting this axis may be a promising approach for the treatment of FOXA1-low CRPC tumors.

scholarly journals Epithelial injury induces an innate repair mechanism linked to cellular senescence and fibrosis involving IGF-binding protein-5

2008 ◽  
Vol 199 (2) ◽  
pp. 155-164 ◽  
Author(s):  
Gordon J Allan ◽  
James Beattie ◽  
David J Flint
Keyword(s):  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Binding Protein ◽  
Transforming Growth Factor Β1 ◽  
Epithelial Injury ◽  
Mesenchymal Transition ◽  
Life Threatening ◽  
Igf Binding ◽  
Igf Binding Protein

Fibrosis is associated with epithelial repair. It involves the activation of fibroblasts, increased production of extracellular matrix proteins and transdifferentiation to contractile, myofibroblasts that aid in wound contraction. This provisional matrix plugs the injured epithelium and provides a scaffold for epithelial cell migration, involving an epithelial–mesenchymal transition (EMT). When epithelial injury involves blood loss, this leads to platelet activation, the production of several growth factors and an acute inflammatory response. Under normal circumstances, the epithelial barrier is repaired and the inflammatory response resolves. However, in fibrotic disease, the fibroblast response continues, resulting in unresolved wound healing. The fibrotic diseases range from scleroderma, where the problem may be restricted to the skin and where it is not life-threatening, through to systemic forms that can manifest as, for example, idiopathic pulmonary fibrosis, in which death is inevitable within 3–5 years. Anti-inflammatory treatments have failed to ameliorate the disease condition and focus has instead turned to transforming growth factor-β1 (TGFB1), since it induces many of the processes involved, including fibroblast activation and EMT. Most recently, however, a new player in this process has been described, IGF-binding protein-5 (IGFBP5). IGFBP5 has also been shown to induce similar effects to TGFB1, but, in addition, it is strongly implicated in the process of senescence which is now believed to be a significant factor in these diseases. We examine the evidence for this role of IGFBP5 and identify some of the therapeutic targets which might be used to ameliorate these diseases of unknown cause.

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