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The Role of Epithelial IKKβ in the Transition from Normal to Precancerous Tissue in Esophageal Epithelium

ABSTRACT: The Role of Epithelial IKKβ in the Transition from Normal to Precancerous Tissue in Esophageal Epithelium

PROVIDER: PRJNA1248913 | ENA |

REPOSITORIES: ENA

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The Role of Epithelial IKKβ in the Transition from Normal to Precancerous Tissue in Esophageal Epithelium

Project description:Esophageal cancer is the 6th leading cause of cancer related death with a 5-year survival rate of under 20%. Esophageal squamous cell carcinoma (ESCC) is associated with chronic inflammation and injury. Currently, little is understood about the molecular mechanisms regulating the early stages of esophageal carcinogenesis. The NFB/IKK pathway plays a central role in inflammation and has been implicated in ESCC. However, its functional role in the transition to esophageal precancer is unknown. To investigate this, we utilized ED-L2/Cre mice to knockout IKKβ (IKKβEEC-KO) in the esophagus. These mice and littermate controls were treated with the carcinogen 4-nitroquinoline-1-oxide (4-NQO) or a vehicle for one month. Esophagi were harvested and examined through histological, protein, flow cytometry, and RNA analyses. Histological analysis showed that 4-NQO treatment led to increased inflammation and intraepithelial CD45+ immune cells which was largely attenuated in IKKβEEC-KO mice. Total T cells, Tregs, CD4+, and CD8+ T cells showed a similar trend, while macrophages showed a reverse trend. RNAseq data showed upregulation of inflammatory pathways and downregulation in wound healing related pathways in 4-NQO treated control mice versus knockout. We also saw increased expression of the chemokine CXCL9, a T cell chemoattractant. This increase was blocked in 4-NQO treated IKKβEEC-KO mice or in mice treated with anti-IFN. Additionally, we demonstrated in vitro that IFN upregulates CXCL9 in a NF-ĸB dependent manner in esophageal keratinocytes. So epithelial IKK regulates the immune landscape in the transition to precancer through IFN/CXCL9 signaling and recruitment of T cells to the esophagus.

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Project description:Epithelial-mesenchymal transition (EMT), which is well known for its role in embryonic development, malignant transformation, and tumor progression, has also been implicated in a variety of retinal diseases, including proliferative vitreoretinopathy (PVR), age-related macular degeneration (AMD), and diabetic retinopathy. EMT of the retinal pigment epithelium (RPE), although important in the pathogenesis of these retinal conditions, is not well understood at the molecular level. We and others have shown that a variety of molecules, including the co-treatment of human stem cell-derived RPE monolayer cultures with transforming growth factor beta (TGF–β) and the inflammatory cytokine tumor necrosis factor alpha (TNF–α), can induce RPE–EMT; however, small molecule inhibitors of RPE–EMT have been less well studied. Here, we demonstrate that BAY651942, a small molecule inhibitor of nuclear factor kapa-B kinase subunit beta (IKKβ) that selectively targets NF-κB signaling, can modulate TGF–β/TNF–α-induced RPE–EMT. Next, we performed RNA-seq studies on BAY651942 treated hRPE monolayers to dissect altered biological pathways and signaling events. Further, we validated the effect of IKKβ inhibition on RPE–EMT-associated factors using a second IKKβ inhibitor, BMS345541, with RPE monolayers derived from an independent stem cell line. Our data highlights the fact that pharmacological inhibition of RPE–EMT restores RPE identity and may provide a promising approach for treating retinal diseases that involve RPE dedifferentiation and EMT.

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IKKβ Inhibition Attenuates Epithelial Mesenchymal Transition of Human Stem Cell-Derived Retinal Pigment Epithelium

Project description:IKKβ Inhibition Attenuates Epithelial Mesenchymal Transition of Human Stem Cell-Derived Retinal Pigment Epithelium

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