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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE294269 | GEO | 2025/09/01

REPOSITORIES: GEO

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Project description:Esophageal cancer is one of the most common cancers where TP53 is mutated frequently. Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer, and is one of the most lethal cancers worldwide. ESCC evolves often to lung metastasis, which is associated with a dismal prognosis. P53R175H (homologous to Trp53R172H in mice) is a common hot spot mutation. How metastasis is regulated by p53R175H in ESCC, or cancers in general, remains to be elucidated. To investigate p53R175H mediated molecular mechanisms, we utilized germline Trp53R172H/- mice, and generated esophageal specific Trp53-/- mice and Trp53+/+ mice treated with the 4-NQO esophageal-specific carcinogen (a common exposure in humans) to model ESCC. In the primary Trp53R172H/- tumor cell lines established from these mouse models, we depleted Trp53R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, to understand the molecular basis for mutant p53 driven lung metastasis, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We performed Gene Set Enrichment Analysis (GSEA) and identified the YAP-BIRC5 axis as a potential mediator of Trp53R172H mediated metastasis. As a target gene of YAP, BIRC5 encodes an anti-apoptotic protein, namely survivin. We demonstrate that survivin expression increases in the presence of Trp53R172H but not wild-type Trp53. Furthermore, depletion of survivin decreases Trp53R172H driven lung metastasis. Mechanistically, Trp53R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce survivin expression. Furthermore, survivin high expression level is associated with increased metastasis in several GI cancer, suggesting that survivin may be a key regulator to metastasis. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.

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

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