ArticleThe American journal of pathology2025
Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer.
Article in The American journal of pathology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- Flavonoid-modulated JAK-STAT signaling mitigates malignant transformation and drug resistance in breast tumors: A clinically relevant 3PM-guided innovation.Journal of advanced research · 2026Review
- Research progress on regulatory mechanisms of mucosal barriers and their applications in allergic diseases.Frontiers in immunology · 2026Review
- Article
- IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy.EXCLI journal · 2025Review
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Authors and funding
11 authors.
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Abstract
During progression, luminal muscle-invasive bladder cancer (MIBC) can transition to the aggressive basal-squamous (Ba/Sq) subtype. Reduced expression of forkhead box A1 (FOXA1) in the urothelium is a hallmark and driver of the Ba/Sq transcriptional state and squamous differentiation. Ba/Sq tumors are highly inflamed; however, the specific inflammatory pathways contributing to the Ba/Sq state are unknown. In this study, transcriptomic analyses of The Cancer Genome Atlas MIBC cohort were performed to determine whether immune response gene signatures were associated with MIBC molecular states. Results showed that Ba/Sq MIBCs were enriched for the interferon-γ (IFN-γ)-dominant signature. Ba/Sq MIBCs exhibited increased IFN-γ/Janus kinase (JAK)/STAT pathway activity, corresponding to reduced FOXA1 regulon activity. Immunohistochemistry of MIBC specimens demonstrated that JAK1 expression was significantly increased in tumor areas with squamous differentiation. IFN-γ treatment of luminal MIBC cell lines significantly decreased the expression of luminal transcriptional drivers, including FOXA1, and increased the expression of Ba/Sq markers in a STAT1-dependent manner. RNA-sequencing analyses identified IFN-γ as a driver of the Ba/Sq state. The ability of IFN-γ to repress FOXA1 in luminal cells was abrogated by ruxolitinib inhibition of JAK1/2 activity. Additionally, pharmacologic inhibition or genetic ablation of JAK1 restored FOXA1 expression in Ba/Sq MIBC cells. These findings are the first to identify IFN-γ as an epithelial cell-extrinsic mechanism to repress FOXA1 and drive the Ba/Sq state in MIBC.
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