Interferon-γ/Janus Kinase 1/STAT1 Signaling Represses Forkhead Box A1 and Drives a Basal Transcriptional State in Muscle-Invasive Bladder Cancer

IF 4.7 2区 医学 Q1 PATHOLOGY
Shamara S. Lawrence , Hironobu Yamashita , Lauren Shuman , Jay D. Raman , Monika Joshi , Gregory S. Yochum , Xue-Ru Wu , Hikmat A. Al-Ahmadie , Joshua I. Warrick , Vonn Walter , David J. DeGraff
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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.
IFNγ/JAK1/STAT1信号抑制FOXA1并驱动肌肉浸润性膀胱癌的基础转录状态。
在进展过程中,管腔肌浸润性膀胱癌(MIBC)可转变为侵袭性基底鳞状(Ba/Sq)亚型。叉头盒A1 (FOXA1)在尿路上皮中的表达减少是Ba/Sq转录状态和鳞状分化(SqD)的标志和驱动因素。Ba/Sq肿瘤是高度炎症的,然而,导致Ba/Sq状态的特定炎症途径尚不清楚。在这项研究中,对癌症基因组图谱(Cancer Genome Atlas)的MIBC队列进行转录组学分析,以确定免疫反应基因特征是否与MIBC分子状态相关。结果显示,Ba/Sq型mibc富集干扰素γ (IFNγ)显性特征。Ba/Sq mibc表现出IFNγ/JAK/STAT通路活性增加,与FOXA1调控活性降低相对应。免疫组化检测显示,在伴有SqD的肿瘤区域,JAK1的表达显著增加。IFNγ处理的管腔MIBC细胞系显著降低了包括FOXA1在内的管腔转录驱动因子的表达,并以stat1依赖的方式增加了Ba/Sq标记的表达。RNA测序分析发现IFNγ是Ba/Sq状态的驱动因素。ruxolitinib对JAK1/2活性的抑制使IFNγ在腔细胞中抑制FOXA1的能力丧失。此外,药理抑制或基因消融JAK1可以恢复Ba/Sq MIBC细胞中FOXA1的表达。这些发现首次确定IFNγ是抑制FOXA1和驱动MIBC中Ba/Sq状态的上皮细胞外源性机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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