Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in Mice.

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-12-02 DOI:10.1016/j.jcmgh.2024.101435

Kensuke Hamada, Yuki Nakanishi, Yu Muta, Mayuki Omatsu, Kosuke Iwane, Munehiro Ikeda, Jiayu Chen, Yoko Masui, Naoki Aoyama, Nobukazu Agatsuma, Go Yamakawa, Takahiro Utsumi, Hiroki Kitamoto, Makoto Okabe, Yoshiro Itatani, Takumi Adachi, Koubun Yasuda, Shuji Yamamoto, Akihisa Fukuda, Etsushi Kuroda, Masaki Ohmuraya, Kazutaka Obama, Seiichi Hirota, Hiroki Ikeuchi, Kenji Nakanishi, Hiroshi Seno

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Abstract

Background & aims: Retinoblastoma-binding protein 9 (RBBP9) was initially reported as cell cycle regulator via RB/E2F. Accumulating evidence has revealed the importance of RBBP9 in physiological and pathological states including inflammatory disease. However, the functional role of RBBP9 in ulcerative colitis (UC) and colitis-associated cancer (CAC) remains elusive.

Methods: Human samples of UC and CAC were examined by immunohistochemical and bioinformatics analyses. We established dextran sodium sulfate (DSS)-induced colitis, azoxymethane (AOM)/DSS-induced CAC model, and Apc^Min/+ sporadic tumor model using wild-type and Rbbp9^-/- mice. RNA sequencing was analyzed to identify the phenotype alternation upon Rbbp9 deletion. In addition, genetic and pharmacological inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) pathway was performed.

Results: The expression of RBBP9 was reduced in human UC and CAC samples. The loss of RBBP9 enhanced the activation of interferon (IFN)/JAK/STAT1 signaling, resulting in susceptibility to DSS-induced colitis and AOM/DSS-induced CAC tumors by increasing epithelial cell apoptosis and immune activation. An in vitro kinase assay revealed that RBBP9 directly regulated JAK/STAT1 signaling by suppressing STAT1 phosphorylation. A positive feedback loop involving epithelial cell apoptosis, commensal microbiome invasion, and activation of submucosal immune activity was identified in Rbbp9^-/- mouse intestines through enhanced JAK/STAT1 signaling in RBBP9-deficient epithelial cells and macrophages. The genetic inhibition of STAT1 or treatment with the JAK/STAT inhibitor reversed epithelial cell apoptosis and mitigated the enhanced susceptibility to DSS-induced colitis in Rbbp9^-/- mice.

Conclusions: RBBP9 suppresses the intestinal inflammation by negatively regulating JAK/STAT1 signaling pathway.

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视网膜母细胞瘤结合蛋白9抑制小鼠肠道炎症和炎症诱导的肿瘤发生

背景与目的：视网膜母细胞瘤结合蛋白9 （RBBP9）最初被报道通过RB/E2F作为细胞周期调节因子。越来越多的证据揭示了RBBP9在包括炎症疾病在内的生理和病理状态中的重要性。然而，RBBP9在溃疡性结肠炎（UC）和结肠炎相关癌症（CAC）中的功能作用仍然是未知的。方法：采用免疫组织化学和生物信息学方法对人UC和CAC进行检测。我们以野生型和Rbbp9-/-小鼠为实验对象，建立了葡聚糖硫酸钠（DSS）诱导的结肠炎、偶氮氧甲烷(AOM)/DSS诱导的CAC模型和ApcMin/+散发性肿瘤模型。分析RNA测序以确定Rbbp9缺失后的表型变化。此外，研究人员还对Janus激酶(JAK)/信号传导和转录激活因子1 （STAT1）通路进行了遗传和药理学抑制。结果：RBBP9在人UC和CAC中表达降低。RBBP9的缺失增强了干扰素(IFN)/JAK/STAT1信号的激活，通过增加上皮细胞凋亡和免疫激活，导致对dss诱导的结肠炎和AOM/ dss诱导的CAC肿瘤的易感性。体外激酶实验显示RBBP9通过抑制STAT1磷酸化直接调控JAK/STAT1信号通路。通过Rbbp9缺失的上皮细胞和巨噬细胞中JAK/STAT1信号的增强，在Rbbp9-/-小鼠肠道中发现了一个涉及上皮细胞凋亡、共生微生物群入侵和粘膜下免疫活性激活的正反馈回路。基因抑制STAT1或JAK/STAT抑制剂治疗可逆转上皮细胞凋亡，减轻Rbbp9-/-小鼠对dss诱导的结肠炎的易感性。结论：RBBP9通过负调控JAK/STAT1信号通路抑制肠道炎症。

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

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.