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

被引：0

作者：

Hamada, Kensuke ^{[1
]}

Nakanishi, Yuki ^{[1
]}

Muta, Yu ^{[1
]}

Omatsu, Mayuki ^{[1
]}

Iwane, Kosuke ^{[1
]}

Ikeda, Munehiro ^{[1
]}

Chen, Jiayu ^{[1
]}

Masui, Yoko ^{[1
]}

Aoyama, Naoki ^{[1
]}

Agatsuma, Nobukazu ^{[1
]}

Yamakawa, Go ^{[1
]}

Utsumi, Takahiro ^{[1
]}

Kitamoto, Hiroki ^{[1
]}

Okabe, Makoto ^{[1
]}

Itatani, Yoshiro ^{[2
]}

Adachi, Takumi ^{[3
]}

Yasuda, Koubun ^{[3
]}

Yamamoto, Shuji ^{[1
]}

Fukuda, Akihisa ^{[1
]}

Kuroda, Etsushi ^{[3
]}

Ohmuraya, Masaki ^{[4
]}

Obama, Kazutaka ^{[2
]}

Hirota, Seiichi ^{[5
]}

Ikeuchi, Hiroki ^{[6
]}

Nakanishi, Kenji ^{[3
]}

Seno, Hiroshi ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, 54 Shogoin Kawahara cho,Sakyo Ku, Kyoto 6068507, Japan

[2] Kyoto Univ, Grad Sch Med, Dept Gastrointestinal Surg, Kyoto, Japan

[3] Hyogo Med Univ, Sch Med, Dept Immunol, Nishinomiya, Japan

[4] Hyogo Med Univ, Sch Med, Dept Genet, Nishinomiya, Japan

[5] Hyogo Med Univ, Sch Med, Dept Surg Pathol, Nishinomiya, Japan

[6] Hyogo Med Univ, Sch Med, Dept Gastroenterol Surg, Nishinomiya, Japan

来源：

CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY | 2025年 / 19卷 / 03期

关键词：

Colitis-associated Cancer; Interferon Signaling; Reti- noblastoma-binding Protein 9; Ulcerative Colitis; BOWEL-DISEASE; MAMMALIAN TARGET; EPITHELIAL-CELLS; BARRIER FUNCTION; COLITIS; ACTIVATION; STAT3; REPRESSION; APOPTOSIS; SURVIVAL;

D O I：

10.1016/j.jcmgh.2024.101435

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页数：20

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