Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary
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...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001905 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Kensuke Hamada |
| collection | DOAJ |
| description | 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 ApcMin/+ 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. |
| format | Article |
| id | doaj-art-7f0bb50c36bb414d9b18bbefcc298d6a |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-7f0bb50c36bb414d9b18bbefcc298d6a2025-01-19T06:26:11ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01193101435Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummaryKensuke Hamada0Yuki Nakanishi1Yu Muta2Mayuki Omatsu3Kosuke Iwane4Munehiro Ikeda5Jiayu Chen6Yoko Masui7Naoki Aoyama8Nobukazu Agatsuma9Go Yamakawa10Takahiro Utsumi11Hiroki Kitamoto12Makoto Okabe13Yoshiro Itatani14Takumi Adachi15Koubun Yasuda16Shuji Yamamoto17Akihisa Fukuda18Etsushi Kuroda19Masaki Ohmuraya20Kazutaka Obama21Seiichi Hirota22Hiroki Ikeuchi23Kenji Nakanishi24Hiroshi Seno25Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Correspondence Address correspondence to: Yuki Nakahishi and Yu Muta, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; tel: +81-75-751-4319.Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Correspondence Address correspondence to: Yuki Nakahishi and Yu Muta, Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan; tel: +81-75-751-4319.Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastrointestinal Surgery, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Genetics, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Gastrointestinal Surgery, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Surgical Pathology, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Gastroenterological Surgery, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Immunology, School of Medicine, Hyogo Medical University, Nishinomiya, JapanDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, JapanBackground & 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 ApcMin/+ 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.http://www.sciencedirect.com/science/article/pii/S2352345X24001905Colitis-associated CancerInterferon SignalingRetinoblastoma-binding Protein 9Ulcerative Colitis |
| spellingShingle | 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 Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Colitis-associated Cancer Interferon Signaling Retinoblastoma-binding Protein 9 Ulcerative Colitis |
| title | Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary |
| title_full | Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary |
| title_fullStr | Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary |
| title_full_unstemmed | Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary |
| title_short | Retinoblastoma-binding Protein 9 Suppresses Intestinal Inflammation and Inflammation-induced Tumorigenesis in MiceSummary |
| title_sort | retinoblastoma binding protein 9 suppresses intestinal inflammation and inflammation induced tumorigenesis in micesummary |
| topic | Colitis-associated Cancer Interferon Signaling Retinoblastoma-binding Protein 9 Ulcerative Colitis |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001905 |
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