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IBD) and IBD-Associated Colorectal Tumorigenesis Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ARC is a critical protector against inflammatory bowel disease (IBD) and IBD-associated colorectal tumorigenesis Qiushi Wang1*, Tianshun Zhang1*, Xiaoyu Chang1, Do Young Lim1, Keke Wang1, Ruihua Bai1,2, Ting Wang1, Joohyun Ryu1, Hanyong Chen1, Ke Yao1, Wei-Ya Ma1, Lisa A. Boardman3, Ann M. Bode1, Zigang Dong1,4+ 1The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912 2The Henan Tumor Hospital, No.127 Dongming Road, Zhengzhou, Henan, China, 450000 3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA, 4Department of Pathophysiology, School of Basic Medical Sciences. College of Medicine. Zhengzhou University, Henan, 450001, China *Qiushi Wang and Tianshun Zhang have contributed equally to this work Corresponding Author: +Address correspondence to Zigang Dong, No.100 Science Avenue, Zhengzhou City, Henan Province, China. Postcode: 450001. Telephone: +86-371-66658803; Email: [email protected] Conflicts of Interest: The authors declare no potential conflicts of interest Running title: ARC for IBD-associated colorectal tumorigenesis 1 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author contributions: QW and TZ contributed equally to the manuscript and designed the experiments, performed experiments, analyzed and interpreted data, prepared figures and wrote the manuscript; XC, DYL and KW conducted experiment and analyzed data; RB performed pathological identification; TW supported for the animal studies; JR performed mass spectrometry analysis. HC contributed to computational analysis; KY and WM assisted in establishing experimental methods. LAB collected and prepared the human samples; AMB contributed to review and revision of manuscript. ZD contributed to study supervision, experimental design, data discussion, and revision of manuscript. Keywords: ARC, TRAF6, ubiquitination, inflammatory bowel disease (IBD), colorectal tumorigenesis 2 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared to wild-type (WT) mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4- positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from IBD patients compared with normal subjects. Additionally, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with tumor necrosis factor receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with nuclear factor-kappa B (NF-kB) signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and AOM/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. 3 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory disease of the gastrointestinal tract (1,2). IBD can cause various complications, such as abscesses, fistulas, colitis-associated neoplasias and cancer (3). Approximately 1.6 million patients suffer from the disease in the United States and 2.5 to 3 million in Europe (4,5). IBD is associated with an immunological imbalance of the intestinal mucosa, mainly related to cells in the adaptive immune system leading to chronic inflammation conditions in patients. The pathophysiological mechanisms of IBD are still not clear, even though these diseases were discovered several decades ago (6-8). The protein apoptosis repressor with caspase recruitment domain (ARC), also referred to as Nol3, plays an important role in suppressing apoptotic responses (9,10). ARC was believed to exert its function through multiple protein-protein interactions and transcriptional regulation (11). ARC was primarily discovered as an endogenous inhibitor of cell death and is highly expressed in cardiomyocytes, skeletal muscle cells, and neurons under physiological conditions (12-14). It was independently identified in later studies as having other functions, including post-translational modifications like phosphorylation, calcium binding, and ubiquitination (15,16). ARC has increased expression in solid tumors and in patients with acute myeloid leukemia to mediate the response of cells to the induction of pharmacological apoptosis (17-20). Intriguingly, studies also revealed that ARC might perform its function as a tumor suppressor in renal cell carcinoma cells and myeloid tumors (21,22). These findings suggest dual roles for ARC in oncogenesis that may be cell type-dependent. The CARD family participates in the 4 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. regulation of apoptosis, inflammation, and NF-κB signaling pathway activation. However, the function of ARC in the inflammation reaction is still not clear (23,24). Recently, ARC was shown to play a pivotal role in the pathogenesis of acute kidney injury and ARC knockout markedly accelerated the expression levels of inflammatory factors (25). Moreover, ARC has been reported to suppress NF-κB pathway activation and to interact directly with p53 to disrupt its transcriptional activity (23,26). These findings suggest that ARC plays potential roles in the inflammatory response and cancer development. Additional, ARC is high expression in almost all primary colon cancers compared with corresponding controls, suggesting that ARC is a novel marker for human colon cancer (27). However, the function of ARC in IBD and colon cancer has not yet been assessed. In this study, we examined the function of ARC in IBD and IBD-associated colon cancer. We demonstrated a role for ARC in regulation of inflammatory response in an ARC-deficient mouse model and clinical biopsy specimens. We identified ARC as a protector for IBD in immune cells and also aimed to ascertain the mechanisms of ARC related to the inflammatory response in IBD development. Furthermore, the bone marrow transplantation and AOM/DSS mouse model were used to study the effect of ARC on IBD and IBD-associated colorectal tumorigenesis. Our findings uncover a critical role for ARC in IBD development and give rise to a potential new strategy for IBD therapy. Materials and Methods Reagents and antibodies 5 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 19, 2020; DOI: 10.1158/0008-5472.CAN-20-0469 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Cell culture media, gentamicin, penicillin, and L-glutamine were all obtained from Invitrogen (Grand Island, NY). Fetal bovine serum (FBS) was from Gemini Bio-Products (West Sacramento, CA) and Tris, NaCl, and SDS for molecular biology and buffer preparation were purchased from Sigma-Aldrich (St. Louis, MO). Antibodies to detect -actin (sc-47778), NF-B (p50) (sc-7178), Lamin B (sc-6216), CD4 (sc-13573), ARC (sc-11435), ENA-78 (sc-377026), RANTES (sc-514019), TRAF1 (sc-271683), TRAF4 (sc-10776), TRAF5 (sc-74502) and TRAF6 (sc-8409) were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). His-HRP (R94125) were from Invitrogen. Anti-HA (901503) was obtained from Covance (Emeryville, CA) and anti-HA-HRP (12013819001) was purchased from Roche (Indianapolis, IN). Anti-Flag (F-3165) was from Millipore sigma. Anti-CCL5 (ab9679) and anti-CXCL5 (ab9802) were purchased from Abcam (Cambridge, MA). NF-B (p65) (#3034), TRAF2 (#14712), PE-ARC (#89210) and TRAF3 (#4729T) antibodies were purchased from Cell Signaling Technology (Danvers,
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