PMID- 37844381 OWN - NLM STAT- MEDLINE DCOM- 20231114 LR - 20231129 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 122 DP - 2024 Jan TI - Ochratoxin A promotes chronic enteritis and early colorectal cancer progression by targeting Rinck signaling. PG - 155095 LID - S0944-7113(23)00455-5 [pii] LID - 10.1016/j.phymed.2023.155095 [doi] AB - BACKGROUND: Mycotoxins, such as aflatoxin and ochratoxin A (OTA), are found at measurable levels in many staple foods; the health implications of long-term exposure of such toxins are poorly understood. Increasing evidence has confirmed the important role of OTA in upregulation of oxidative stress- and inflammatory response-induced tissue injury. However, it remains unknown whether ochratoxin A can promote chronic colitis and its associated colon cancer (CRC) development, and potential molecular mechanism. Additionally, RING finger-interacting protein with C kinase (RINCK) is a ubiquitin ligase and mediates immune response. Unfortunately, the potential molecular function of RINCK on regulation of colitis is still largely unknown. PURPOSE: This study aims to provide mechanistic evidence that the role of RINCK in colitis and early colorectal cancer progression in response to OTA treatment via targeting nuclear factor erythroid 2-related factor 2 (NRF2). METHODS: The Cancer Genome Atlas (TCGA) database, GEO database, human subjects with CC phenotype and CC cell lines were used in this work. Pathological links between OTA, RINCK and treatment of CC are revealed through comprehensive means such as biological information analysis, clinical experiments, RNA-seq, and verification experiments. RESULTS: In this study, under oxidative stress in setting of colitis, we first identified RINCK as a key regulatory factor and a novel endogenous suppressor of nuclear factor erythroid 2-related factor 2 (NRF2), and we also confirm that RINCK is a NRF2 partner protein that catalyses its ubiquitination and degradation in intestinal epithelial cells (IECs). Notably, in vivo study, pathological phenotypes triggered by OTA pretreatment, accompanied by post-treatment of dextran sulfate sodium (DSS)-induced colitis was significantly mitigated by IEC-specific deficiency of Rinck, IEC-Rinck(KO) and adenovirus-associated virus (AAV)-triggered suppression of Rinck in rodent model, and lentivirus (LV)-mediated downregulation of Rinck (LV-shRinck) in rabbit model, as determined by decreased endogenous reactive oxygen species (ROS) production, pro-inflammatory cytokines contents, improved body weights, reduced survival rates, restored colon length, assuasive DAI and histological scores. Inversely, transgenic mice by IEC-specific Rinck overexpression, IEC-Rinck(OE) accelerated colitis in acute or chronic colitis rodent models and in vitro experiments. Moreover, we found that OTA pretreatment-promoted azoxymethane (AOM)/DSS-induced colitis-associated early colorectal cancer (CRC) was also dramatically reduced by IEC-Rinck(KO), indicated by the decreased tumor number and corresponding KI-67 levels. Clinical samples analysis revealed that RINCK levels were greatly increased in tumor tissues of patients with CRC phenotypes. In parallel, RINCK deletion remarkably retarded the proliferation of colon cancer and tumor growth in vitro and in vivo, respectively. Mechanistically, in response to onset of colitis, RINCK directly interacts with NRF2 and promotes ubiquitin-proteasome degradation via increasing K48-linkage ubiquitin chain, thus leads in suppression of NRF2 nuclear translocation and its downstream cascade inactivation, which retards antioxidant defense. CONCLUSION: The findings suggested that oral sub-chronic exposure of OTA significantly facilitates DSS-induced colitis and colitis-associated CRC development. These results further elucidated the potential role of RINCK in colitis progression by mediating NRF2 degradation, and could be considered as a therapeutic target for the treatment of such disease. CI - Copyright (c) 2023. Published by Elsevier GmbH. FAU - Liu, Xin AU - Liu X AD - Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Yan, Chunli AU - Yan C AD - Department of Breast Internal Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Chang, Chunxiao AU - Chang C AD - Ward 2 of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Meng, Fansong AU - Meng F AD - Department of Medical Management, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Shen, Wenjie AU - Shen W AD - Clinical Trial Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Wang, Song AU - Wang S AD - Department of Medical Management, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. FAU - Zhang, Yi AU - Zhang Y AD - Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China. Electronic address: zhangyi_sdfmu@yeah.net. LA - eng PT - Journal Article DEP - 20230920 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 1779SX6LUY (ochratoxin A) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Ubiquitins) RN - 9042-14-2 (Dextran Sulfate) SB - IM MH - Mice MH - Animals MH - Humans MH - Rabbits MH - NF-E2-Related Factor 2 MH - *Colorectal Neoplasms/chemically induced/drug therapy/genetics MH - *Inflammatory Bowel Diseases MH - *Colitis/chemically induced/drug therapy/metabolism MH - Mice, Transgenic MH - Chronic Disease MH - *Enteritis/complications MH - *Colonic Neoplasms MH - Ubiquitins/therapeutic use MH - Dextran Sulfate/adverse effects MH - Mice, Inbred C57BL MH - Disease Models, Animal OTO - NOTNLM OT - Colitis OT - Colorectal cancer (CRC) OT - Ochratoxin A OT - Oxidative stress OT - RINCK COIS- Declaration of Competing Interest The authors declare that they have no competing interests. EDAT- 2023/10/17 00:42 MHDA- 2023/11/14 06:42 CRDT- 2023/10/16 18:02 PHST- 2023/01/04 00:00 [received] PHST- 2023/06/01 00:00 [revised] PHST- 2023/09/15 00:00 [accepted] PHST- 2023/11/14 06:42 [medline] PHST- 2023/10/17 00:42 [pubmed] PHST- 2023/10/16 18:02 [entrez] AID - S0944-7113(23)00455-5 [pii] AID - 10.1016/j.phymed.2023.155095 [doi] PST - ppublish SO - Phytomedicine. 2024 Jan;122:155095. doi: 10.1016/j.phymed.2023.155095. Epub 2023 Sep 20.