Ochratoxin A promotes chronic enteritis and early colorectal cancer progression by targeting Rinck signaling

• Published in: Phytomedicine (Stuttgart) Vol. 122; p. 155095
• Main Authors: Liu, Xin, Yan, Chunli, Chang, Chunxiao, Meng, Fansong, Shen, Wenjie, Wang, Song, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: Elsevier GmbH 01.01.2024
• Subjects: aflatoxins; animal models; antioxidant activity; azoxymethane; chronic exposure; Colitis; colon; Colorectal cancer (CRC); colorectal neoplasms; cytokines; dextran sulfate; enteritis; epithelium; genetically modified organisms; genome; histology; humans; immune response; neoplasm progression; Ochratoxin A; Oxidative stress; phenotype; rabbits; reactive oxygen species; RINCK; rodents; sequence analysis; subchronic exposure; therapeutics; ubiquitin; ubiquitin-protein ligase; ubiquitination; viruses; Oxidative stress; RINCK; Colitis; Ochratoxin A; Colorectal cancer (CRC)
• ISSN: 0944-7113; 1618-095X; 1618-095X
• DOI: 10.1016/j.phymed.2023.155095

•Oral sub-chronic OTA treatment facilitates DSS-triggered colitis pathological phenotypes in rodent model.•RINCK expression is positively correlated with IBD and CRC severity in human patients and rodent model.•Intestinal epithelial cells-specific Rinck knockout retards OTA-DSS co-triggered colitis phenotypes.•Intestinal epithelial cells-specific Rinck overexpression promotes OTA-DSS co-triggered colitis phenotypes.•Rinck promotes colitis by directly interacting with Nrf2, thereby facilitating its ubiquitination degradation.•Forced Rinck suppression mitigates OTA-DSS triggered acute colitis in rodent and rabbit model. 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. 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). 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. 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. 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. [Display omitted]