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Vajsova A, Cahova M, Bajer L, Sticova E, Juskova I, Hlavaty M, Fabian O. Unique clinical, morphological, and molecular characteristics of tumors associated with PSC-IBD. Virchows Arch 2025; 486:651-661. [PMID: 40102272 PMCID: PMC12018527 DOI: 10.1007/s00428-025-04072-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/27/2025] [Accepted: 03/04/2025] [Indexed: 03/20/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by chronic inflammation and progressive fibrosis of the biliary tree, leading to significant liver function impairment over time. There is a strong association with inflammatory bowel diseases (IBD), together representing a distinct and complex medical condition. Patients with PSC-IBD face a heightened risk of various cancers, particularly colorectal carcinoma (CRC) and cholangiocarcinoma (CCA) as the most common types. In this review, we aim to characterize the distinctive features of PSC-IBD-associated carcinomas. Cancer pathogenesis in PSC-IBD is shaped by various factors including dysregulated bile acid metabolism, gut dysbiosis, and unique immune responses. PSC-IBD-associated CRC is often right-sided and warrants vigilant monitoring due to its higher incidence and unique morphological features compared to CRC arising in the terrain of IBD alone. CCA shares substantial genetic similarities with extrahepatic CCA and poses diagnostic challenges since it is frequently detected at advanced stages due to symptom overlap with PSC. Besides, reliable predictive biomarkers for targeted therapy remain largely unexplored. The distinct molecular, genetic, and histopathological profiles of CRC and CCA in PSC-IBD underscore the complexity of these malignancies and highlight the need for continued research to develop precise therapeutic strategies.
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Affiliation(s)
- Andrea Vajsova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic.
- Institute of Pathology of the First Faculty of Medicine and General Teaching Hospital, Prague, 12800, Czech Republic.
| | - Monika Cahova
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
| | - Lukas Bajer
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, 14021 , Czech Republic
- Department of Internal Medicine, Second Faculty of Medicine, Charles University, Prague, 15000, Czech Republic
| | - Eva Sticova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
- Department of Pathology, Royal Vinohrady Teaching Hospital, Srobarova 1150/50, Prague, 10000, Czech Republic
| | - Ivana Juskova
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
| | - Mojmir Hlavaty
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, 14021 , Czech Republic
| | - Ondrej Fabian
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague, 14021, Czech Republic
- Department of Pathology and Molecular Medicine, 3rd Faculty of Medicine, Charles University and Thomayer Hospital, Prague, 14059, Czech Republic
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Yang J, Bernard L, Chen J, Sullivan VK, Deal JA, Kim H, Yu B, Steffen LM, Rebholz CM. Plasma Proteins Associated with the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) Diet and Incident Dementia. J Nutr 2025:S0022-3166(25)00167-1. [PMID: 40118346 DOI: 10.1016/j.tjnut.2025.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 01/22/2025] [Accepted: 03/10/2025] [Indexed: 03/23/2025] Open
Abstract
BACKGROUND The Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet slows cognitive decline and protects brain health, but the mechanisms are poorly understood. OBJECTIVES We aimed to determine the plasma proteins associated with the MIND diet score and their ability to predict incident dementia in the Atherosclerosis Risk in Communities study. METHODS We analyzed 10,230 Black and White participants at visit 3 (1993-1995) with food frequency questionnaire and proteomics data and randomly divided them into discovery (n = 6850) and replication (n = 3380) samples. We examined associations between the MIND diet score and 4955 proteins using multivariable linear regression and elastic net regression. C-statistics were calculated to assess if proteins improved the prediction of high MIND diet adherence beyond participant characteristics. Cox proportional hazards models were used to assess associations between significant diet-related proteins and incident dementia over 2 decades. C-statistics assessed the ability of significant proteins to improve dementia prediction beyond known risk factors. RESULTS Of 316 proteins associated with the MIND diet score in the discovery sample at a false discovery rate <0.05, 62 were internally replicated. Of these, 21 proteins selected by the elastic net individually improved MIND diet score prediction. After a median follow-up of 21 y, there were 2311 dementia cases. Five diet-related proteins, thrombospondin-2 [hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.11, 1.29], protein ABHD14A (HR: 1.23; 95% CI: 1.11, 1.37), structural maintenance of chromosomes protein 3 (HR: 1.19; 95% CI: 1.08, 1.31), epidermal growth factor receptor (HR: 0.68; 95% CI: 0.53, 0.86), and interleukin-12 subunit beta (HR: 1.14; 95% CI: 1.05, 1.25) were significantly associated with incident dementia. All 5 proteins individually and together improved the prediction of dementia risk. CONCLUSIONS Using high-throughput proteomics, we identified candidate biomarkers of the MIND diet score and incident dementia, which are implicated in neural signaling, angiogenesis, and anti-inflammatory pathways.
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Affiliation(s)
- Jiaqi Yang
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, United States
| | - Lauren Bernard
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, United States; School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Jingsha Chen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, United States
| | - Valerie K Sullivan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, United States
| | - Jennifer A Deal
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
| | - Hyunju Kim
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, United States
| | - Bing Yu
- Department of Epidemiology, University of Texas Health Science Center at Houston School of Public Health, Houston, TX, United States
| | - Lyn M Steffen
- Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, United States
| | - Casey M Rebholz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, United States.
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Sanchez Alvarez R, Montalban-Arques A, Morsy Y, Gottier C, Häfliger J, Atrott K, Bircher A, Katkeviciute E, Pöhlmann D, Linzmeier L, Determann M, Mamie C, Niechcial A, Schwarzfischer M, Zeissig S, Lang S, Scharl M, Spalinger M. Intestinal epithelial PTPN23 is essential for gut barrier integrity and prevention of fatal bacterial translocation. J Crohns Colitis 2025; 19:jjaf016. [PMID: 39873381 PMCID: PMC11815487 DOI: 10.1093/ecco-jcc/jjaf016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Indexed: 01/30/2025]
Abstract
BACKGROUND AND AIMS Protein tyrosine phosphatase nonreceptor type 23 (PTPN23) regulates the internalization of growth factor receptors such as the epithelial growth factor receptor (EGFR). Given the crucial function of such receptors in intestinal epithelial cells (IECs), we assessed the involvement of PTPN23 in intestinal homeostasis and epithelial proliferation. METHODS We generated mouse models with constitutive (PTPN23fl/flVilCre+/-) or inducible (PTPN23fl/flVilCreERT+/-) deletion of PTPN23 in IEC. To elucidate the functional consequences of PTPN23 deletion in IEC, we performed barrier function studies, flow cytometry, RNAseq, and in vivo experiments applying EGFR inhibition, antibiotic treatment, or co-housing approaches to further delineate the observed phenotype. RESULTS Deletion of PTPN23 in IECs resulted in a severe early-onset phenotype in both models. Mice were characterized by elongated colon, epithelial hyperproliferation, splenomegaly, and diarrhea leading to the death of the mice within 3 weeks of PTNP23 deletion. Compromised gut barrier integrity resulted in enhanced bacterial translocation accompanied by reduced IgA transcytosis in PTPN23fl/flVilCreERT+/- compared to wild-type mice. Although EGFR surface expression was increased upon PTPN23-deletion, inhibition of EGFR signaling did not prevent disease. In contrast, and in accordance with defective bacterial handling, antibiotic treatment, but not co-housing, fully rescued the phenotype. CONCLUSIONS The absence of PTPN23 in IECs leads to lethal dysregulation of intestinal homeostasis, triggered by bacterial infiltration due to defects in the intestinal epithelial barrier and impaired IgA transcytosis. Thus, we identify PTPN23 as a novel key player in preserving intestinal epithelial homeostasis, ultimately preventing bacterial overgrowth and excessive immune activation in the intestine.
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Affiliation(s)
- Rocio Sanchez Alvarez
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ana Montalban-Arques
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Yasser Morsy
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Claudia Gottier
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Janine Häfliger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Anna Bircher
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Egle Katkeviciute
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Doris Pöhlmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Luise Linzmeier
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Madita Determann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Anna Niechcial
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Sebastian Zeissig
- Department of Medicine I, Center for Regenerative Therapies Dresden (CRTD), University Medical Center Dresden, Technische Universität (TU) Dresden, Dresden, Germany
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Marianne Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
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Zhao Q, Yu H, Shi M, Wang X, Fan Z, Wang Z. Tumor microenvironment characteristics of lipid metabolism reprogramming related to ferroptosis and EndMT influencing prognosis in gastric cancer. Int Immunopharmacol 2024; 137:112433. [PMID: 38870879 DOI: 10.1016/j.intimp.2024.112433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/05/2024] [Accepted: 06/05/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Gastric cancer (GC) is a refractory malignant tumor with high tumor heterogeneity, a low rate of early diagnosis, and poor patient prognosis. Lipid metabolism reprogramming plays a critical role in tumorigenesis and progression, but its prognostic role and regulatory mechanism in GC are rarely studied. Thus, the identification of signatures related to lipid metabolism is necessary and may present a new avenue for improving the overall prognosis of GC. METHODS Lipid metabolism-associated genes (LMAGs) with differential expression in tumor and tumor-adjacent tissue were acquired to identify lipid metabolism-associated subtypes. The differentially expressed genes (DEGs) between the two clusters were then utilized for prognostic analysis and signature construction. Additionally, pathway enrichment analysis and immune cell infiltration analysis were employed to identify the characteristics of the prognostic model. Further analyses were conducted at the single-cell level to better understand the model's prognostic mechanism. Finally, the prediction of immunotherapy response was used to suggest potential treatments. RESULTS Two lipid metabolism-associated subtypes were identified and 9 prognosis-related genes from the DEGs between the two clusters were collected for the construction of the prognostic model named lipid metabolism-associated signature (LMAS). Then we found the low LMAS patients with favorable prognoses were more sensitive to ferroptosis in the Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD). Meanwhile, the tumor cells exhibiting high levels of lipid peroxidation and accumulation of reactive oxygen species (ROS) in single-cell levels were primarily enriched in the low LMAS group, which was more likely to induce ferroptosis. In addition, endothelial cells and cancer-associated fibroblasts (CAFs) facilitated tumor angiogenesis, proliferation, invasion, and metastasis through endothelial-mesenchymal transition (EndMT), affecting the prognosis of the patients with high LMAS scores. Moreover, CD1C- CD141- dendritic cells (DCs) also secreted pro-tumorigenic cytokines to regulate the function of endothelial cells and CAFs. Finally, the patients with low LMAS scores might have better efficacy in immunotherapy. CONCLUSIONS A LMAS was constructed to guide GC prognosis and therapy. Meanwhile, a novel anti-tumor effect was found in lipid metabolism reprogramming of GC which improved patients' prognosis by regulating the sensitivity of tumor cells to ferroptosis. Moreover, EndMT may have a negative impact on GC prognosis.
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Affiliation(s)
- Qian Zhao
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou 014030, China; School of Basic Medicine, Baotou Medical College, Baotou 014040, China
| | - Hui Yu
- Translational Medicine Center, Baotou Medical College, Baotou 014040, China
| | - Mengqi Shi
- School of Basic Medicine, Baotou Medical College, Baotou 014040, China
| | - Xujie Wang
- School of Basic Medicine, Baotou Medical College, Baotou 014040, China
| | - Zixu Fan
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou 014030, China
| | - Zhanli Wang
- Inner Mongolia Key Laboratory of Disease-Related Biomarkers, The Second Affiliated Hospital, Baotou Medical College, Baotou 014030, China.
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Zhang P, Zhang X, Lang J, Wu S, Sun Y, Wang P, Qiu S, Huang X, Ren G, Liu K, Du X, Xiao S, Wang Z, Weng Y, Zhang Y, Zhou H, Tu W, Zhang C, Yi J. Epidermal growth factor receptor‑targeted antibody nimotuzumab combined with chemoradiotherapy improves survival in patients with locally advanced head and neck squamous cell carcinoma: a propensity score matching real-world study. MedComm (Beijing) 2024; 5:e608. [PMID: 38962426 PMCID: PMC11220178 DOI: 10.1002/mco2.608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 05/06/2024] [Accepted: 05/17/2024] [Indexed: 07/05/2024] Open
Abstract
Patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) have poor survival outcomes. The real-world efficacy of nimotuzumab plus intensity modulated radiotherapy (IMRT)-based chemoradiotherapy in patients with LA-HNSCC remains unclear. A total of 25,442 HNSCC patients were screened, and 612 patients were matched by propensity score matching (PSM) (1:1). PSM was utilized to balance known confounding factors. Patients who completed at least five doses of nimotuzumab were identified as study group. The primary end point was 3-year overall survival (OS) rate. Log-rank test examined the difference between two survival curves and Cloglog transformation test was performed to compare survival at a fixed time point. The median follow-up time was 54.2 (95% confidence interval [CI]: 52.7-55.9) months. The study group was associated with improved OS (hazard ratio [HR] = 0.75, 95% CI: 0.57-0.99, p = 0.038) and progression-free survival (PFS) (HR = 0.74, 95% CI: 0.58-0.96, p = 0.021). Subgroup analysis revealed that aged 50-60 year, IV, N2, radiotherapy dose ≥ 60 Gy, without previous surgery, and neoadjuvant therapy have a trend of survival benefit with nimotuzumab. Nimotuzumab showed favorable safety, only 0.2% had nimotuzumab-related severe adverse events. Our study indicated the nimotuzumab plus chemoradiotherapy provides survival benefits and safety for LA-HNSCC patients in an IMRT era.
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Affiliation(s)
- Peng Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for CancerSichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduChina
| | - Xinxin Zhang
- Senior Department of Otolaryngology‐Head & Neck Surgerythe Sixth Medical Center of PLA General Hospital, National Clinical Research Center for Otolaryngologic DiseasesBeijingChina
| | - Jinyi Lang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for CancerSichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduChina
| | - Shaoxiong Wu
- Department of Radiation Oncology, State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Yan Sun
- Department of Radiation OncologyBeijing Cancer HospitalBeijingChina
| | - Peiguo Wang
- Department of Radiation OncologyTianjin Medical University Cancer Institute & HospitalTianjinChina
| | - Sufang Qiu
- Department of Radiation Head and Neck OncologyFujian Cancer HospitalFuzhouChina
| | - Xiaodong Huang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Guoxin Ren
- Department of Oral and Maxillofacial Tumor SurgeryShanghai Ninth People's Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Kun Liu
- Senior Department of Otolaryngology‐Head & Neck Surgerythe Sixth Medical Center of PLA General Hospital, National Clinical Research Center for Otolaryngologic DiseasesBeijingChina
| | - Xiaojing Du
- Department of Radiation Oncology, State Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Shaowen Xiao
- Department of Radiation OncologyBeijing Cancer HospitalBeijingChina
| | - Zhongqiu Wang
- Department of Radiation OncologyTianjin Medical University Cancer Institute & HospitalTianjinChina
| | - Youliang Weng
- Department of Radiation Head and Neck OncologyFujian Cancer HospitalFuzhouChina
| | - Ye Zhang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hang Zhou
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for CancerSichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengduChina
| | - Wenyong Tu
- Department of Oral and Maxillofacial Tumor SurgeryShanghai Ninth People's Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Chenping Zhang
- Department of Oral and Maxillofacial Tumor SurgeryShanghai Ninth People's Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Junlin Yi
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Zhao J, Guo M, Yan Y, Wang Y, Zhao X, Yang J, Chen J, Chen C, Tang L, Zeng W, Liu Y, Qin M, Zhou Y, Xu L. The miR-7/EGFR axis controls the epithelial cell immunomodulation and regeneration and orchestrates the pathology in inflammatory bowel disease. J Adv Res 2024; 57:119-134. [PMID: 37094666 PMCID: PMC10918346 DOI: 10.1016/j.jare.2023.04.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 04/12/2023] [Indexed: 04/26/2023] Open
Abstract
INTRODUCTION The epithelial immunomodulation and regeneration are intrinsic critical events against inflammatory bowel disease (IBD). MiR-7 is well documented as a promising regulator in the development of various diseases including inflammatory diseases. OBJECTIVES This study aimed to assess the effect of miR-7 in intestinal epithelial cells (IECs) in IBD. METHODS MiR-7def mice were given dextran sulfate sodium (DSS) to induce enteritis model. The infiltration of inflammatory cells was measured by FCM and immunofluorescence assay. 5'deletion assay and EMSA assays were performed to study the regulatory mechanism of miR-7 expression in IECs. The inflammatory signals and the targets of miR-7 were analyzed by RNA-seq and FISH assay. IECs were isolated from miR-7def, miR-7oe and WT mice to identify the immunomodulation and regeneration capacity. IEC-specific miR-7 silencing expression vector was designed and administered by the tail vein into murine DSS-induced enteritis model to evaluate the pathological lesions of IBD. RESULTS We found miR-7 deficiency improved the pathological lesions of DSS-induced murine enteritis model, accompanied by elevated proliferation and enhanced transduction of NF-κB/AKT/ERK signals in colonic IECs, as well as decreased local infiltration of inflammatory cells. MiR-7 was dominantly upregulated in colonic IECs in colitis. Moreover, the transcription of pre-miR-7a-1, orchestrated by transcription factor C/EBPα, was a main resource of mature miR-7 in IECs. As for the mechanism, EGFR, a miR-7 target gene, was downregulated in colonic IECs in colitis model and Crohn's disease patients. Furthermore, miR-7 also controlled the proliferation and inflammatory-cytokine secretion of IECs in response to inflammatory-signals through EGFR/NF-κB/AKT/ERK pathway. Finally, IEC-specific miR-7 silencing promoted the proliferation and transduction of NF-κB pathway in IECs and alleviated the pathological damage of colitis. CONCLUSION Our results present the unknown role of miR-7/EGFR axis in IEC immunomodulation and regeneration in IBD and might provide clues for the application of miRNA-based therapeutic strategies in colonic diseases.
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Affiliation(s)
- Juanjuan Zhao
- School of Medicine, Guizhou University, Guiyang 550025, Guizhou, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Mengmeng Guo
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Yaping Yan
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Ya Wang
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Xu Zhao
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Jing Yang
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Jing Chen
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Chao Chen
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Lin Tang
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Wenhuan Zeng
- Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Yiting Liu
- Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Ming Qin
- Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Ya Zhou
- Department of Medical Physics, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China
| | - Lin Xu
- School of Medicine, Guizhou University, Guiyang 550025, Guizhou, China; Department of Immunology, Zunyi Medical University, Guizhou 563000, China; Key Laboratory of Gene Detection and Treatment of Guizhou Province, Guizhou, Zunyi 563000, China; Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou 563000, China.
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Mohamed ME, El-Shafae AM, Fikry E, Elbaramawi SS, Elbatreek MH, Tawfeek N. Casuarina glauca branchlets' extract as a potential treatment for ulcerative colitis: chemical composition, in silico and in vivo studies. Front Pharmacol 2023; 14:1322181. [PMID: 38196993 PMCID: PMC10774231 DOI: 10.3389/fphar.2023.1322181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/20/2023] [Indexed: 01/11/2024] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease that is often resistant to current treatment options, leading to a need for alternative therapies. Herbal products have shown promise in managing various conditions, including UC. However, the potential of Casuarina glauca branchlets ethanolic extract (CGBRE) in treating UC has not been explored. This study aimed to analyze the chemical composition of CGBRE and evaluate its efficacy in UC treatment through in silico and in vivo experiments. LC-ESI-MS/MS was used to identify 86 compounds in CGBRE, with 21 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 171 potential UC targets for the bioactive compounds, including EGFR, LRRK2, and HSP90 as top targets, which were found to bind to key CGBRE compounds through molecular docking. Molecular docking findings suggested that CGBRE may be effective in the prevention or treatment of ulcerative colitis mediated by these proteins, where key CGBRE compounds exhibited good binding affinities through formation of numerous interactions. In vivo studies in rats with acetic acid-induced UC demonstrated that oral administration of 300 mg/kg CGBRE for 6 days reduced UC symptoms and colonic expression of EGFR, LRRK2, and HSP90. These findings supported the therapeutic potential of CGBRE in UC and suggested the need for further preclinical and clinical investigation.
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Affiliation(s)
- Maged E. Mohamed
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Azza M. El-Shafae
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Eman Fikry
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Samar S. Elbaramawi
- Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mahmoud H. Elbatreek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Nora Tawfeek
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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Ahmad R, Kumar B, Thapa I, Tamang RL, Yadav SK, Washington MK, Talmon GA, Yu AS, Bastola DK, Dhawan P, Singh AB. Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing. J Clin Invest 2023; 133:e170771. [PMID: 37815870 PMCID: PMC10688979 DOI: 10.1172/jci170771] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
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Affiliation(s)
- Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska Omaha, Omaha, Nebraska, USA
| | - Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Santosh K. Yadav
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Mary K. Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Alan S. Yu
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Dhundy K. Bastola
- School of Interdisciplinary Informatics, University of Nebraska Omaha, Omaha, Nebraska, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
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9
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Computer-Aided Screening and Revealing Action Mechanism of Food-Derived Tripeptides Intervention in Acute Colitis. Int J Mol Sci 2022; 23:ijms232113471. [PMID: 36362252 PMCID: PMC9655126 DOI: 10.3390/ijms232113471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Food-derived tripeptides can relieve colitis symptoms; however, their alleviation mode has not been systematically evaluated as an alternative nutritional compound. This study aimed to reveal the potential mechanism of 8000 food-derived tripeptides against acute colitis using a computer-aided screening strategy. Forty-one potential hub targets related to colitis with a Fit score > 4.0 were screened to construct the protein-protein and protein-tripeptide network based on the PharmMapper database and STRING software (Ver. 11.5). In addition, 30 significant KEGG signaling pathways with p-values < 0.001 that the 41 hub targets mainly participated in were identified using DAVID software (Ver. 6.8), including inflammatory, immunomodulatory, and cell proliferation and differentiation-related signaling pathways, particularly in the Ras- and PI3K-Akt signaling pathways. Furthermore, molecular docking was performed using the Autodock against majorly targeted proteins (AKT1, EGFR, and MMP9) with the selected 52 tripeptides. The interaction model between tripeptides and targets was mainly hydrogen-bonding and hydrophobic interactions, and most of the binding energy of the tripeptide target was less than −7.13 kcal/mol. This work can provide valuable insight for exploring food-derived tripeptide mechanisms and therapeutic indications.
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10
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Cao Y, Oh J, Xue M, Martin AL, Song D, Crawford JM, Herzon SB, Palm NW. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science 2022; 378:eabm3233. [PMID: 36302024 PMCID: PMC9993714 DOI: 10.1126/science.abm3233] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Microbiota-derived metabolites that elicit DNA damage can contribute to colorectal cancer (CRC). However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of an extensive collection of gut commensals from inflammatory bowel disease patients. We identified isolates from divergent phylogenies whose metabolites caused DNA damage and discovered a distinctive family of genotoxins-termed the indolimines-produced by the CRC-associated species Morganella morganii. A non-indolimine-producing M. morganii mutant lacked genotoxicity and failed to exacerbate colon tumorigenesis in mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the microbiome that may affect host biology in homeostasis and disease.
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Affiliation(s)
- Yiyun Cao
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
| | - Joonseok Oh
- Department of Chemistry, Yale University, New Haven, CT 06520, USA
- Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA
| | - Mengzhao Xue
- Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY 10065, USA
| | - Anjelica L. Martin
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
| | - Deguang Song
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
| | - Jason M. Crawford
- Department of Chemistry, Yale University, New Haven, CT 06520, USA
- Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT 06516, USA
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA
| | - Seth B. Herzon
- Department of Chemistry, Yale University, New Haven, CT 06520, USA
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Noah W. Palm
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06519, USA
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11
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Kaur H, Ali SA, Yan F. Interactions between the gut microbiota-derived functional factors and intestinal epithelial cells - implication in the microbiota-host mutualism. Front Immunol 2022; 13:1006081. [PMID: 36159834 PMCID: PMC9492984 DOI: 10.3389/fimmu.2022.1006081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 08/23/2022] [Indexed: 12/13/2022] Open
Abstract
Mutual interactions between the gut microbiota and the host play essential roles in maintaining human health and providing a nutrient-rich environment for the gut microbial community. Intestinal epithelial cells (IECs) provide the frontline responses to the gut microbiota for maintaining intestinal homeostasis. Emerging evidence points to commensal bacterium-derived components as functional factors for the action of commensal bacteria, including protecting intestinal integrity and mitigating susceptibility of intestinal inflammation. Furthermore, IECs have been found to communicate with the gut commensal bacteria to shape the composition and function of the microbial community. This review will discuss the current understanding of the beneficial effects of functional factors secreted by commensal bacteria on IECs, with focus on soluble proteins, metabolites, and surface layer components, and highlight the impact of IECs on the commensal microbial profile. This knowledge provides a proof-of-concept model for understanding of mechanisms underlying the microbiota-host mutualism.
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Affiliation(s)
- Harpreet Kaur
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Syed Azmal Ali
- German Cancer Research Center, Division of Proteomics of Stem Cell and Cancer, Heidelberg, Germany
| | - Fang Yan
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States,Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States,*Correspondence: Fang Yan,
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12
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Cui H, Wei W, Qian M, Tian R, Fu X, Li H, Nan G, Yang T, Lin P, Chen X, Zhu Y, Wang B, Sun X, Dou J, Jiang J, Li L, Wang S, Chen Z. PDGFA-associated protein 1 is a novel target of c-Myc and contributes to colorectal cancer initiation and progression. Cancer Commun (Lond) 2022; 42:750-767. [PMID: 35716012 PMCID: PMC9395323 DOI: 10.1002/cac2.12322] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/26/2022] [Accepted: 06/06/2022] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA-associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target. METHODS Multi-omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient-derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target. RESULTS PDAP1 was identified as a potential key player in CRC development using multi-omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt-induced colitis and inhibited tumor initiation and growth in colitis-associated cancers. Mechanistic studies showed that c-Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR-mitogen-activated protein kinase (MAPK) signaling activation, which resulted in FOS-related antigen 1 (FRA-1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient-derived xenografts that sustain high PDAP1 levels. CONCLUSIONS PDAP1 facilitates mucosal restitution and carcinogenesis in colitis-associated cancer. c-Myc-driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR-MAPK-FRA-1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.
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Affiliation(s)
- Hong‐Yong Cui
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Wei Wei
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Mei‐Rui Qian
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Ruo‐Fei Tian
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Xin Fu
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Hong‐Wei Li
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Gang Nan
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Ting Yang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
- Department of Clinical MedicineMedical College of Yan'an UniversityYan'anShaanxi716000P. R. China
| | - Peng Lin
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Xi Chen
- Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of EducationCollege of Chemistry and Materials ScienceNorthwest UniversityXi'anShaanxi710127P. R. China
| | - Yu‐Meng Zhu
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Bin Wang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Xiu‐Xuan Sun
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Jian‐Hua Dou
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Jian‐Li Jiang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Ling Li
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Shi‐Jie Wang
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
| | - Zhi‐Nan Chen
- National Translational Science Center for Molecular Medicine & Department of Cell BiologyFourth Military Medical UniversityXi'anShaanxi710032P. R. China
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13
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Lin Z, Chen L, Cheng M, Zhu F, Yang X, Zhao W, Zuo J, He S. Cortex periplocae modulates the gut microbiota to restrict colitis and colitis-associated colorectal cancer via suppression of pathogenic Th17 cells. Biomed Pharmacother 2022; 153:113399. [PMID: 35834986 DOI: 10.1016/j.biopha.2022.113399] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/05/2022] [Accepted: 07/08/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant microbe-immune cell interaction is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Cortex Periplocae is a famous traditional Chinese medicine with putative anti-rheumatoid arthritis and anti-dyspepsia effects. Here, we show that the Periploca sepium periplosides (PePs), a cardiac glycosides-free pregnane glycosides extract from root bark of Cortex Periplocae, alleviates colon inflammation, improves intestinal epithelial barrier function, and prevents colitis-associated tumorigenesis in mice with colitis and CAC. Mechanistically, PePs treatment modulates abnormal gut microbiota composition in model mice, especially enriches an anti-inflammatory commensal bacterium A. muciniphila BAA-835. We further demonstrate that the altered gut microbiota following PePs treatment plays an important role in modulation of intestinal Type 17 immunity in both colitis and CAC mouse model. Our results indicate that PePs may be used as a potential gut microbiota modulator to treat IBD and CAC.
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Affiliation(s)
- Zemin Lin
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Li Chen
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengnan Cheng
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Fenghua Zhu
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xiaoqian Yang
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Weimin Zhao
- University of Chinese Academy of Sciences, Beijing 100049, China; Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jianping Zuo
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Shijun He
- Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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14
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Effects of Spore-Displayed p75 Protein from Lacticaseibacillus rhamnosus GG on the Transcriptional Response of HT-29 Cells. Microorganisms 2022; 10:microorganisms10071276. [PMID: 35888995 PMCID: PMC9323162 DOI: 10.3390/microorganisms10071276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/20/2022] [Accepted: 06/22/2022] [Indexed: 12/10/2022] Open
Abstract
A Lacticaseibacillus rhamnosus GG-derived protein, p75, is one of the key molecules exhibiting probiotic activity. However, the molecular mechanism and transcriptional response of p75 in human intestinal epithelial cells are not completely understood. To gain a deeper understanding of its potential probiotic action, this study investigated genome-wide responses of HT-29 cells to stimulation by spore-displayed p75 (CotG-p75) through a transcriptome analysis based on RNA sequencing. Analysis of RNA-seq data showed significant changes of gene expression in HT-29 cells stimulated by CotG-p75 compared to the control. A total of 189 up-regulated and 314 down-regulated genes was found as differentially expressed genes. Gene ontology enrichment analysis revealed that a large number of activated genes was involved in biological processes, such as epithelial cell differentiation, development, and regulation of cell proliferation. A gene–gene interaction network analysis showed that several DEGs, including AREG, EREG, HBEGF, EPGN, FASLG, GLI2, CDKN1A, FOSL1, MYC, SERPINE1, TNFSF10, BCL6, FLG, IVL, SPRR1A, SPRR1B, SPRR3, and MUC5AC, might play a critical role in these biological processes. RNA-seq results for selected genes were verified by reverse transcription-quantitative polymerase chain reaction. Overall, these results provide extensive knowledge about the transcriptional responses of HT-29 cells to stimulation by CotG-p75. This study showed that CotG-p75 can contribute to cell survival and epithelial development in human intestinal epithelial cells.
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15
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Liu CY, Girish N, Gomez ML, Dubé PE, Washington MK, Simons BD, Polk DB. Transitional Anal Cells Mediate Colonic Re-epithelialization in Colitis. Gastroenterology 2022; 162:1975-1989. [PMID: 35227778 PMCID: PMC9402284 DOI: 10.1053/j.gastro.2022.02.031] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS Epithelial wound healing is compromised and represents an unleveraged therapeutic target in inflammatory bowel disease (IBD). Intestinal epithelial cells exhibit plasticity that facilitates dedifferentiation and repair during the response to injury. However, it is not known whether epithelial cells of a neighboring organ can be activated to mediate re-epithelialization in acute colitis. Histological findings of a permanent squamous tissue structure in the distal colon in human IBD could suggest diverse cellular origins of repair-associated epithelium. Here, we tested whether skin-like cells from the anus mediate colonic re-epithelialization in murine colitis. METHODS We studied dextran sulfate sodium-induced colitis and interleukin 10-deficient colitis in transgenic mice. We performed lineage tracing, 3-dimensional (3D) imaging, single-cell transcriptomics, and biophysical modeling to map squamous cell fates and to identify squamous cell types involved in colonic repair. RESULTS In acute and chronic colitis, we found a large squamous epithelium, called squamous neo-epithelium of the colon (SNEC), near the anorectal junction. Neighboring squamous cells of the anus rapidly migrate into the ulcerated colon and establish this permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, distal to the border of colonic and anal epithelium, that resists colitic injury. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair. CONCLUSION Transitional anal cells represent unique reserve cells capable of rebuilding epithelial structures in the colon after colitis. Further study of these cells could reveal novel approaches to direct mucosal healing in inflammation and disease.
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Affiliation(s)
- Cambrian Y Liu
- Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Nandini Girish
- Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California
| | - Marie L Gomez
- Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Philip E Dubé
- Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Benjamin D Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
| | - D Brent Polk
- Division of Pediatric Gastroenterology and Nutrition, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California; Department of Pediatrics, Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California.
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16
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Arredondo-Amador M, González R, Aranda CJ, Martínez-Augustin O, Sánchez de Medina F. Mice carrying an epithelial deletion of the glucocorticoid receptor NR3C1 develop a higher tumor load in experimental colitis-associated cancer. Am J Physiol Gastrointest Liver Physiol 2021; 321:G705-G718. [PMID: 34669484 DOI: 10.1152/ajpgi.00384.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The glucocorticoid receptor NR3C1 is expressed in multiple cell types in the gut and elsewhere. Intestinal epithelial cells both produce and respond to glucocorticoids in different physiological and pathological contexts. In experimental colitis, glucocorticoids have been shown to exert a dual role, dampening inflammation while producing a deterioration in animal status, including death. Mice with tamoxifen-inducible, intestinal epithelial-specific deletion of NR3C1 (NR3C1ΔIEC mice) are protected against experimental colitis, suggesting glucocorticoid epithelial actions are deleterious. Since glucocorticoids modulate epithelial proliferation, it follows that they may affect the development of colon cancer. In this study, we set out to test this hypothesis using the dextran sulfate sodium-azoxymethane model of colitis-associated cancer. Knockout (KO) mice were found to exhibit a twofold higher tumor load but similar incidence and tumor size. Tumors had a higher trend to extend close to the submucosal layer (36% vs. 0%) in NR3C1ΔIEC mice, and overexpressed Lgr5, Egfr, and Myc, consistent with distinct expression of proliferative/stemness markers. Snai1 and Snai2 were upregulated specifically in tumors of NR3C1ΔIEC mice, suggesting enhanced epithelial to mesenchymal transition in the absence of the intestinal epithelial glucocorticoid (GC) receptor. We conclude that endogenous GC epithelial signaling is involved in colitis-associated cancer.NEW & NOTEWORTHY Mice carrying a tamoxifen-inducible deletion of the glucocorticoid receptor in intestinal epithelial cells (NR3C1ΔIEC mice) and their corresponding controls were subjected to the azoxymethane-dextran sulfate sodium model of colitis-associated cancer. KO mice exhibit a twofold higher tumor load, with a higher trend to extend close to the submucosal layer (36% vs. 0%), but with similar incidence and tumor size. Colonic tumors in NR3C1ΔIEC mice showed signs of increased neoplastic transformation and tumor-associated inflammation.
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Affiliation(s)
- María Arredondo-Amador
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Raquel González
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Carlos J Aranda
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Olga Martínez-Augustin
- Department of Biochemistry and Molecular Biology II, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
| | - Fermín Sánchez de Medina
- Department of Pharmacology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
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17
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Skibbe K, Brethack AK, Sünderhauf A, Ragab M, Raschdorf A, Hicken M, Schlichting H, Preira J, Brandt J, Castven D, Föh B, Pagel R, Marquardt JU, Sina C, Derer S. Colorectal Cancer Progression Is Potently Reduced by a Glucose-Free, High-Protein Diet: Comparison to Anti-EGFR Therapy. Cancers (Basel) 2021; 13:cancers13225817. [PMID: 34830971 PMCID: PMC8616508 DOI: 10.3390/cancers13225817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 11/28/2022] Open
Abstract
Simple Summary To study the interplay between nutrition and intestinal metabolism in the context of colitis-driven colorectal carcinoma (CRC), we here investigated a nutritional therapy strategy in the presence or absence of EGFR-directed antibody therapy in mice to treat established colitis-driven CRCs in vivo. After CRC development, mice were fed a control diet or an isoenergetic glucose-free high-protein (GFHP) diet in the presence or absence of EGFR-directed antibody therapy. The GFHP diet was accompanied by a metabolic shift of the mice towards lower glycolysis activity. Both, GFHP diet or anti-EGFR antibody treatment, improved tumor differentiation and anti-tumor immune response, resulting in an efficient reduction of colonic tumor burden. Abstract To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.
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Affiliation(s)
- Kerstin Skibbe
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Ann-Kathrin Brethack
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Annika Sünderhauf
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Mohab Ragab
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Annika Raschdorf
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Maren Hicken
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Heidi Schlichting
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Joyce Preira
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Jennifer Brandt
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - Darko Castven
- 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (D.C.); (J.U.M.)
| | - Bandik Föh
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
| | - René Pagel
- Institute of Anatomy, University of Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany;
| | - Jens U. Marquardt
- 1st Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (D.C.); (J.U.M.)
| | - Christian Sina
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
- 1st Department of Medicine, Division of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany
| | - Stefanie Derer
- Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Schleswig-Holstein, Germany; (K.S.); (A.-K.B.); (A.S.); (M.R.); (A.R.); (M.H.); (H.S.); (J.P.); (J.B.); (B.F.); (C.S.)
- Correspondence:
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18
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Liu CY, Cham CM, Chang EB. Epithelial wound healing in inflammatory bowel diseases: the next therapeutic frontier. Transl Res 2021; 236:35-51. [PMID: 34126257 PMCID: PMC8380699 DOI: 10.1016/j.trsl.2021.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/25/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023]
Abstract
Patients with one of the many chronic inflammatory disorders broadly classified as inflammatory bowel disease (IBD) now have a diverse set of immunomodulatory therapies at their disposal. Despite these recent medical advances, complete sustained remission of disease remains elusive for most patients. The full healing of the damaged intestinal mucosa is the primary goal of all therapies. Achieving this requires not just a reduction of the aberrant immunological response, but also wound healing of the epithelium. No currently approved therapy directly targets the epithelium. Epithelial repair is compromised in IBD and normally facilitates re-establishment of the homeostatic barrier between the host and the microbiome. In this review, we summarize the evidence that epithelial wound healing represents an important yet underdeveloped therapeutic modality for IBD. We highlight 3 general approaches that are promising for developing a new class of epithelium-targeted therapies: epithelial stem cells, cytokines, and microbiome engineering. We also provide a frank discussion of some of the challenges that must be overcome for epithelial repair to be therapeutically leveraged. A concerted approach by the field to develop new therapies targeting epithelial wound healing will offer patients a game-changing, complementary class of medications and could dramatically improve outcomes.
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Affiliation(s)
- Cambrian Y Liu
- Department of Medicine, The University of Chicago, Chicago, Illinois.
| | - Candace M Cham
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Eugene B Chang
- Department of Medicine, The University of Chicago, Chicago, Illinois.
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19
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McElrath C, Espinosa V, Lin JD, Peng J, Sridhar R, Dutta O, Tseng HC, Smirnov SV, Risman H, Sandoval MJ, Davra V, Chang YJ, Pollack BP, Birge RB, Galan M, Rivera A, Durbin JE, Kotenko SV. Critical role of interferons in gastrointestinal injury repair. Nat Commun 2021; 12:2624. [PMID: 33976143 PMCID: PMC8113246 DOI: 10.1038/s41467-021-22928-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/06/2021] [Indexed: 12/13/2022] Open
Abstract
The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.
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Affiliation(s)
- Constance McElrath
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Vanessa Espinosa
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Jian-Da Lin
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Jianya Peng
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Raghavendra Sridhar
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Orchi Dutta
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Hsiang-Chi Tseng
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergey V Smirnov
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Heidi Risman
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Marvin J Sandoval
- Department of Pathology, New York University School of Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
| | - Viralkumar Davra
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- School of Graduate Studies, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Yun-Juan Chang
- Office of Advance Research Computing, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Brian P Pollack
- Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
| | - Raymond B Birge
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Mark Galan
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Amariliz Rivera
- Pediatrics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Joan E Durbin
- Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA
| | - Sergei V Kotenko
- Department of Microbiology, Biochemistry, and Molecular Genetics, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Cell Signaling, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Cancer Institute of New Jersey, Rutgers-The State University of New Jersey, Newark, NJ, USA.
- Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ, USA.
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20
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TNF Receptor 1 Promotes Early-Life Immunity and Protects against Colitis in Mice. Cell Rep 2020; 33:108275. [PMID: 33086075 PMCID: PMC7682618 DOI: 10.1016/j.celrep.2020.108275] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 08/05/2020] [Accepted: 09/23/2020] [Indexed: 02/08/2023] Open
Abstract
Neutralization of tumor necrosis factor (TNF) represents a widely used therapeutic strategy for autoimmune diseases including inflammatory bowel disease (IBD). However, the fact that many patients with IBD are non-responsive to anti-TNF therapies suggests the need for a better understanding of TNF signaling in IBD. Here, we show that co-deletion of TNF receptor 1 (TNFR1, Tnfrsf1a) in the Il10-/- spontaneous colitis model exacerbates disease, resulting in very-early-onset inflammation after weaning. The disease can be interrupted by treatment with antibiotics. The single deletion of TNFR1 induces subclinical colonic epithelial dysfunction and mucosal immune abnormalities, including accumulation of neutrophils and depletion of B cells. During the pre-disease period (before weaning), both Tnfr1-/- and Il10-/-Tnfr1-/- animals exhibit impaired expression of pro-inflammatory cytokines compared with wild-type and Il10-/- controls, respectively. Collectively, these results demonstrate the net anti-inflammatory functions of TNF/TNFR1 signaling through the regulation of colonic immune homeostasis in early life.
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21
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Caveolar communication with xenobiotic-stalled ribosomes compromises gut barrier integrity. Commun Biol 2020; 3:270. [PMID: 32461676 PMCID: PMC7253476 DOI: 10.1038/s42003-020-0994-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 05/04/2020] [Indexed: 12/15/2022] Open
Abstract
In response to internal and external insults, the intestinal lining undergoes various types of epithelial adaptation or pathologic distress via stress-responsive eIF2α kinase signaling and subsequent cellular reprogramming. As a vital platform for growth factor-linked adaptive signaling, caveolae were evaluated for epithelial modulation of the insulted gut. Patients under ulcerative insult displayed enhanced expression of caveolin-1, the main structural component of caveolae, which was positively associated with expression of protein kinase R (PKR), the ribosomal stress-responsive eIF2α kinase. PKR-linked biological responses were simulated in experimental gut models of ribosome-inactivating stress using mice and Caenorhabditis elegans. Caveolar activation counteracted the expression of wound-protective epidermal growth factor receptor (EGFR) and its target genes, such as chemokines that were pivotal for epithelial integrity in the ribosome-inactivated gut. Mechanistic findings regarding ribosomal inactivation-associated disorders in the gut barrier provide crucial molecular evidence for detrimental caveolar actions against EGFR-mediated epithelial protection in patients with IBD.
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22
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Human Colorectal Cancer from the Perspective of Mouse Models. Genes (Basel) 2019; 10:genes10100788. [PMID: 31614493 PMCID: PMC6826908 DOI: 10.3390/genes10100788] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 09/25/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.
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23
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Shipman WD, Chyou S, Ramanathan A, Izmirly PM, Sharma S, Pannellini T, Dasoveanu DC, Qing X, Magro CM, Granstein RD, Lowes MA, Pamer EG, Kaplan DH, Salmon JE, Mehrara BJ, Young JW, Clancy RM, Blobel CP, Lu TT. A protective Langerhans cell-keratinocyte axis that is dysfunctional in photosensitivity. Sci Transl Med 2019; 10:10/454/eaap9527. [PMID: 30111646 DOI: 10.1126/scitranslmed.aap9527] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 07/13/2018] [Indexed: 12/14/2022]
Abstract
Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.
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Affiliation(s)
- William D Shipman
- Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA.,Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.,Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Susan Chyou
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Anusha Ramanathan
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Peter M Izmirly
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
| | - Sneh Sharma
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Tania Pannellini
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Dragos C Dasoveanu
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA.,Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Xiaoping Qing
- Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA
| | - Cynthia M Magro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | | | | | - Eric G Pamer
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Daniel H Kaplan
- Department of Dermatology, University of Pittsburgh, PA 15260, USA.,Department of Immunology, University of Pittsburgh, PA 15260, USA
| | - Jane E Salmon
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.,Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA.,Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.,Division of Rheumatology and Pediatric Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA
| | - Babak J Mehrara
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - James W Young
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Rockefeller University, New York, NY 10065, USA.,Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.,Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Robert M Clancy
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
| | - Carl P Blobel
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10065, USA.,Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.,Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.,Institute for Advanced Studies, Technical University Munich, Munich, Germany
| | - Theresa T Lu
- Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. .,Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA.,Division of Rheumatology and Pediatric Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA.,Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10065, USA
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24
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Chen W, Shen B, Sun X. Analysis of Progress and Challenges of EGFR-Targeted Molecular Imaging in Cancer With a Focus on Affibody Molecules. Mol Imaging 2019; 18:1536012118823473. [PMID: 30799684 PMCID: PMC6348515 DOI: 10.1177/1536012118823473] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted cancer therapy requires an accurate estimation of EGFR expression in tumors to identify responsive patients, monitor therapeutic effect, and estimate prognosis. The EGFR molecular imaging is an optimal method for evaluating EGFR expression in vivo accurately and noninvasively. In this review, we discuss the recent advances in EGFR-targeted molecular imaging in cancer, with a special focus on the development of imaging agents, including epidermal growth factor (EGF) ligand, monoclonal antibodies, antibody fragments, Affibody, and small molecules. Each substrate or probe, whether it is an endogenous ligand, antibody, peptide, or small molecule labeled with fluorochrome or radionuclide, has unique advantages and limitations. Antibody-based probes have high affinity but a long metabolic cycle and therefore offer poor imaging quality. Affibody molecules promise to surpass antibody-based probes due to their small size, stable chemical properties, and high affinity to the target. Small-molecule probes are safe, have favorable pharmacokinetics, and show high affinity and specificity, in addition to having an ideal size, but are inadequate for delayed imaging after injection due to their fast clearance.
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Affiliation(s)
- Weizhi Chen
- 1 Molecular Imaging Research Center, Harbin Medical University, Heilongjiang, China.,2 TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Heilongjiang, China
| | - Baozhong Shen
- 1 Molecular Imaging Research Center, Harbin Medical University, Heilongjiang, China.,2 TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Heilongjiang, China
| | - Xilin Sun
- 1 Molecular Imaging Research Center, Harbin Medical University, Heilongjiang, China.,2 TOF-PET/CT/MR Center, The Fourth Hospital of Harbin Medical University, Heilongjiang, China
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25
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Yu M, Kim J, Ahn JH, Moon Y. Nononcogenic restoration of the intestinal barrier by E. coli-delivered human EGF. JCI Insight 2019; 4:125166. [PMID: 31434808 DOI: 10.1172/jci.insight.125166] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 07/26/2019] [Indexed: 02/06/2023] Open
Abstract
Although mucoactive proteins, such as epidermal growth factor (EGF), could improve clinical outcomes of intestinal ulcerative diseases, their gastrointestinal application is limited because of their proteolytic digestion or concerns about tumor promotion. In the present study, ATP-binding cassette (ABC) transporter-linked secretion of human EGF from probiotic Escherichia coli (EGF-EcN) was created to promote beneficial actions of the EGF receptor, which is notably attenuated in patients with intestinal ulcerative injuries. Preventive and postinjury treatment with EGF-EcN alleviated intestinal ulcers and other readouts of disease severity in murine intestinal ulcer models. EGF-EcN administration promoted the restitutive recovery of damaged epithelial layers, particularly via upward expansion of highly proliferating progenitor cells from the lower crypts. Along with the epithelial barrier benefit, EGF-EcN improved goblet cell-associated mucosal integrity, which controls the access of luminal microbiota to the underlying host tissues. Despite concern about the oncogenic action of EGF, EGF-EcN did not aggravate colitis-associated colon cancer; instead, it alleviated protumorigenic activities and improved barrier integrity in the lesions. All findings indicate that probiotic bacteria-based precision delivery of human EGF is a promising mucosal intervention against gastrointestinal ulcers and malignant distress through crypt-derived barrier restoration.
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Affiliation(s)
- Mira Yu
- Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Biomedical Research Institute, Pusan National University, Yangsan, South Korea
| | - Juil Kim
- Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Biomedical Research Institute, Pusan National University, Yangsan, South Korea
| | | | - Yuseok Moon
- Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Biomedical Research Institute, Pusan National University, Yangsan, South Korea.,College of Information and BioMedical Engineering, Pusan National University, Yangsan, South Korea
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26
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Wang L, Yang B, Jiang H, Yu G, Feng M, Lu X, Luo Q, Wu H, Zhang S, Liu H. The molecular mechanism study of insulin in promoting wound healing under high-glucose conditions. J Cell Biochem 2019; 120:16244-16253. [PMID: 31081255 DOI: 10.1002/jcb.28905] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 03/15/2019] [Accepted: 03/22/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND Wound healing is a complex process in bone development. The aim of this study was to explore the molecular mechanism study of insulin in promoting wound healing. METHODS Firstly, the acute human monocyte leukemia cell lines were induced to differentiate into macrophages. Secondly, the porphyromonas gingivalis was applied to mix with the differentiated macrophages. Thirdly, the effect of different concentrations of insulin (0 ng/mL, 5 ng/mL, 50 ng/mL, 100 ng/mL, 200 ng/mL, 500 ng/mL, and 1,000 ng/mL) on the phagocytosis of macrophages and production of reactive oxygen species was investigated. Depending on these experiments, the optimal insulin concentration was used to treat the macrophages at different time points (0 hours and 0.5 hours) to identify the differentially expressed mRNAs. Finally, functional analysis including gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) analysis was carried out to explore the biological function of these differentially expressed mRNAs. RESULTS The test of phagocytosis function and production of reactive oxygen species showed that 200 ng/mL insulin treatment had a significant influence on antibacterial and production of reactive oxygen species. In RNA sequencing, a total of 415 (245 upregulated and 170 downregulated) differentially expressed mRNAs were identified between different time points. Two important signaling pathways including endocytosis and systemic lupus erythematosus were found in the KEGG enrichment analysis. In the PPI network, several hub proteins encoded by differentially expressed mRNA including ALB, HIP1R, RAB5A, HIST1H2BJ, HIST1H3G, and HIST1H2BO were identified. CONCLUSION Our work demonstrated that several differentially expressed mRNAs, such as EGR1, RAB34, ALB, HIP1R, RAB5A, HIST1H2BJ, HIST1H3G, and HIST1H2BO and two important signaling pathways including endocytosis and systemic lupus erythematosus may play important roles in the bone wound healing.
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Affiliation(s)
- Lin Wang
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Bai Yang
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Hua Jiang
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Guo Yu
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Mi Feng
- Department of applied chemistry, Chinese Academy of sciences key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.,Department of applied chemistry, College of Chemical and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Xingmei Lu
- Department of chemical engineering and technology, Chinese Academy of sciences key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China.,Department of chemical engineering and technology, College of Chemical and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Luo
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Hao Wu
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Shuo Zhang
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Hongchen Liu
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Beijing, China
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27
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Triner D, Devenport SN, Ramakrishnan SK, Ma X, Frieler RA, Greenson JK, Inohara N, Nunez G, Colacino JA, Mortensen RM, Shah YM. Neutrophils Restrict Tumor-Associated Microbiota to Reduce Growth and Invasion of Colon Tumors in Mice. Gastroenterology 2019; 156:1467-1482. [PMID: 30550822 PMCID: PMC6441634 DOI: 10.1053/j.gastro.2018.12.003] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 11/26/2018] [Accepted: 12/05/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Neutrophils are among the most prevalent immune cells in the microenvironment of colon tumors; they are believed to promote growth of colon tumors, and their numbers correlate with outcomes of patients with colon cancer. Trials of inhibitors of neutrophil trafficking are underway in patients with cancer, but it is not clear how neutrophils contribute to colon tumorigenesis. METHODS Colitis-associated colon cancer was induced in mice with conditional deletion of neutrophils (LysMCre;Mcl1fl/fl) and wild-type littermates (LysMCre;Mcl1wt/wt, control mice) by administration of azoxythmethane and/or dextran sulfate sodium. Sporadic colon tumorigenesis was assessed in neutrophil-deficient and neutrophil-replete mice with conditional deletion of colon epithelial Apc (Cdx2-CreERT2;Apcfl/fl). Primary colon tumor tissues from these mice were assessed by histology, RNA sequencing, quantitative polymerase chain reaction, and fluorescence in situ hybridization analyses. Fecal and tumor-associated microbiota were assessed by 16s ribosomal RNA sequencing. RESULTS In mice with inflammation-induced and sporadic colon tumors, depletion of neutrophils increased the growth, proliferation, and invasiveness of the tumors. RNA sequencing analysis identified genes that regulate antimicrobial and inflammatory processes that were dysregulated in neutrophil-deficient colon tumors compared with colon tumors from control mice. Neutrophil depletion correlated with increased numbers of bacteria in tumors and proliferation of tumor cells, tumor-cell DNA damage, and an inflammatory response mediated by interleukin 17 (IL17). The 16s ribosomal RNA sequencing identified significant differences in the composition of the microbiota between colon tumors from neutrophil-deficient vs control mice. Administration of antibiotics or a neutralizing antibody against IL17 to neutrophil-deficient mice resulted in development of less-invasive tumors compared with mice given vehicle. We found bacteria in tumors to induce production of IL17, which promotes influx of intratumor B cells that promote tumor growth and progression. CONCLUSIONS In comparisons of mice with vs without neutrophils, we found neutrophils to slow colon tumor growth and progression by restricting numbers of bacteria and tumor-associated inflammatory responses.
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Affiliation(s)
- Daniel Triner
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI
| | - Samantha N. Devenport
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI
| | | | - Xiaoya Ma
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI
| | - Ryan A. Frieler
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI
| | - Joel K. Greenson
- Department of Pathology, University of Michigan Medical School, Ann Arbor MI
| | - Naohiro Inohara
- Department of Pathology, University of Michigan Medical School, Ann Arbor MI
| | - Gabriel Nunez
- Department of Pathology, University of Michigan Medical School, Ann Arbor MI,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor MI
| | - Justin A. Colacino
- Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor MI,Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor MI
| | - Richard M. Mortensen
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI,Internal Medicine Division of Metabolism, Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor MI
| | - Yatrik M. Shah
- Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor MI,Internal Medicine Division of Gastroenterology, University of Michigan Medical School, Ann Arbor MI,Rogel Cancer Center, University of Michigan Medical School, Ann Arbor MI
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28
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Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 2018; 11:1316-1328. [PMID: 29875401 PMCID: PMC6162144 DOI: 10.1038/s41385-018-0034-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 04/01/2018] [Accepted: 04/15/2018] [Indexed: 02/04/2023]
Abstract
The beneficial effects of the gut microbiota on growth in early life are well known. However, knowledge about the mechanisms underlying regulating intestinal development by the microbiota is limited. p40, a Lactobacillus rhamnosus GG-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells for protecting the intestinal epithelium against injury and inflammation. Here, we developed p40-containing pectin/zein hydrogels for targeted delivery of p40 to the small intestine and the colon. Treatment with p40-containing hydrogels from postnatal day 2 to 21 significantly enhanced bodyweight gain prior to weaning and functional maturation of the intestine, including intestinal epithelial cell proliferation, differentiation, and tight junction formation, and IgA production in early life in wild-type mice. These p40-induced effects were abolished in mice with specific deletion of EGFR in intestinal epithelial cells, suggesting that transactivation of EGFR in intestinal epithelial cells may mediate p40-regulated intestinal development. Furthermore, neonatal p40 treatment reduced the susceptibility to intestinal injury and colitis and promoted protective immune responses, including IgA production and differentiation of regulatory T cells, in adult mice. These findings reveal novel roles of neonatal supplementation of probiotic-derived factors in promoting EGFR-mediated maturation of intestinal functions and innate immunity, which likely promote long-term beneficial outcomes.
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29
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Dubé PE, Liu CY, Girish N, Washington MK, Polk DB. Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice. Sci Rep 2018; 8:9119. [PMID: 29904166 PMCID: PMC6002410 DOI: 10.1038/s41598-018-27353-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/30/2018] [Indexed: 12/15/2022] Open
Abstract
Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity ("early"), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation ("late") increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.
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Affiliation(s)
- Philip E Dubé
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
- Taconic Biosciences, Hudson, NY, USA
| | - Cambrian Y Liu
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA, USA.
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
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30
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Ahmad R, Kumar B, Chen Z, Chen X, Müller D, Lele SM, Washington MK, Batra SK, Dhawan P, Singh AB. Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/β-catenin signaling. Oncogene 2017; 36:6592-6604. [PMID: 28783170 PMCID: PMC6512312 DOI: 10.1038/onc.2017.259] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/28/2017] [Accepted: 06/19/2017] [Indexed: 12/12/2022]
Abstract
The Hyperactivated Wnt/β-catenin signaling acts as a switch to induce EMT and promote colorectal cancer. However, due to its essential role in gut homeostasis, therapeutic targeting of this pathway has proven challenging. Additionally, IL-6/Stat-3 signaling, activated by microbial translocation through the dysregulated mucosal barrier in colon adenomas, facilitates the adenoma to adenocarcinomas transition. However, inter-dependence between these signaling pathways and key mucosal barrier components in regulating colon tumorigenesis and cancer progression remains unclear. In current study, we have discovered, using a comprehensive investigative regimen, a novel and tissue specific role of claudin-3, a tight junction integral protein, in inhibiting colon cancer progression by serving as the common rheostat of Stat-3 and Wnt-signaling activation. Loss of claudin-3 also predicted poor patient survival. These findings however contrasted an upregulated claudin-3 expression in other cancer types and implicated role of the epigenetic regulation. Claudin-3−/− mice revealed dedifferentiated and leaky colonic epithelium, and developed invasive adenocarcinoma when subjected to colon cancer. Wnt-signaling hyperactivation, albeit in GSK-3β independent manner, differentiated colon cancer in claudin-3−/− mice versus WT-mice. Claudin-3 loss also upregulated the gp130/IL6/Stat3 signaling in colonic epithelium potentially assisted by infiltrating immune components. Genetic and pharmacological studies confirmed that claudin-3 loss induces Wnt/β-catenin activation, which is further exacerbated by Stat-3-activation and help promote colon cancer. Overall, these novel findings identify claudin-3 as a therapeutic target for inhibiting overactivation of Wnt-signaling to prevent CRC malignancy.
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Affiliation(s)
- R Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - B Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Z Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - X Chen
- Division of Biostatistics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Müller
- Department of Pediatric Nephrology, Charité, and Berlin Institute of Health, Berlin, Germany
| | - S M Lele
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - M K Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - S K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - P Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - A B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
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31
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Hardbower DM, Coburn LA, Asim M, Singh K, Sierra JC, Barry DP, Gobert AP, Piazuelo MB, Washington MK, Wilson KT. EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene 2017; 36:3807-3819. [PMID: 28263971 PMCID: PMC5501754 DOI: 10.1038/onc.2017.23] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 01/12/2017] [Accepted: 01/25/2017] [Indexed: 02/08/2023]
Abstract
Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+ blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
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Affiliation(s)
- Dana M. Hardbower
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Lori A. Coburn
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System; Nashville, TN, USA
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Kshipra Singh
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Johanna C. Sierra
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Daniel P. Barry
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Alain P. Gobert
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - M. Blanca Piazuelo
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - M. Kay Washington
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
| | - Keith T. Wilson
- Department of Pathology, Microbiology and Immunology; Vanderbilt University Medical Center; Nashville, TN, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine; Vanderbilt University Medical Center; Nashville, TN, USA
- Department of Cancer Biology; Vanderbilt University Medical Center; Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Vanderbilt Ingram Cancer Center; Vanderbilt University Medical Center; Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System; Nashville, TN, USA
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32
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Srivatsa S, Paul MC, Cardone C, Holcmann M, Amberg N, Pathria P, Diamanti MA, Linder M, Timelthaler G, Dienes HP, Kenner L, Wrba F, Prager GW, Rose-John S, Eferl R, Liguori G, Botti G, Martinelli E, Greten FR, Ciardiello F, Sibilia M. EGFR in Tumor-Associated Myeloid Cells Promotes Development of Colorectal Cancer in Mice and Associates With Outcomes of Patients. Gastroenterology 2017; 153:178-190.e10. [PMID: 28400195 PMCID: PMC5766132 DOI: 10.1053/j.gastro.2017.03.053] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 03/13/2017] [Accepted: 03/27/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND & AIMS Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis. METHODS We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfrf/f and Villin-CreERT2; Egfrf/f mice) or myeloid cells (LysM-Cre; Egfrf/f mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. RESULTS We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in mice given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre; Egfrf/f mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared with controls. Administration of recombinant IL6 to LysM-Cre; Egfrf/f mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice. CONCLUSIONS Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.
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Affiliation(s)
- Sriram Srivatsa
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Mariel C Paul
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Claudia Cardone
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Martin Holcmann
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Nicole Amberg
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Paulina Pathria
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Michaela A Diamanti
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Markus Linder
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Gerald Timelthaler
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Hans P Dienes
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria
| | - Lukas Kenner
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research LBI-CR, Vienna, Austria; Department of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University Vienna, Vienna, Austria
| | - Gerald W Prager
- Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria
| | - Stefan Rose-John
- Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Medical Faculty, Olshausenstraße 40, Kiel, Germany
| | - Robert Eferl
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria
| | - Giuseppina Liguori
- Pathology Unit, National Cancer Institute, G. Pascale Foundation, Via M Semmola, Naples, Italy
| | - Gerardo Botti
- Pathology Unit, National Cancer Institute, G. Pascale Foundation, Via M Semmola, Naples, Italy
| | - Erika Martinelli
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fortunato Ciardiello
- Università degli Studi della Campania L. Vanvitelli, Department of Clinical and Experimental Medicine, Via Pansini 5, Naples, Italy
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria.
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Yang YP, Ma H, Starchenko A, Huh WJ, Li W, Hickman FE, Zhang Q, Franklin JL, Mortlock DP, Fuhrmann S, Carter BD, Ihrie RA, Coffey RJ. A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Rep 2017; 19:1257-1267. [PMID: 28494873 PMCID: PMC5517093 DOI: 10.1016/j.celrep.2017.04.048] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/31/2017] [Accepted: 04/17/2017] [Indexed: 01/06/2023] Open
Abstract
EGF receptor (EGFR) is a critical signaling node throughout life. However, it has not been possible to directly visualize endogenous Egfr in mice. Using CRISPR/Cas9 genome editing, we appended a fluorescent reporter to the C terminus of the Egfr. Homozygous reporter mice appear normal and EGFR signaling is intact in vitro and in vivo. We detect distinct patterns of Egfr expression in progenitor and differentiated compartments in embryonic and adult mice. Systemic delivery of EGF or amphiregulin results in markedly different patterns of Egfr internalization and trafficking in hepatocytes. In the normal intestine, Egfr localizes to the crypt rather than villus compartment, expression is higher in adjacent epithelium than in intestinal tumors, and following colonic injury expression appears in distinct cell populations in the stroma. This reporter, under control of its endogenous regulatory elements, enables in vivo monitoring of the dynamics of Egfr localization and trafficking in normal and disease states.
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Affiliation(s)
- Yu-Ping Yang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Haiting Ma
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Alina Starchenko
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Won Jae Huh
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Wei Li
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - F Edward Hickman
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Qin Zhang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Jeffrey L Franklin
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA
| | - Douglas P Mortlock
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA
| | - Sabine Fuhrmann
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Bruce D Carter
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA
| | - Rebecca A Ihrie
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Robert J Coffey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA; Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA.
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Liu Y, Song L, Ni H, Sun L, Jiao W, Chen L, Zhou Q, Shen T, Cui H, Gao T, Li J. ERBB4 acts as a suppressor in the development of hepatocellular carcinoma. Carcinogenesis 2017; 38:465-473. [PMID: 28334319 DOI: 10.1093/carcin/bgx017] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 02/07/2017] [Indexed: 01/22/2023] Open
Abstract
ERBB4, one member of the epidermal growth factor receptor (EGFR) family, plays a key role in physiological and pathological processes. Recently, we identified that ERBB4 played a protective role from chronic hepatitis B virus infection. However, the role of ERBB4 in hepatocellular carcinoma (HCC) is still unclear. Here, we explore the role of ERBB4 in the development of HCC using in vitro models, in vivo animal models and clinical samples of HCC. Liver-specific ERBB4 knockout alleles and full ERBB4 except heart knockout mice were used in this study. Liver inflammation and tumor models of mice were produced by carbon tetrachloride (CCl4) and diethylnitrosamine (DEN) administration, respectively. Commercial tissue arrays of 90 HCC patients with paired counterparts were used to evaluate the expression and the prognostic value of ERBB4. Genes altered in the setting of ERBB4 loss was studied by microarray analysis and further validated by real-time PCR. We have found that depletion of ERBB4 in mice leads to more severe injury and liver tumor formation and loss of ERBB4 contributes to the development of hepatocellular tumor. In clinic samples of HCC, ERBB4 is down-regulated and exhibit prognostic value of HCC patients. Mechanistically, loss of ERBB4 suppressed p53 expression by inhibiting the expression of the tumor suppressor tp53inp1. Our study uncovers ERBB4 as a suppressor in the development of HCC and implies an ERBB4-TP53INP1-P53 axis in HCC.
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Affiliation(s)
- Yao Liu
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Liming Song
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Hengli Ni
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Lina Sun
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Weijuan Jiao
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Lin Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Qun Zhou
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Tong Shen
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China
| | - Hongxia Cui
- Department of Pathology, Second Affiliated Hospital of Soochow University, Suzhou 215004, People's Republic of China and
| | - Tianming Gao
- Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, People's Republic of China
| | - Jianming Li
- Department of Pathology and Pathophysiology, Medical College of Soochow University, Soochow University, Suzhou 215123, People's Republic of China.,Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China
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Activation of muscarinic receptors prevents TNF-α-mediated intestinal epithelial barrier disruption through p38 MAPK. Cell Signal 2017; 35:188-196. [PMID: 28412413 DOI: 10.1016/j.cellsig.2017.04.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 03/30/2017] [Accepted: 04/10/2017] [Indexed: 02/08/2023]
Abstract
Intestinal epithelial cells form a tight barrier to act as selective physical barriers, repelling hostile substances. Tumor necrosis factor-α (TNF-α) is a well characterized pro-inflammatory cytokine which can compromise intestinal barrier function and the suppression of TNF-α function is important for treatment of inflammatory bowel disease (IBD). In this study, we investigated the contribution of G-protein-coupled receptor (GPCR)-induced signalling pathways to the maintenance of epithelial barrier function. We first demonstrated the existence of functional muscarinic M3 and histamine H1 receptors in colonic epithelial cell HT-29/B6. As we previously reported, muscarinic M3 receptor prevented TNF-α-induced barrier disruption through acceleration of TNF receptor (TNFR) shedding which is carried out by TNF-α converting enzyme (TACE). M3 receptor-mediated suppression of TNF-α function depends on Gαq/11 protein, however, histamine H1 receptor could not ameliorate TNF-α function, while which could induce Gαq/11 dependent intracellular Ca2+ mobilization. We found that p38 MAPK was predominantly phosphorylated by M3 receptor through Gαq/11 protein, whereas H1 receptor barely upregulated the phosphorylation. Inhibition of p38 MAPK abolished M3 receptor-mediated TNFR shedding and suppression of TNF-α-induced NF-κB signalling. The p38 MAPK was also involved in TACE- mediated EGFR transactivation followed by ERK1/2 phosphorylation. These results indicate that not H1 but M3 receptor-induced activation of p38 MAPK might contribute to the maintenance of epithelial barrier function through down-regulation of TNF-α signalling and activation of EGFR.
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Ahmad R, Sorrell MF, Batra SK, Dhawan P, Singh AB. Gut permeability and mucosal inflammation: bad, good or context dependent. Mucosal Immunol 2017; 10:307-317. [PMID: 28120842 PMCID: PMC6171348 DOI: 10.1038/mi.2016.128] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 11/29/2016] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease (IBD) is a multifactorial disease. A breach in the mucosal barrier, otherwise known as "leaky gut," is alleged to promote mucosal inflammation by intensifying immune activation. However, interaction between the luminal antigen and mucosal immune system is necessary to maintain mucosal homeostasis. Furthermore, manipulations leading to deregulated gut permeability have resulted in susceptibility in mice to colitis as well as to creating adaptive immunity. These findings implicate a complex but dynamic association between mucosal permeability and immune homeostasis; however, they also emphasize that compromised gut permeability alone may not be sufficient to induce colitis. Emerging evidence further supports the role(s) of proteins associated with the mucosal barrier in epithelial injury and repair: manipulations of associated proteins also modified epithelial differentiation, proliferation, and apoptosis. Taken together, the role of gut permeability and proteins associated in regulating mucosal inflammatory diseases appears to be more complex than previously thought. Herein, we review outcomes from recent mouse models where gut permeability was altered by direct and indirect effects of manipulating mucosal barrier-associated proteins, to highlight the significance of mucosal permeability and the non-barrier-related roles of these proteins in regulating chronic mucosal inflammatory conditions.
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Affiliation(s)
- R Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska, USA
| | - MF Sorrell
- Department of Internal Medicine, Omaha, Nebraska, USA
| | - SK Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska, USA.,Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska USA and VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA
| | - P Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska USA and VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA.,VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA
| | - AB Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska, USA.,Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska USA and VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA.,VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska USA
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Schumacher MA, Hedl M, Abraham C, Bernard JK, Lozano PR, Hsieh JJ, Almohazey D, Bucar EB, Punit S, Dempsey PJ, Frey MR. ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation. Cell Death Dis 2017; 8:e2622. [PMID: 28230865 PMCID: PMC5386486 DOI: 10.1038/cddis.2017.42] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 01/14/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Efficient clearance of pro-inflammatory macrophages from tissues after resolution of a challenge is critical to prevent prolonged inflammation. Defects in clearance can contribute to conditions such as inflammatory bowel disease, and thus may be therapeutically targetable. However, the signaling pathways that induce termination of pro-inflammatory macrophages are incompletely defined. We tested whether the ErbB4 receptor tyrosine kinase, previously not known to have role in macrophage biology, is involved in this process. In vitro, pro-inflammatory activation of cultured murine and human macrophages induced ErbB4 expression; in contrast, other ErbB family members were not induced in pro-inflammatory cells, and other innate immune lineages (dendritic cells, neutrophils) did not express detectable ErbB4 levels. Treatment of activated pro-inflammatory macrophages with the ErbB4 ligand neuregulin-4 (NRG4) induced apoptosis. ErbB4 localized to the mitochondria in these cells. Apoptosis was accompanied by loss of mitochondrial membrane potential, and was dependent upon the proteases that generate the cleaved ErbB4 intracellular domain fragment, suggesting a requirement for this fragment and mitochondrial pathway apoptosis. In vivo, ErbB4 was highly expressed on pro-inflammatory macrophages but not neutrophils during experimental DSS colitis in C57Bl/6 mice. Active inflammation in this model suppressed NRG4 expression, which may allow for macrophage persistence and ongoing inflammation. Consistent with this notion, NRG4 levels rebounded during the recovery phase, and administration of exogenous NRG4 during colitis reduced colonic macrophage numbers and ameliorated inflammation. These data define a novel role for ErbB4 in macrophage apoptosis, and outline a mechanism of feedback inhibition that may promote resolution of colitis.
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Affiliation(s)
- Michael A Schumacher
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Matija Hedl
- Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Clara Abraham
- Department of Medicine, Yale School of Medicine, New Haven, CT 06510, USA
| | - Jessica K Bernard
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.,University of Southern California Herman Ostrow School of Dentistry, Los Angeles, CA 90089, USA
| | - Patricia R Lozano
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jonathan J Hsieh
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Dana Almohazey
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.,University of Southern California Herman Ostrow School of Dentistry, Los Angeles, CA 90089, USA
| | - Edie B Bucar
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
| | - Shivesh Punit
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Peter J Dempsey
- Department of Pediatrics, University of Colorado Medical School, Aurora, CO 80045, USA
| | - Mark R Frey
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.,Departments of Pediatrics and of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA
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Abstract
A fundamental function of the intestinal epithelium is to act as a barrier that limits interactions between luminal contents such as the intestinal microbiota, the underlying immune system and the remainder of the body, while supporting vectorial transport of nutrients, water and waste products. Epithelial barrier function requires a contiguous layer of cells as well as the junctions that seal the paracellular space between epithelial cells. Compromised intestinal barrier function has been associated with a number of disease states, both intestinal and systemic. Unfortunately, most current clinical data are correlative, making it difficult to separate cause from effect in interpreting the importance of barrier loss. Some data from experimental animal models suggest that compromised epithelial integrity might have a pathogenic role in specific gastrointestinal diseases, but no FDA-approved agents that target the epithelial barrier are presently available. To develop such therapies, a deeper understanding of both disease pathogenesis and mechanisms of barrier regulation must be reached. Here, we review and discuss mechanisms of intestinal barrier loss and the role of intestinal epithelial barrier function in pathogenesis of both intestinal and systemic diseases. We conclude with a discussion of potential strategies to restore the epithelial barrier.
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Affiliation(s)
- Matthew A Odenwald
- Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, Illinois 60637, USA
| | - Jerrold R Turner
- Department of Pathology, The University of Chicago, 5841 South Maryland, Chicago, Illinois 60637, USA
- Departments of Pathology and Medicine (Gastroenterology), Brigham and Women's Hospital and Harvard Medical School, 20 Shattuck Street, Thorn 1428, Boston, Massachusetts 02115, USA
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Tanabe Y, Sasaki S, Mukaida N, Baba T. Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation. Oncotarget 2016; 7:48335-48345. [PMID: 27340784 PMCID: PMC5217021 DOI: 10.18632/oncotarget.10227] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 06/07/2016] [Indexed: 12/19/2022] Open
Abstract
We previously demonstrated that cancer-associated fibroblasts (CAFs) accumulate at tumor sites through the interaction between a chemokine, CCL3, and its receptor, CCR5, in the late phase of colitis-associated colon carcinogenesis. Here we examined the effect of a CCR5 antagonist, maraviroc, on tumor growth arising from the orthotopic injection of mouse or human colon cancer cell lines into the cecal wall by focusing on CAFs. Orthotopic injection of either cell line caused tumor formation together with leukocyte infiltration and fibroblast accumulation. Concomitant oral administration of maraviroc reduced tumor formation with few effects on leukocyte infiltration. In contrast, maraviroc reduced the intratumor number of α-smooth muscle actin-positive fibroblasts, which express epidermal growth factor, a crucial growth factor for colon cancer cell growth. These observations suggest that maraviroc or other CCR5 antagonists might act as novel anti-CRC drugs to dampen CAFs, an essential cell component for tumor progression.
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Affiliation(s)
- Yamato Tanabe
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Soichiro Sasaki
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tomohisa Baba
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
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Chen J, Zeng F, Forrester SJ, Eguchi S, Zhang MZ, Harris RC. Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease. Physiol Rev 2016; 96:1025-1069. [DOI: 10.1152/physrev.00030.2015] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.
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Affiliation(s)
- Jianchun Chen
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Fenghua Zeng
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Steven J. Forrester
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Satoru Eguchi
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Ming-Zhi Zhang
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Raymond C. Harris
- Departments of Medicine, Cancer Biology, and Molecular Physiology and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Hospital, Nashville, Tennessee; and Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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Pathway-based Genome-wide Association Studies Reveal the Association Between Growth Factor Activity and Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:1540-51. [PMID: 27104816 DOI: 10.1097/mib.0000000000000785] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The inflammatory bowel diseases known as Crohn's disease (CD) and ulcerative colitis (UC) are related autoimmune conditions with a complex etiology composed of genetic and environmental factors. Genetic studies have revealed 200 susceptibility loci for inflammatory bowel diseases, but these only account for a small fraction of the genetic heritability of the disease. We employed pathway-based approaches to identify genes that cooperatively make contributions to the genetic etiology of CD. METHODS We exploited the largest CD dataset (20,000 cases + 28,000 controls) and UC dataset (17,000 cases + 33,500 controls) to date. We conducted a meta-analysis of 5 CD cohorts of European ancestry using 3 pathway-based approaches and further performed replication studies in an independent cohort genotyped on the Immunochip and in another pediatric cohort of European ancestry. Similar meta-analysis was performed for UC cohorts. RESULTS In addition to the multiple immune-related pathways that have been implicated in the genetic etiology of inflammatory bowel diseases before, we found significant associations involving genes in growth factor signaling for CD. This result was replicated in 2 independent cohorts of European ancestry. This association with growth factor activity is not unique to CD. We found a similar significant association with UC cohorts. CONCLUSIONS Our findings suggest that genes involved in pathways of growth factor signaling may make joint contributions to the etiology of CD and UC, providing novel insight into the genetic mechanisms of these diseases.
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Mukaida N, Sasaki S. Fibroblasts, an inconspicuous but essential player in colon cancer development and progression. World J Gastroenterol 2016; 22:5301-5316. [PMID: 27340347 PMCID: PMC4910652 DOI: 10.3748/wjg.v22.i23.5301] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 04/22/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
Tumor microenvironments have a crucial role in cancer initiation and progression, and share many molecular and pathological features with wound healing process. Unless treated, tumors, however, do not heal in contrast to wounds that heal within a limited time framework. Wounds heal in coordination of a myriad of types of cells, particularly endothelial cells, leukocytes, and fibroblasts. Similar sets of cells also contribute to cancer initiation and progression, and as a consequence, anti-cancer treatment strategies have been proposed and tested by targeting endothelial cells and/or leukocytes. Compared with endothelial cells and leukocytes, less attention has been paid to the roles of cancer-associated fibroblasts (CAFs), fibroblasts present in tumor tissues, because their heterogeneity hinders the elucidation on them at cellular and molecular levels. Here, we will discuss the origin of CAFs and their crucial roles in cancer initiation and progression, and the possibility to develop a novel type of anti-cancer treatment by manipulating the migration and functions of CAFs.
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Muraro D, Simmons A. An integrative analysis of gene expression and molecular interaction data to identify dys-regulated sub-networks in inflammatory bowel disease. BMC Bioinformatics 2016; 17:42. [PMID: 26787018 PMCID: PMC4719745 DOI: 10.1186/s12859-016-0886-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 01/08/2016] [Indexed: 01/12/2023] Open
Abstract
Background Inflammatory bowel disease (IBD) consists of two main disease-subtypes, Crohn’s disease (CD) and ulcerative colitis (UC); these subtypes share overlapping genetic and clinical features. Genome-wide microarray data enable unbiased documentation of alterations in gene expression that may be disease-specific. As genetic diseases are believed to be caused by genetic alterations affecting the function of signalling pathways, module-centric optimisation algorithms, whose aim is to identify sub-networks that are dys-regulated in disease, are emerging as promising approaches. Results In order to account for the topological structure of molecular interaction networks, we developed an optimisation algorithm that integrates databases of known molecular interactions with gene expression data; such integration enables identification of differentially regulated network modules. We verified the performance of our algorithm by testing it on simulated networks; we then applied the same method to study experimental data derived from microarray analysis of CD and UC biopsies and human interactome databases. This analysis allowed the extraction of dys-regulated subnetworks under different experimental conditions (inflamed and uninflamed tissues in CD and UC). Optimisation was performed to highlight differentially expressed network modules that may be common or specific to the disease subtype. Conclusions We show that the selected subnetworks include genes and pathways of known relevance for IBD; in particular, the solutions found highlight cross-talk among enriched pathways, mainly the JAK/STAT signalling pathway and the EGF receptor signalling pathway. In addition, integration of gene expression with molecular interaction data highlights nodes that, although not being differentially expressed, interact with differentially expressed nodes and are part of pathways that are relevant to IBD. The method proposed here may help identifying dys-regulated sub-networks that are common in different diseases and sub-networks whose dys-regulation is specific to a particular disease. Electronic supplementary material The online version of this article (doi:10.1186/s12859-016-0886-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Daniele Muraro
- Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DS Oxford, UK.
| | - Alison Simmons
- Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DS Oxford, UK.
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45
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Punit S, Dubé PE, Liu CY, Girish N, Washington MK, Polk DB. Tumor Necrosis Factor Receptor 2 Restricts the Pathogenicity of CD8(+) T Cells in Mice With Colitis. Gastroenterology 2015; 149:993-1005.e2. [PMID: 26072395 PMCID: PMC4841683 DOI: 10.1053/j.gastro.2015.06.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 05/19/2015] [Accepted: 06/03/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Tumor necrosis factor receptor 2 (TNFR2, Tnfrsf1b) regulates multiple aspects of immune function, but little is known about its role in the immunopathogenesis of inflammatory bowel disease (IBD). We investigated whether TNFR2 restricts the activity of specific immune cell subtypes to protect against the development of colitis in mice. METHODS Tnfr2(-/-) mice were crossed with interleukin (Il) 10(-/-) mice, which spontaneously develop colitis, to generate Il10(-/-)Tnfr2(-/-) mice. Colonic tissues were collected from Il10(-/-)Tnfr2(-/-) mice along with Il10(-/-) mice (controls) and analyzed by flow cytometry and histology. Bone marrow was transplanted into Il10(-/-) and Il10(-/-)Tnfr2(-/-) mice from Il10(-/-) or Il10(-/-)Tnfr2(-/-) donors by intravenous injection. CD8(+) T cells were neutralized in Il10(-/-)Tnfr2(-/-) mice by intraperitoneal injection of anti-CD8 or isotype control antibodies. Colitis was induced in Rag2(-/-) mice by intravenous injections of naïve CD8(+) T cells isolated from C57BL/6 or Tnfr2(-/-) mice. RESULTS Il10(-/-)Tnfr2(-/-) mice spontaneously developed more severe colitis compared with Il10(-/-) controls, characterized by selective expansion of colonic CD8(+) T cells. Transplantation of TNFR2-deficient bone marrow resulted in significantly increased incidence and severity of colitis. Transcriptome analyses showed that the expression of genes regulated by TNFR2 were specific to CD8(+) T cells and included genes associated with risk for IBD. Depletion of CD8(+) T cells from Il10(-/-)Tnfr2(-/-) mice prevented colonic inflammation. Adoptive transfer of TNFR2-null naïve CD8(+) T cells compared with CD8(+) T cells from control mice increased the severity of colitis that developed in Rag2(-/-) mice. CONCLUSIONS TNFR2 protects mice from colitis by inhibiting the expansion of colonic CD8(+) T cells. TNFR2 regulates expression of genes that regulate CD8(+) T cells and have been associated with susceptibility to IBD. Disruption in TNFR2 signaling might therefore be associated with pathogenesis. Strategies to increase levels or activity of TNFR2 and thereby reduce the activity of CD8(+) T cells might be developed to treat IBD patients with CD8(+) T cell dysfunction.
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Affiliation(s)
- Shivesh Punit
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California,Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
| | - Philip E. Dubé
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California,Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
| | - Cambrian Y. Liu
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California,Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
| | - Nandini Girish
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California,Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
| | - M. Kay Washington
- Department of Pathology, Vanderbilt University, Nashville, Tennessee
| | - D. Brent Polk
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, California,Department of Pediatrics, Children’s Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California,Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California
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Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft-versus-host disease. Mucosal Immunol 2015; 8:720-30. [PMID: 25943273 DOI: 10.1038/mi.2015.40] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 04/08/2015] [Indexed: 02/04/2023]
Abstract
Compromised intestinal barrier function is a prominent feature of inflammatory bowel disease (IBD). However, links between intestinal barrier loss and disease extend much further, including documented associations with celiac disease, type I diabetes, rheumatoid arthritis, and multiple sclerosis. Intestinal barrier loss has also been proposed to have a critical role in the pathogenesis of graft-versus-host disease (GVHD), a serious, potentially fatal consequence of hematopoietic stem cell transplantation. Experimental evidence has begun to support this view, as barrier loss and its role in initiating and establishing a pathogenic inflammatory cycle in GVHD is emerging. Here we discuss similarities between IBD and GVHD, mechanisms of intestinal barrier loss in these diseases, and the crosstalk between barrier loss and the immune system, with a special focus on natural killer (NK) cells. Unanswered questions and future research directions on the topic are discussed along with implications for treatment.
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Liu CY, Dubé PE, Girish N, Reddy AT, Polk DB. Optical reconstruction of murine colorectal mucosa at cellular resolution. Am J Physiol Gastrointest Liver Physiol 2015; 308:G721-35. [PMID: 25721303 PMCID: PMC4421015 DOI: 10.1152/ajpgi.00310.2014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 02/18/2015] [Indexed: 02/07/2023]
Abstract
The mucosal layer of the colon is a unique and dynamic site where host cells interface with one another and the microbiome, with major implications for physiology and disease. However, the cellular mechanisms mediating colonic regeneration, inflammation, dysplasia, and dysbiosis remain undercharacterized, partly because the use of thin tissue sections in many studies removes important volumetric context. To address these challenges in visualization, we have developed the deep mucosal imaging (DMI) method to reconstruct continuous extended volumes of mouse colorectal mucosa at cellular resolution. Use of ScaleA2 and SeeDB clearing agents enabled full visualization of the colonic crypt, the fundamental unit of adult colon. Confocal imaging of large colorectal expanses revealed epithelial structures involved in repair, inflammation, tumorigenesis, and stem cell function, in fluorescent protein-labeled, immunostained, paraffin-embedded, or human biopsy samples. We provide freely available software to reconstruct and explore on computers with standard memory allocations the large DMI datasets containing in toto representations of distal colonic mucosal volume. Extended-volume imaging of colonic mucosa through the novel, extensible, and readily adopted DMI approach will expedite mechanistic investigations of intestinal physiology and pathophysiology at intracrypt to multicrypt length scales.
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Affiliation(s)
- Cambrian Y. Liu
- 1The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - Philip E. Dubé
- 1The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - Nandini Girish
- 1The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - Ajay T. Reddy
- 1The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and
| | - D. Brent Polk
- 1The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California; ,2Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California; and ,3Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California
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Turker NS, Heidari P, Kucherlapati R, Kucherlapati M, Mahmood U. An EGFR targeted PET imaging probe for the detection of colonic adenocarcinomas in the setting of colitis. Am J Cancer Res 2014; 4:893-903. [PMID: 25057314 PMCID: PMC4107290 DOI: 10.7150/thno.9425] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 06/04/2014] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer is a serious complication associated with inflammatory bowel disease, often indistinguishable by screening with conventional FDG PET probes. We have developed an alternative EGFR-targeted PET imaging probe that may be used to overcome this difficulty, and successfully assessed its utility for neoplastic lesion detection in preclinical models. Cetuximab F(ab′)2 fragments were enzymatically generated, purified, and DOTA-conjugated. Radiolabeling was performed with 67Ga for cell based studies and 64Cu for in vivo imaging. Competitive binding studies were performed on CT26 cells to assess affinity (KD) and receptors per cell (Bmax). In vivo imaging using the EGFR targeted PET probe and 18F FDG was performed on CT26 tumor bearing mice in both control and dextran sodium sulfate (DSS) induced colitis settings. Spontaneous adenomas in genetically engineered mouse (GEM) models of colon cancer were additionally imaged. The EGFR imaging agent was generated with high purity (> 98%), with a labeling efficiency of 60 ± 5% and ≥99% radiochemical purity. The KD was 6.6 ± 0.7 nM and the Bmax for CT26 cells was 3.3 ± 0.1 × 106 receptors/cell. Target to background ratios (TBR) for CT26 tumors compared to colonic uptake demonstrated high values for both 18F-FDG (3.95 ± 0.13) and the developed 64Cu-DOTA-cetuximab-F(ab′)2 probe (4.42 ± 0.11) in control mice. The TBR for the EGFR targeted probe remained high (3.78 ± 0.06) in the setting of colitis, while for 18F FDG, this was markedly reduced (1.54 ± 0.08). Assessment of the EGFR targeted probe in the GEM models demonstrated a correlation between radiotracer uptake in spontaneous colonic lesions and the EGFR staining level ex vivo. A clinically translatable PET imaging probe was successfully developed to assess EGFR. The imaging agent can detect colonic tumors with a high TBR for detection of in situ lesions in the setting of colitis, and opens the possibility for a new approach for screening high-risk patients.
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Seo GS, Jiang WY, Park PH, Sohn DH, Cheon JH, Lee SH. Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction. Biochem Pharmacol 2014; 90:115-125. [DOI: 10.1016/j.bcp.2014.05.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/12/2014] [Accepted: 05/12/2014] [Indexed: 12/12/2022]
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Zarepoor L, Lu JT, Zhang C, Wu W, Lepp D, Robinson L, Wanasundara J, Cui S, Villeneuve S, Fofana B, Tsao R, Wood GA, Power KA. Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate. Am J Physiol Gastrointest Liver Physiol 2014; 306:G1042-55. [PMID: 24763556 DOI: 10.1152/ajpgi.00253.2013] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n-3 polyunsaturated fatty acid (PUFA) α-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1β), and NF-κB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNγ, and IL-1β) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation.
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Affiliation(s)
- Leila Zarepoor
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Jenifer T Lu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Claire Zhang
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | - Wenqing Wu
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Dion Lepp
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Lindsay Robinson
- Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada
| | | | - Steve Cui
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | | | - Bourlaye Fofana
- Crops and Livestock Research Centre, AAFC, Charlottetown, Prince Edward Island, Canada; and
| | - Rong Tsao
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada
| | - Geoffrey A Wood
- Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada
| | - Krista A Power
- Guelph Food Research Centre, Agriculture and Agri-Food Canada (AAFC), Guelph, Ontario, Canada; Department of Human Health and Nutritional Science, University of Guelph, Guelph, Ontario, Canada;
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