|
1
|
Glymenaki M, Curio S, Shrestha S, Zhong Q, Rushton L, Barry R, El-Bahrawy M, Marchesi JR, Wang Y, Gooderham NJ, Guerra N, Li JV. Roux-en-Y gastric bypass-associated fecal tyramine promotes colon cancer risk via increased DNA damage, cell proliferation, and inflammation. MICROBIOME 2025; 13:60. [PMID: 40022152 PMCID: PMC11869571 DOI: 10.1186/s40168-025-02049-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/29/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND Fecal abundances of Enterobacteriaceae and Enterococcaceae are elevated in patients following Roux-en-Y gastric bypass (RYGB) surgery. Concurrently, fecal concentrations of tyramine, derived from gut bacterial metabolism of tyrosine and/or food, increased post-RYGB. Furthermore, emerging evidence suggests that RYGB is associated with increased colorectal cancer (CRC) risk. However, the causal link between RYGB-associated microbial metabolites and CRC risk remains unclear. Hence, this study investigated the tyrosine metabolism of Enterobacteriaceae and Enterococcaceae strains isolated from patients post-RYGB and explored the causal effects of tyramine on the CRC risk and tumorigenesis using both human colonic cancer cell line (HCT 116) and wild-type and ApcMin/+ mice. RESULTS We isolated 31 bacterial isolates belonging to Enterobacteriaceae and Enterococcaceae families from the feces of patients with RYGB surgery. By culturing the isolates in tyrosine-supplemented medium, we found that Citrobacter produced phenol as a main product of tyrosine, whereas Enterobacter and Klebsiella produced 4-hydroxyphenylacetate, Escherichia produced 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate, and Enterococcus and two Klebsiella isolates produced tyramine. These observations suggested the gut bacterial contribution to increased fecal concentrations of tyramine post-RYGB. We subsequently evaluated the impact of tyramine on CRC risk and development. Tyramine induced necrosis and promoted cell proliferation and DNA damage of HCT 116 cells. Daily oral administration of tyramine for 49 days to wild-type mice resulted in visible adenomas in 5 out of 12 mice, accompanied by significantly enhanced DNA damage (γH2AX +) and an increased trend of cell proliferation (Ki67 +) in the ileum, along with an upregulated expression of the cell division cycle gene (Cdc34b) in the colon. To evaluate the impact of tyramine on intestinal tumor growth, we treated ApcMin/+ mice with the same doses of tyramine and duration. These mice showed larger colonic tumor size and increased intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and higher number of Ly6G + neutrophils) compared to water-treated ApcMin/+ control mice. CONCLUSIONS Our results collectively suggested that RYGB-associated fecal bacteria could contribute to tyramine production and tyramine increased CRC risk by increasing DNA damage, cell proliferation, and pro-inflammatory responses of the gut. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management. Video Abstract.
Collapse
Affiliation(s)
- Maria Glymenaki
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Sophie Curio
- Department of Life Sciences, Imperial College London, London, UK
- The University of Queensland Frazer Institute, The University of Queensland, Woolloongabba, QLD, 4102, Australia
| | - Smeeta Shrestha
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore
| | - Qi Zhong
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Laura Rushton
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Department for Environment Food and Rural Affairs, London, UK
| | - Rachael Barry
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Mona El-Bahrawy
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Julian R Marchesi
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Yulan Wang
- Singapore Phenome Center, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 308232, Singapore
| | - Nigel J Gooderham
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Nadia Guerra
- Department of Life Sciences, Imperial College London, London, UK
| | - Jia V Li
- Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
| |
Collapse
|
|
2
|
García-García CA, Cruz-Gregorio A, Pedraza-Chaverri J, Montaño LF, Rendón-Huerta EP. NDMA enhances claudin-1 and -6 expression viaCYP2E1/ROS in AGS cells. Toxicol In Vitro 2025; 102:105952. [PMID: 39395750 DOI: 10.1016/j.tiv.2024.105952] [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: 06/19/2024] [Revised: 09/23/2024] [Accepted: 10/09/2024] [Indexed: 10/14/2024]
Abstract
Carcinogenic N-nitroso compounds, especially N-nitroso dimethylamine, increase the risk of gastric cancer development. Cytochrome P450-2E1 metabolizes this compound, thus generating an oxidant microenvironment. We aimed to evaluate in gastric adenocarcinoma cells if its effect on CYP2E1 and ROS affects signaling pathways associated with gastric cancer oncogenesis. The impact of N- nitroso dimethylamine upon CYP2E1 and ROS activation/secretion was evaluated by the DCFDA assay protocol, TER measurements, Stat3, pSTAT3, ERK1/2, and pERK1/2 expression, claudins-1 and -6 expression, and finally mRNA values of IL-1β IL-6, IL-8 and TNFα. Our results showed that exposure to N- N-nitroso dimethylamine disrupts the regulation of Stat3 and Erk1/2, alters the expression of claudin-1 and claudin-6 tight junction proteins, and increases the secretion of pro-inflammatory cytokines. These alterations induce a continuous local inflammatory process, an event identified as a gastric cancer promoter. In summary, N-nitroso dimethylamine can disrupt cell mechanisms associated with gastric cancer oncogenesis.
Collapse
Affiliation(s)
| | - Alfredo Cruz-Gregorio
- Departamento de Fisiología, Instituto Nacional de Cardiología "Ignacio Chávez", Mexico
| | | | - Luis F Montaño
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico
| | - Erika P Rendón-Huerta
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico.
| |
Collapse
|
|
3
|
Chen H, Cheng Z, Wang M, Huang Q, Zheng D, Huang Q, Cai K. Circ_0020887 Silencing Combats Hypoxic-Induced Cardiomyocyte Injury in an MiR-370-3p/CYP1B1-Dependent Manner. Int Heart J 2024; 65:308-317. [PMID: 38479850 DOI: 10.1536/ihj.23-325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Targeting circular RNA has been a novel approach to preventing and limiting acute myocardial infarction (AMI). Here, we planned to investigate the role and mechanism of circ_0020887 in AMI progression.Hypoxic injury in human cardiomyocytes (AC16) was measured using cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, and colorimetric assay kits. RNA and protein expressions were determined using real-time quantitative PCR and western blotting. Direct interplay between RNAs was determined using dual-luciferase reporter, RNA pull-down, and RIP assays.In the plasma and hypoxia-induced AC16 cells of patients with AMI, circ_0020887 and miR-370-3p were upregulated and downregulated, respectively, concomitant with the upregulation of cytochrome P450 1B1 (CYP1B1). Circ_0020887 interference could inhibit hypoxia-induced AC16 cell apoptosis, oxidative stress, and inflammatory response. Circ_0020887 could sponge miR-370-3p, and miR-370-3p could target CYP1B1. The inhibition effect of circ_0020887 knockdown on hypoxia-induced AC16 cell injury could be reversed by the miR-370-3p inhibitor. Besides, CYP1B1 overexpression also overturned the suppressive effect of miR-370-3p on hypoxia-induced AC16 cell apoptosis, oxidative stress, and inflammatory response.In conclusion, circ_0020887 regulated the miR-370-3p/CYP1B1 axis to regulate hypoxia-induced cardiomyocyte injury, confirming that circ_0020887 might promote cardiomyocyte injury.
Collapse
Affiliation(s)
- Huiqin Chen
- Department of Basic Medical, Quanzhou Medical College
| | - Zhendong Cheng
- Department of Cardiovascular, The Second Affiliated Hospital of Fujian Medical University
| | - Meiai Wang
- Department of Basic Medical, Quanzhou Medical College
| | - Qian Huang
- Department of Basic Medical, Quanzhou Medical College
| | - Dandan Zheng
- Department of Basic Medical, Quanzhou Medical College
| | - Qiuhong Huang
- Department of Basic Medical, Quanzhou Medical College
| | - Kefeng Cai
- Department of Cardiovascular, The Second Affiliated Hospital of Fujian Medical University
| |
Collapse
|
|
4
|
Jin L, Huang J, Guo L, Zhang B, Li Q, Li H, Yu M, Xie P, Yu Q, Chen Z, Liu S, Xu Y, Xiao Y, Lu M, Ye Q. CYP1B1 promotes colorectal cancer liver metastasis by enhancing the growth of metastatic cancer cells via a fatty acids-dependent manner. J Gastrointest Oncol 2023; 14:2448-2465. [PMID: 38196537 PMCID: PMC10772677 DOI: 10.21037/jgo-23-895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/14/2023] [Indexed: 01/11/2024] Open
Abstract
Background Liver metastasis (LM) accounts for most colorectal cancer (CRC)-related deaths. However, how metastatic CRC cells gain the ability to survive and grow in liver remains largely unknown. Methods First, we screened differentially expressed genes (DEGs) between LM and paired primary tumors (PTs) in Gene Expression Omnibus (GEO) database, and identified cytochrome P450 1B1 (CYP1B1) as the only common differential gene. Then, we verified messenger RNA (mRNA) and protein expression level in clinical specimens. After constructing stable up-regulated CYP1B1 versions of HCT116 and RKO CRC cells and stable down-regulated CYP1B1 versions of SW480 and HT29 CRC cells, cell proliferation assays, subcutaneous tumor formation, and mouse LM models were used to comprehend its function. Next, we used RNA-seq to uncover specific mechanisms of growth; cell cycle, polymerase chain reaction (PCR), western blot (WB) and GEO series (GSE) datasets were used to verify its mechanism. Last, gas chromatography tandem mass spectrometry (GC-MS/MS) was adopted to examine which fatty acids were changed. Results A significantly higher level of CYP1B1 was found in LM than in PT in paired clinical CRC LM samples (P<0.05). After CYP1B1 overexpression in HCT116 and RKO cells, cell proliferation abilities in vitro and in vivo were enhanced; LM of NOD.Cg-PrkdcscidIl2rgem1Smoc (NSG) mice were enhanced. And knockdown of CYP1B1 in SW480 and HT29 cells, cell proliferation abilities in vitro and in vivo were reduced; LM of NSG mice were declined (P<0.05). RNA-seq showed 59 common genes from upregulated genes of RKO overexpression group and downregulated genes of SW480 knockdown group were enriched in cell cycle and DNA replication. Further investigation revealed CYP1B1 regulated alternation of MCM5, PCNA, and FEN1 genes, and G1/S transition in CRC cells. GC-MS/MS revealed long chain fatty acids (LCFAs) made a difference in SW480 knockdown group (P<0.05). Through adding LCFAs into SW480 and HT29 knockdown groups, cell proliferation abilities in vitro and in vivo were enhanced, and expressions of MCM5, PCNA, FEN1 were upregulated (P<0.05). Conclusions CYP1B1 exerts a significant influence on LM of CRC by modulating tumor cell proliferation via "CYP1B1-LCFAs-G1/S transition". This finding suggests CYP1B1 could be a promising target for CRC LM.
Collapse
Affiliation(s)
- Lei Jin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Ju Huang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Lei Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Bo Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qin Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
- Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Transfer Center, Shanghai, China
| | - Mincheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Peiyi Xie
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Qiang Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Zheng Chen
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Shuang Liu
- Neurosurgery Department of Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yongfeng Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Yongsheng Xiao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Ming Lu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Qinghai Ye
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| |
Collapse
|
|
5
|
Larsen MC, Rondelli CM, Almeldin A, Song YS, N’Jai A, Alexander DL, Forsberg EC, Sheibani N, Jefcoate CR. AhR and CYP1B1 Control Oxygen Effects on Bone Marrow Progenitor Cells: The Enrichment of Multiple Olfactory Receptors as Potential Microbiome Sensors. Int J Mol Sci 2023; 24:16884. [PMID: 38069208 PMCID: PMC10706615 DOI: 10.3390/ijms242316884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Polycyclic aromatic hydrocarbon (PAH) pollutants and microbiome products converge on the aryl hydrocarbon receptor (AhR) to redirect selective rapid adherence of isolated bone marrow (BM) cells. In young adult mice, Cyp1b1-deficiency and AhR activation by PAH, particularly when prolonged by Cyp1a1 deletion, produce matching gene stimulations in these BM cells. Vascular expression of Cyp1b1 lowers reactive oxygen species (ROS), suppressing NF-κB/RelA signaling. PAH and allelic selectivity support a non-canonical AhR participation, possibly through RelA. Genes stimulated by Cyp1b1 deficiency were further resolved according to the effects of Cyp1b1 and Cyp1a1 dual deletions (DKO). The adherent BM cells show a cluster of novel stimulations, including select developmental markers; multiple re-purposed olfactory receptors (OLFR); and α-Defensin, a microbial disruptor. Each one connects to an enhanced specific expression of the catalytic RNA Pol2 A subunit, among 12 different subunits. Mesenchymal progenitor BMS2 cells retain these features. Cyp1b1-deficiency removes lymphocytes from adherent assemblies as BM-derived mesenchymal stromal cells (BM-MSC) expand. Cyp1b1 effects were cell-type specific. In vivo, BM-MSC Cyp1b1 expression mediated PAH suppression of lymphocyte progenitors. In vitro, OP9-MSC sustained these progenitors, while Csf1 induced monocyte progenitor expansion to macrophages. Targeted Cyp1b1 deletion (Cdh5-Cre; Cyp1b1fl/fl) established endothelium control of ROS that directs AhR-mediated suppression of B cell progenitors. Monocyte Cyp1b1 deletion (Lyz2-Cre; Cyp1b1fl/fl) selectively attenuated M1 polarization of expanded macrophages, but did not enhance effects on basal M2 polarization. Thus, specific sources of Cyp1b1 link to AhR and to an OLFR network to provide BM inflammatory modulation via diverse microbiome products.
Collapse
Affiliation(s)
- Michele C. Larsen
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (A.A.)
| | | | - Ahmed Almeldin
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (A.A.)
| | - Yong-Seok Song
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Alhaji N’Jai
- Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA;
| | - David L. Alexander
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA 95064, USA; (D.L.A.); (E.C.F.)
| | - E. Camilla Forsberg
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA 95064, USA; (D.L.A.); (E.C.F.)
| | - Nader Sheibani
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (A.A.)
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA;
| | - Colin R. Jefcoate
- Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA; (M.C.L.); (A.A.)
| |
Collapse
|
|
6
|
Wang P, Lu H, Rong H, Wang Y, Wang L, He X, Yuan D, He Y, Jin T. The Association of Methylation Level in the CYP39A1 Gene with High Altitude Pulmonary Edema in the Chinese Population. Pharmgenomics Pers Med 2023; 16:617-628. [PMID: 37366513 PMCID: PMC10290841 DOI: 10.2147/pgpm.s397862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Background High altitude pulmonary edema (HAPE) is still the most common fatal disease at high altitudes. DNA methylation proceeds with an important role in HAPE progression. This study was designed to investigate the association between CYP39A1 methylation and HAPE. Methods Peripheral blood samples were enrolled from 106 participants (53 HAPE patients and 53 healthy subjects) to study the association of CYP39A1 methylation with HAPE. DNA methylation site in the promoter region of CYP39A1 was detected by Sequenom MassARRAY EpiTYPER platform. Results Probability analysis showed that the methylation probabilities of CYP39A1_1_CpG_5 and CYP39A1_3_CpG_21 are significant differences between the cases and controls (p< 0.05). The methylation level analysis indicated that CYP39A1_1_CpG_2.3.4, CYP39A1_5_CpG_6.7, and CYP39A1_5_CpG_9.10 were higher methylation in HAPE compared to the controls (p< 0.05). CYP39A1_3_CpG_21 and CYP39A1_4_CpG_3 exhibited a lower methylation level in HAPE than that in the controls (p< 0.05). The association analysis given that CYP39A1_1_CpG_2.3.4 (OR 2.56, p= 0.035), CYP39A1_5_CpG_6.7 (OR 3.99, p= 0.003), CYP39A1_5_CpG_9.10 (OR 3.99, p= 0.003), CYP39A1_5_CpG_16.17.18 (OR 2.53, p= 0.033), and CYP39A1_5_CpG_20 (OR 3.05, p= 0.031) are associated with an increased risk of HAPE. Whereas CYP39A1_1_CpG_5 (OR 0.33, p= 0.016) and CYP39A1_3_CpG_21 (OR 0.18, p= 0.005) have a protective role in HAPE. Besides, age-stratification analysis showed that CYP39A1_1_CpG_5 (OR 0.16, p= 0.014) and CYP39A1_3_CpG_21 (OR 0.08, p= 0.023) had a protective impact on HAPE in people aged ≤32 years. CYP39A1_5_CpG_6.7 (OR 6.70, p= 0.008) and CYP39A1_5_CpG_9.10 (OR 6.70, p= 0.008) were related to an increased susceptibility to HAPE aged >32 years. Moreover, the diagnostic value of CYP39A1_3_CpG_21 (AUC = 0.712, p< 0.001) was significantly better than other CpG sites. Conclusion The methylation level of CYP39A1 was associated with a risk of HAPE in the Chinese population, which provided new perspective for preventing and diagnosing of HAPE.
Collapse
Affiliation(s)
- Pingyi Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Hongyan Lu
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Hao Rong
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Yuhe Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Department of Clinical Laboratory, the Affiliated Hospital of Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Li Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Xue He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Dongya Yuan
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Yongjun He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- Key Laboratory of High Altitude Hypoxia Environment and Life Health, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
- School of Basic Medical Sciences, Xizang Minzu University, Xianyang, Shaanxi, People’s Republic of China
| |
Collapse
|
|
7
|
Franzin R, Stasi A, De Palma G, Picerno A, Curci C, Sebastiano S, Campioni M, Cicirelli A, Rizzo A, Di Lorenzo VF, Pontrelli P, Pertosa GB, Castellano G, Gesualdo L, Sallustio F. Human Adult Renal Progenitor Cells Prevent Cisplatin-Nephrotoxicity by Inducing CYP1B1 Overexpression and miR-27b-3p Down-Regulation through Extracellular Vesicles. Cells 2023; 12:1655. [PMID: 37371125 DOI: 10.3390/cells12121655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Cisplatin is one of the most effective chemotherapeutic agents strongly associated with nephrotoxicity. Tubular adult renal progenitor cells (tARPC) can regenerate functional tubules and participate in the repair processes after cisplatin exposition. This study investigated the molecular mechanisms underlying the protective effect of tARPC on renal epithelium during cisplatin nephrotoxicity. By performing a whole-genome transcriptomic analysis, we found that tARPC, in presence of cisplatin, can strongly influence the gene expression of renal proximal tubular cell [RPTEC] by inducing overexpression of CYP1B1, a member of the cytochrome P450 superfamily capable of metabolizing cisplatin and of hypoxia/cancer-related lncRNAs as MIR210HG and LINC00511. Particularly, tARPC exerted renoprotection and regeneration effects via extracellular vesicles (EV) enriched with CYP1B1 and miR-27b-3p, a well-known CYP1B1 regulatory miRNA. The expression of CYP1B1 by tARPC was confirmed by analyzing biopsies of cisplatin-treated renal carcinoma patients that showed the colocalization of CYP1B1 with the tARPC marker CD133. CYP1B1 was also overexpressed in urinary EV purified from oncologic patients that presented nephrotoxicity episodes after cisplatin treatment. Interestingly CYP1B1 expression significantly correlated with creatinine and eGFR levels. Taken together, our results show that tARPC are able to counteract cisplatin-induced nephrotoxicity via CYP1B1 release through EV. These findings provide a promising therapeutic strategy for nephrotoxicity risk assessment that could be related to abundance of renal progenitors.
Collapse
Affiliation(s)
- Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Giuseppe De Palma
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Angela Picerno
- Department Interdisciplinary of Medicine (DIM), University of Bari, 70124 Bari, Italy
| | - Claudia Curci
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Serena Sebastiano
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Monica Campioni
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Antonella Cicirelli
- Department Interdisciplinary of Medicine (DIM), University of Bari, 70124 Bari, Italy
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, 70124 Bari, Italy
| | | | - Paola Pontrelli
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Giovanni Battista Pertosa
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Giuseppe Castellano
- Unit of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Fabio Sallustio
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| |
Collapse
|
|
8
|
Alotaibi AG, Li JV, Gooderham NJ. Tumour Necrosis Factor-Alpha (TNF-α)-Induced Metastatic Phenotype in Colorectal Cancer Epithelial Cells: Mechanistic Support for the Role of MicroRNA-21. Cancers (Basel) 2023; 15:627. [PMID: 36765584 PMCID: PMC9913347 DOI: 10.3390/cancers15030627] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Colorectal cancer is driven by genetic and epigenetic changes in cells to confer phenotypes that promote metastatic transformation and development. Tumour necrosis factor-alpha (TNF-α), a pro-inflammatory mediator, regulates cellular communication within the tumour microenvironment and is associated with the progression of the metastatic phenotype. Oncogenic miR-21 has been shown to be overexpressed in most solid tumours, including colorectal cancer, and is known to target proteins involved in metastatic transformation. In this study, we investigated the relationship between TNF-α and miR-21 regulation in colorectal cancer epithelial cells (SW480 and HCT116). We observed that TNF-α, at concentrations reported to be present in serum and tumour tissue from colorectal cancer patients, upregulated miR-21 expression in both cell lines. TNF-α treatment also promoted cell migration, downregulation of the expression of E-cadherin, a marker of epithelial to mesenchymal transition, and anti-apoptotic BCL-2 (a validated target for miR-21). Knockdown of miR-21 had the opposite effect on each of these TNF-a induced phenotypic changes. Additionally, in the SW480 cell line, although TNF-α treatment selectively induced expression of a marker of metastatic progression VEGF-A, it failed to affect MMP2 expression or invasion activity. Our data indicate that exposing colorectal cancer epithelial cells to TNF-α, at concentrations occurring in the serum and tumour microenvironment of colorectal cancer patients, upregulated miR-21 expression and promoted the metastatic phenotype.
Collapse
Affiliation(s)
- Aminah G. Alotaibi
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
- National Centre for Genomic Technology, King Abdulaziz City for Science and Technology, KACST, Riyadh 11442, Saudi Arabia
| | - Jia V. Li
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - Nigel J. Gooderham
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| |
Collapse
|
|
9
|
Li L, Yuan Q, Chu YM, Jiang HY, Zhao JH, Su Q, Huo DQ, Zhang XF. Advances in holliday junction recognition protein (HJURP): Structure, molecular functions, and roles in cancer. Front Cell Dev Biol 2023; 11:1106638. [PMID: 37025176 PMCID: PMC10070699 DOI: 10.3389/fcell.2023.1106638] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/13/2023] [Indexed: 04/08/2023] Open
Abstract
Oncogenes are increasingly recognized as important factors in the development and progression of cancer. Holliday Junction Recognition Protein (HJURP) is a highly specialized mitogenic protein that is a chaperone protein of histone H3. The HJURP gene is located on chromosome 2q37.1 and is involved in nucleosome composition in the mitotic region, forming a three-dimensional crystal structure with Centromere Protein A (CENP-A) and the histone 4 complex. HJURP is involved in the recruitment and assembly of centromere and kinetochore and plays a key role in stabilizing the chromosome structure of tumor cells, and its dysfunction may contribute to tumorigenesis. In the available studies HJURP is upregulated in a variety of cancer tissues and cancer cell lines and is involved in tumor proliferation, invasion, metastasis and immune response. In an in vivo model, overexpression of HJURP in most cancer cell lines promotes cell proliferation and invasiveness, reduces susceptibility to apoptosis, and promotes tumor growth. In addition, upregulation of HJURP was associated with poorer prognosis in a variety of cancers. These properties suggest that HJURP may be a possible target for the treatment of certain cancers. Various studies targeting HJURP as a prognostic and therapeutic target for cancer are gradually attracting interest and attention. This paper reviews the functional and molecular mechanisms of HJURP in a variety of tumor types with the aim of providing new targets for future cancer therapy.
Collapse
Affiliation(s)
- Lin Li
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
| | - Qiang Yuan
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Yue-Ming Chu
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Hang-Yu Jiang
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Ju-Hua Zhao
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
| | - Qiang Su
- Institute of Tissue Engineering and Stem Cells, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, China
| | - Dan-Qun Huo
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China
- *Correspondence: Dan-Qun Huo, ; Xiao-Fen Zhang,
| | - Xiao-Fen Zhang
- Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
- *Correspondence: Dan-Qun Huo, ; Xiao-Fen Zhang,
| |
Collapse
|
|
10
|
Boros É, Hegedűs Z, Kellermayer Z, Balogh P, Nagy I. Global alteration of colonic microRNAome landscape associated with inflammatory bowel disease. Front Immunol 2022; 13:991346. [PMID: 36177008 PMCID: PMC9513375 DOI: 10.3389/fimmu.2022.991346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that associates with, among others, increased risk of colorectal cancer. There is a growing evidence that miRNAs have important roles in pathological processes, such as inflammation or carcinogenesis. Understanding the molecular mechanisms such as alterations in microRNAome upon chronic intestinal inflammation is critical for understanding the exact pathomechanism of IBD. Hence, we conducted a genome wide microRNAome analysis by applying miRNA-Seq in a rat model of experimental colitis, validated the data by QPCR, examined the expression of a selection of precursor and mature miRNAs, performed in depth biological interpretation using Ingenuity Pathway Analysis and tested the obtained results on samples derived from human patients. We identified specific, interdependent expression pattern of activator/repressor transcription factors, miRNAs and their direct targets in the inflamed colon samples. Particularly, decreased expression of the miR-200 family members (miR-200a/b/c,-141, and -429) and miR-27b correlates with the reduced level of their enhancers (HNF1B, E2F1), elevated expression of their repressors (ZEB2, NFKB1) and increased expression of their target genes (ZEB2, RUNX1). Moreover, the marked upregulation of six miR-27b target genes (IFI16, GCA, CYP1B1, RUNX1, MEF2C and MMP13) in the inflamed colon tissues is a possible direct consequence of the lack of repression due to the downregulated miRNA-27b expression. Our data indicate that changes in microRNAome are associated with the pathophysiology of IBD, consequently, microRNAs offer potential targets for the diagnosis, prognosis and treatment of IBD.
Collapse
Affiliation(s)
- Éva Boros
- Seqomics Biotechnology Ltd., Mórahalom, Hungary
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
| | - Zoltán Hegedűs
- Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
- Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary
| | - Zoltán Kellermayer
- Department of Immunology and Biotechnology, University of Pécs, Pécs, Hungary
- Lymphoid Organogenesis Research Group, Szentágothai János Research Center, University of Pécs, Pécs, Hungary
| | - Péter Balogh
- Department of Immunology and Biotechnology, University of Pécs, Pécs, Hungary
- Lymphoid Organogenesis Research Group, Szentágothai János Research Center, University of Pécs, Pécs, Hungary
| | - István Nagy
- Seqomics Biotechnology Ltd., Mórahalom, Hungary
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary
| |
Collapse
|
|
11
|
Alimohammadi M, Makaremi S, Rahimi A, Asghariazar V, Taghadosi M, Safarzadeh E. DNA methylation changes and inflammaging in aging-associated diseases. Epigenomics 2022; 14:965-986. [PMID: 36043685 DOI: 10.2217/epi-2022-0143] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aging as an inevitable phenomenon is associated with pervasive changes in physiological functions. There is a relationship between aging and the increase of several chronic diseases. Most age-related disorders are accompanied by an underlying chronic inflammatory state, as demonstrated by local infiltration of inflammatory cells and greater levels of proinflammatory cytokines in the bloodstream. Within inflammaging, many epigenetic events, especially DNA methylation, change. During the aging process, due to aberrations of DNA methylation, biological processes are disrupted, leading to the emergence or progression of a variety of human diseases, including cancer, neurodegenerative disorders, cardiovascular disease and diabetes. The focus of this review is on DNA methylation, which is involved in inflammaging-related activities, and how its dysregulation leads to human disorders.
Collapse
Affiliation(s)
- Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1983969411, Iran
| | - Shima Makaremi
- School of Medicine & Allied Medical Sciences, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Ali Rahimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, 5618985991, Iran
| | - Vahid Asghariazar
- Deputy of Research & Technology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| | - Mahdi Taghadosi
- Department of Immunology, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran
| | - Elham Safarzadeh
- Department of Microbiology, Parasitology, & Immunology, Ardabil University of Medical Sciences, Ardabil, 5618985991, Iran
| |
Collapse
|
|
12
|
Zafari N, Khosravi F, Rezaee Z, Esfandyari S, Bahiraei M, Bahramy A, Ferns GA, Avan A. The role of the tumor microenvironment in colorectal cancer and the potential therapeutic approaches. J Clin Lab Anal 2022; 36:e24585. [PMID: 35808903 PMCID: PMC9396196 DOI: 10.1002/jcla.24585] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/07/2022] [Accepted: 06/23/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) with a high prevalence is recognized as the fourth most common cause of cancer-related death globally. Over the past decade, there has been growing interest in the network of tumor cells, stromal cells, immune cells, blood vessel cells, and fibroblasts that comprise the tumor microenvironment (TME) to identify new therapeutic interventions. METHODS Databases, such as Google Scholar, PubMed, and Scopus, were searched to provide an overview of the recent research progress related to targeting the TME as a novel therapeutic approach. RESULTS Tumor microenvironment as a result of the cross talk between these cells may result in either advantages or disadvantages in tumor development and metastasis, affecting the signals and responses from the surrounding cells. Whilst chemotherapy has led to an improvement in CRC patients' survival, the metastatic aspect of the disease remains difficult to avoid. CONCLUSIONS The present review emphasizes the structure and function of the TME, alterations in the TME, its role in the incidence and progression of CRC, the effects on tumor development and metastasis, and also the potential of its alterations as therapeutic targets. It should be noted that providing novel studies in this field of research might help us to achieve practical therapeutic strategies based on their interaction.
Collapse
Affiliation(s)
- Narges Zafari
- Department of Medical Genetics, School of MedicineTehran University of Medical SciencesTehranIran
| | - Fatemeh Khosravi
- Molecular Medicine Research Center, Hormozgan Health InstituteHormozgan University of Medical SciencesBandar AbbasIran
| | - Zahra Rezaee
- Department of Medical Genetics, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Sahar Esfandyari
- Department of Anatomy, School of MedicineTehran University of Medical SciencesTehranIran
| | - Mohamad Bahiraei
- Department of Radiology, Besat HospitalHamedan University of Medical SciencesHamedanIran
| | - Afshin Bahramy
- Department of Medical Genetics, Faculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Gordon A. Ferns
- Brighton & Sussex Medical SchoolDivision of Medical EducationSussexUK
| | - Amir Avan
- Metabolic Syndrome Research CenterMashhad University of Medical SciencesMashhadIran
- Basic Medical Sciences InstituteMashhad University of Medical SciencesMashhadIran
- Medical Genetics Research CenterMashhad University of Medical SciencesMashhadIran
| |
Collapse
|
|
13
|
Morin SM, Majhi PD, Crisi GM, Gregory KJ, Franca R, Schalet B, Mason H, Casaubon JT, Cao QJ, Haddad S, Makari-Judson G, Jerry DJ, Schneider SS. Interindividual variation contributes to differential PCB 126 induced gene expression in primary breast epithelial cells and tissues. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 241:113722. [PMID: 35724515 DOI: 10.1016/j.ecoenv.2022.113722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/27/2022] [Accepted: 05/29/2022] [Indexed: 06/15/2023]
Abstract
PCB 126 is a pervasive, dioxin-like chemical pollutant which can activate the aryl hydrocarbon receptor (AhR). Despite being banned from the market, PCB 126 can be detected in breast milk to this day. The extent to which interindividual variation impacts the adverse responses to this chemical in the breast tissue remains unclear. This study aimed to investigate the impact of 3 nM PCB 126 on gene expression in a panel of genetically diverse benign human breast epithelial cell (HBEC) cultures and patient derived breast tissues. Six patient derived HBEC cultures were treated with 3 nM PCB 126. RNAseq was used to interrogate the impact of exposure on differential gene expression. Gene expression changes from the top critical pathways were confirmed via qRT-PCR in a larger panel of benign patient derived HBEC cultures, as well as in patient-derived breast tissue explant cultures. RNAseq analysis of HBEC cultures revealed a signature of 144 genes significantly altered by 3 nM PCB 126 treatment. Confirmation of 8 targets using a panel of 12 HBEC cultures and commercially available breast cell lines demonstrated that while the induction of canonical downstream target gene, CYP1A1, was consistent across our primary HBECs, other genes including AREG, S100A8, IL1A, IL1B, MMP7, and CCL28 exhibited significant variability across individuals. The dependence on the activity of the aryl hydrocarbon receptor was confirmed using inhibitors. PCB 126 can induce significant and consistent changes in gene expression associated with xenobiotic metabolism in benign breast epithelial cells. Although the induction of most genes was reliant on the AhR, significant variability was noted between genes and individuals. These data suggest that there is a bifurcation of the pathway following AhR activation that contributes to the variation in interindividual responses.
Collapse
Affiliation(s)
- Stephanie M Morin
- Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States; Dept of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, United States
| | - Prabin Dhangada Majhi
- Dept of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, United States
| | - Giovanna M Crisi
- University of Massachusetts Chan Medical School-Baystate, Department of Pathology, Springfield, MA 01199, United States
| | - Kelly J Gregory
- Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States
| | - Renata Franca
- Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States
| | - Benjamin Schalet
- University of Massachusetts Chan Medical School-Baystate, Department of Surgery, Springfield, MA 01199, United States
| | - Holly Mason
- University of Massachusetts Chan Medical School-Baystate, Department of Surgery, Springfield, MA 01199, United States
| | - Jesse Thomas Casaubon
- University of Massachusetts Chan Medical School-Baystate, Department of Surgery, Springfield, MA 01199, United States
| | - Qing Jackie Cao
- University of Massachusetts Chan Medical School-Baystate, Department of Pathology, Springfield, MA 01199, United States
| | - Sandra Haddad
- Dept of Science, Bay Path University, Longmeadow, MA 01106, United States
| | - Grace Makari-Judson
- University of Massachusetts Chan Medical School-Baystate, Division of Hematology-Oncology, Springfield, MA, United States
| | - D Joseph Jerry
- Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States; Dept of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, United States
| | - Sallie S Schneider
- Pioneer Valley Life Sciences Institute, Springfield, MA 01199, United States; Dept of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, United States; University of Massachusetts Chan Medical School-Baystate, Department of Surgery, Springfield, MA 01199, United States.
| |
Collapse
|
|
14
|
Jin Y, Qi G, Shou Y, Li D, Liu Y, Guan H, Zhang Q, Chen S, Luo J, Xu L, Li C, Ma W, Chen N, Zheng Y, Yu D. High throughput data-based, toxicity pathway-oriented development of a quantitative adverse outcome pathway network linking AHR activation to lung damages. JOURNAL OF HAZARDOUS MATERIALS 2022; 425:128041. [PMID: 34906874 DOI: 10.1016/j.jhazmat.2021.128041] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 06/14/2023]
Abstract
The quantitative adverse outcome pathway (qAOP) is proposed to inform dose-responses at multiple biological levels for the purpose of toxicity prediction. So far, qAOP models concerning human health are scarce. Previously, we proposed 5 key molecular pathways that led aryl hydrogen receptor (AHR) activation to lung damages. The present study assembled an AOP network based on the gene expression signatures of these toxicity pathways, and validated the network using publicly available high throughput data combined with machine learning models. In addition, the AOP network was quantitatively evaluated with omics approaches and bioassays, using 16HBE-CYP1A1 cells exposed to benzo(a)pyrene (BaP), a prototypical AHR activator. Benchmark dose (BMD) analysis of transcriptomics revealed that AHR gene held the lowest BMD value, whereas AHR pathway held the lowest point of departure (PoD) compared to the other 4 pathways. Targeted bioassays were further performed to quantitatively understand the cellular responses, including ROS generation, DNA damage, interleukin-6 production, and extracellular matrix increase marked by collagen expression. Eventually, response-response relationships were plotted using nonlinear model fitting. The present study developed a highly reliable AOP model concerning human health, and validated as well as quantitatively evaluated it, and such a method is likely to be adoptable for risk assessment.
Collapse
Affiliation(s)
- Yuan Jin
- School of Public Health, Qingdao University, Qingdao, China
| | - Guangshuai Qi
- School of Public Health, Qingdao University, Qingdao, China
| | - Yingqing Shou
- School of Public Health, Qingdao University, Qingdao, China
| | - Daochuan Li
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yuzhen Liu
- School of Public Health, Qingdao University, Qingdao, China
| | - Heyuan Guan
- School of Public Health, Qingdao University, Qingdao, China
| | - Qianqian Zhang
- School of Public Health, Qingdao University, Qingdao, China
| | - Shen Chen
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jiao Luo
- School of Public Health, Qingdao University, Qingdao, China
| | - Lin Xu
- School of Public Health, Qingdao University, Qingdao, China
| | - Chuanhai Li
- School of Public Health, Qingdao University, Qingdao, China
| | - Wanli Ma
- School of Public Health, Qingdao University, Qingdao, China
| | - Ningning Chen
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- School of Public Health, Qingdao University, Qingdao, China.
| |
Collapse
|
|
15
|
miR-27b inhibition contributes to cytotoxicity in patulin-exposed HEK293 cells. Toxicon 2022; 210:58-65. [PMID: 35217024 DOI: 10.1016/j.toxicon.2022.02.018] [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: 11/30/2021] [Revised: 01/25/2022] [Accepted: 02/19/2022] [Indexed: 11/20/2022]
Abstract
Patulin (PAT) is a mycotoxin produced by Penicillium and other fungi that contaminate fruit. PAT targets the kidney and is associated with nephrotoxicity. Micro-RNAs (miRNA) may offer new insights into PAT-induced nephrotoxicity. Cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), involved in metabolism of dietary toxins is negatively regulated by miR-27b and linked with the nuclear factor kappa B (NF-κB) pathway and peroxisome proliferator activated receptor gamma (PPARɣ) in renal fibrosis. This study investigated the effects of PAT on miR-27b, CYP1B1, PPARɣ and cytotoxicity in human kidney (HEK293) cells. HEK293 cells were exposed to PAT (2.5 μM, 24h). Protein expression of CYP1B1, PPARɣ, NF-κB (p65), pNF-κB (p65) (phospho-Ser563) and cleaved PARP-1 was quantified using western blotting. QPCR evaluated mRNA levels of CYP1B1, IL-6, miR-27b, OGG1, mtDNA, TFAM and UCP2. Mitochondrial membrane potential and phosphatidylserine (PS) externalization was evaluated by flow cytometry while levels of ATP and caspase -9, -8, -3/7 activity was measured using luminometry. PAT significantly decreased miR-27b levels (p = 0.0014) and increased CYP1B1 mRNA (p = 0.0015) and protein (p = 0.0013) levels. PPARɣ protein expression was significantly increased (p = 0.0002) and associated with decreased NF-κB activation (p = 0.0273) and IL-6 mRNA levels (p = 0.0265). Finally, PAT significantly compromised mitochondrial repair mechanisms and increased apoptotic biomarkers. PAT altered miR-27b levels and PPARɣ, with associated changes to NF-κB activation, downstream IL-6 and CYP1B1 expression. These results show that PAT impairs detoxification mechanisms leading to mitochondrial damage and apoptosis. In conclusion, PAT altered the epigenetic environment and impaired detoxification processes, supporting a mechanism for nephrotoxic outcomes.
Collapse
|
|
16
|
Wang C, Gao N, Yang L, Guo Y, Fang Y, Wang T, Xu C, Li GF, Zhou J, Zhang Y, Wen Q, Qiao H. Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway. Cell Death Dis 2022; 13:130. [PMID: 35136014 PMCID: PMC8826371 DOI: 10.1038/s41419-022-04584-4] [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: 08/27/2021] [Revised: 01/06/2022] [Accepted: 01/20/2022] [Indexed: 12/25/2022]
Abstract
Although there are many studies on the relationship between genetic polymorphisms and the incidence of diseases, mechanisms are rarely known. We report the mechanism by which signal transducer and activator of transcription 4 (stat4) rs7574865 promotes the occurrence and progression of hepatocellular carcinoma (HCC). We found that the GG genotype at stat4 rs7574865 was a risk genotype, and STAT4 levels in serum and peritumoral tissue from HCC patients with the GG genotype were significantly higher than those found in TT or TG carriers. Furthermore, HCC patients with the GG genotype or elevated STAT4 levels had poor prognoses. In vitro experiments demonstrated that STAT4 silencing promoted apoptosis and inhibited the invasion and migration of HepG2 and L02 cells. Proteomic analysis of HCC peritumors identified 273 proteins related to STAT4, of which CYP2E1 activity and FGL2 content exhibited the highest positive correlation. The relationship between CYP2E1 and FGL2 was also confirmed in cyp2e1−/− mice and in CYP2E1 inhibitor-treated mice. In conclusion, this study elucidates the mechanism by which the stat4 rs7574865 polymorphism promotes the occurrence and progression of HCC via the Stat4/CYP2E1/FGL2 pathway.
Collapse
Affiliation(s)
- Caie Wang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China.,Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Na Gao
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Lukui Yang
- Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Yuanyuan Guo
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yan Fang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Tong Wang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Chen Xu
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Gui Fang Li
- Department of Pharmacy, the First Affiliated Hospital of Henan University of Science and Technology, Clinical Medical College of Henan University of Science and Technology, Luoyang, Henan, China
| | - Jun Zhou
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Yunfei Zhang
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Qiang Wen
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China
| | - Hailing Qiao
- Institute of Clinical Pharmacology, School of Medicine, Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
17
|
Burrows K, Figueroa-Hall LK, Kuplicki R, Stewart JL, Alarbi AM, Ramesh R, Savitz JB, Teague TK, Risbrough VB, Paulus MP. Neuronally-enriched exosomal microRNA-27b mediates acute effects of ibuprofen on reward-related brain activity in healthy adults: a randomized, placebo-controlled, double-blind trial. Sci Rep 2022; 12:861. [PMID: 35039595 PMCID: PMC8764091 DOI: 10.1038/s41598-022-04875-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/03/2022] [Indexed: 01/01/2023] Open
Abstract
This double-blind, randomized, within-subjects design evaluated whether acute administration of an anti-inflammatory drug modulates neuron-specific, inflammation-modulating microRNAs linked to macroscopic changes in reward processing. Twenty healthy subjects (10 females, 10 males) underwent a functional magnetic resonance imaging scan while performing a monetary incentive delay (MID) task and provided blood samples after administration of placebo, 200 mg, or 600 mg of ibuprofen. Neuronally-enriched exosomal microRNAs were extracted from serum and sequenced. Results showed that: (1) 600 mg of ibuprofen exhibited higher miR-27b-3p, miR-320b, miR-23b and miR-203a-3p expression than placebo; (2) higher mir-27b-3p was associated with lower insula activation during MID loss anticipation; and (3) there was an inverse relationship between miR-27b-3p and MID gain anticipation in bilateral putamen during placebo, a pattern attenuated by both 200 mg and 600 mg of ibuprofen. These findings are consistent with the hypothesis that miR-27b could be an important messaging molecule that is associated with regulating the processing of positive or negative valenced information.
Collapse
Affiliation(s)
- Kaiping Burrows
- Laureate Institute for Brain Research, 6655 South Yale Ave, Tulsa, OK, 74136, USA.
| | | | - Rayus Kuplicki
- Laureate Institute for Brain Research, 6655 South Yale Ave, Tulsa, OK, 74136, USA
| | - Jennifer L Stewart
- Laureate Institute for Brain Research, 6655 South Yale Ave, Tulsa, OK, 74136, USA
- Department of Community Medicine, University of Tulsa, Tulsa, OK, USA
| | - Ahlam M Alarbi
- Departments of Surgery and Psychiatry, School of Community Medicine, The University of Oklahoma, Tulsa, OK, USA
| | - Rajagopal Ramesh
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Jonathan B Savitz
- Laureate Institute for Brain Research, 6655 South Yale Ave, Tulsa, OK, 74136, USA
- Department of Community Medicine, University of Tulsa, Tulsa, OK, USA
| | - T Kent Teague
- Departments of Surgery and Psychiatry, School of Community Medicine, The University of Oklahoma, Tulsa, OK, USA
- Department of Biochemistry and Microbiology, The Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
- Department of Pharmaceutical Sciences, The University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
| | - Victoria B Risbrough
- Center of Excellence for Stress and Mental Health, La Jolla, CA, USA
- Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA
| | - Martin P Paulus
- Laureate Institute for Brain Research, 6655 South Yale Ave, Tulsa, OK, 74136, USA
- Department of Community Medicine, University of Tulsa, Tulsa, OK, USA
| |
Collapse
|
|
18
|
Das D, Karthik N, Taneja R. Crosstalk Between Inflammatory Signaling and Methylation in Cancer. Front Cell Dev Biol 2021; 9:756458. [PMID: 34901003 PMCID: PMC8652226 DOI: 10.3389/fcell.2021.756458] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/11/2021] [Indexed: 01/08/2023] Open
Abstract
Inflammation is an intricate immune response against infection and tissue damage. While the initial immune response is important for preventing tumorigenesis, chronic inflammation is implicated in cancer pathogenesis. It has been linked to various stages of tumor development including transformation, proliferation, angiogenesis, and metastasis. Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules contribute to the survival, growth, and progression of the tumor in its microenvironment. The aberrant expression and secretion of pro-inflammatory and growth factors by the tumor cells result in the recruitment of immune cells, thus creating a mutual crosstalk. The reciprocal signaling between the tumor cells and the immune cells creates and maintains a successful tumor niche. Many inflammatory factors are regulated by epigenetic mechanisms including DNA methylation and histone modifications. In particular, DNA and histone methylation are crucial forms of transcriptional regulation and aberrant methylation has been associated with deregulated gene expression in oncogenesis. Such deregulations have been reported in both solid tumors and hematological malignancies. With technological advancements to study genome-wide epigenetic landscapes, it is now possible to identify molecular mechanisms underlying altered inflammatory profiles in cancer. In this review, we discuss the role of DNA and histone methylation in regulation of inflammatory pathways in human cancers and review the merits and challenges of targeting inflammatory mediators as well as epigenetic regulators in cancer.
Collapse
Affiliation(s)
- Dipanwita Das
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nandini Karthik
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Reshma Taneja
- Department of Physiology, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
19
|
Gargalionis AN, Papavassiliou KA, Papavassiliou AG. Targeting STAT3 Signaling Pathway in Colorectal Cancer. Biomedicines 2021; 9:biomedicines9081016. [PMID: 34440220 PMCID: PMC8392110 DOI: 10.3390/biomedicines9081016] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/31/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.
Collapse
Affiliation(s)
- Antonios N. Gargalionis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.N.G.); (K.A.P.)
- Department of Biopathology, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Kostas A. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.N.G.); (K.A.P.)
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.N.G.); (K.A.P.)
- Correspondence: ; Tel.: +30-210-746-2508; Fax: +30-210-746-2703
| |
Collapse
|
|
20
|
Alotaibi AG, Li JV, Gooderham NJ. Tumour necrosis factor-α (TNF-α) enhances dietary carcinogen-induced DNA damage in colorectal cancer epithelial cells through activation of JNK signaling pathway. Toxicology 2021; 457:152806. [PMID: 33961948 PMCID: PMC8211460 DOI: 10.1016/j.tox.2021.152806] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. Benzo[a]pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazol [4,5-b] pyridine (PhIP) present in cooked meat are pro-carcinogens and considered to be potential risk factors for CRC. Their carcinogenic and mutagenic effects require metabolic activation primarily by cytochrome P450 1 family enzymes (CYPs); the expression of these enzymes can be modulated by aryl hydrocarbon receptor (AhR) activation and the tumour microenvironment, involving mediators of inflammation. In this study, we hypothesized that tumour necrosis factor-α (TNF-α), a key mediator of inflammation, modulates BaP- and PhIP-induced DNA damage in colon cancer epithelial cells. Importantly, we observed that TNF-α alone (0.1-100 pg/ml) induced DNA damage (micronuclei formation) in HCT-116 cells and co-treatment of TNF-α with BaP or PhIP showed higher levels of DNA damage compared to the individual single treatments. TNF-α alone or in combination with BaP or PhIP did not affect the expression levels of CYP1A1 and CYP1B1 (target genes of AhR signaling pathways). The DNA damage induced by TNF-α was elevated in p53 null HTC-116 cells compared to wild type cells, suggesting that TNF-α-induced DNA damage is suppressed by functional p53. In contrast, p53 status failed to affect BaP and PhIP induced micronucleus frequency. Furthermore, JNK and NF-κB signaling pathway were activated by TNF-α treatment but only inhibition of JNK significantly reduced TNF-α-induced DNA damage. Collectively, these findings suggest that TNF-α induced DNA damage involves JNK signaling pathway rather than AhR and NF-κB pathways in colon cancer epithelial cells.
Collapse
Affiliation(s)
- Aminah G Alotaibi
- Section of Biomolecular Medicine; National Centre for Genomic Technology, King Abdulaziz City for Science and Technology, KACST, Riyadh, Saudi Arabia
| | - Jia V Li
- Section of Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | | |
Collapse
|
|
21
|
CYP1B1 as a therapeutic target in cardio-oncology. Clin Sci (Lond) 2021; 134:2897-2927. [PMID: 33185690 PMCID: PMC7672255 DOI: 10.1042/cs20200310] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/12/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023]
Abstract
Cardiovascular complications have been frequently reported in cancer patients and survivors, mainly because of various cardiotoxic cancer treatments. Despite the known cardiovascular toxic effects of these treatments, they are still clinically used because of their effectiveness as anti-cancer agents. In this review, we discuss the growing body of evidence suggesting that inhibition of the cytochrome P450 1B1 enzyme (CYP1B1) can be a promising therapeutic strategy that has the potential to prevent cancer treatment-induced cardiovascular complications without reducing their anti-cancer effects. CYP1B1 is an extrahepatic enzyme that is expressed in cardiovascular tissues and overexpressed in different types of cancers. A growing body of evidence is demonstrating a detrimental role of CYP1B1 in both cardiovascular diseases and cancer, via perturbed metabolism of endogenous compounds, production of carcinogenic metabolites, DNA adduct formation, and generation of reactive oxygen species (ROS). Several chemotherapeutic agents have been shown to induce CYP1B1 in cardiovascular and cancer cells, possibly via activating the Aryl hydrocarbon Receptor (AhR), ROS generation, and inflammatory cytokines. Induction of CYP1B1 is detrimental in many ways. First, it can induce or exacerbate cancer treatment-induced cardiovascular complications. Second, it may lead to significant chemo/radio-resistance, undermining both the safety and effectiveness of cancer treatments. Therefore, numerous preclinical studies demonstrate that inhibition of CYP1B1 protects against chemotherapy-induced cardiotoxicity and prevents chemo- and radio-resistance. Most of these studies have utilized phytochemicals to inhibit CYP1B1. Since phytochemicals have multiple targets, future studies are needed to discern the specific contribution of CYP1B1 to the cardioprotective and chemo/radio-sensitizing effects of these phytochemicals.
Collapse
|
|
22
|
Clinical and genomic characteristics of metabolic syndrome in colorectal cancer. Aging (Albany NY) 2021; 13:5442-5460. [PMID: 33582655 PMCID: PMC7950286 DOI: 10.18632/aging.202474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 11/30/2020] [Indexed: 12/27/2022]
Abstract
Metabolic syndrome (MetS) is characterized by a group of metabolic disturbances which leads to the enhanced risk of cancer development. Elucidating the mechanisms between these two pathologies is essential to identify the potential therapeutic molecular targets for colorectal cancer (CRC). 716 colorectal patients from the First and Second Affiliated Hospital of Wenzhou Medical University were involved in our study and metabolic disorders were proven to increase the risk of CRC. The prognostic value of the MetS factors was analyzed using the Cox regression model and a clinical MetS-based nomogram was established. Then by using multi-omics techniques, the distinct molecular mechanism of MetS genes in CRC was firstly systematically characterized. Strikingly, MetS genes were found to be highly correlated with the effectiveness of targeted chemotherapy administration, especially for mTOR and VEGFR pathways. Our results further demonstrated that overexpression of MetS core gene IL6 would promote the malignancy of CRC, which was highly dependent on mTOR-S6K signaling. In conclusion, we comprehensively explored the clinical value and molecular mechanism of MetS in the progression of CRC, which may serve as a candidate option for cancer management and therapy in the future.
Collapse
|
|
23
|
Muthusami S, Ramachandran I, Krishnamoorthy S, Sambandam Y, Ramalingam S, Queimado L, Chaudhuri G, Ramachandran IK. Regulation of MicroRNAs in Inflammation-Associated Colorectal Cancer: A Mechanistic Approach. Endocr Metab Immune Disord Drug Targets 2021; 21:67-76. [PMID: 32940190 DOI: 10.2174/1871530320666200917112802] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/29/2020] [Accepted: 04/29/2020] [Indexed: 11/22/2022]
Abstract
The development of colorectal cancer (CRC) is a multistage process. The inflammation of
the colon as in inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn’s disease
(CD) is often regarded as the initial trigger for the development of inflammation-associated CRC.
Many cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins (ILs) are known to exert
proinflammatory actions, and inflammation initiates or promotes tumorigenesis of various cancers,
including CRC, through differential regulation of microRNAs (miRNAs/miRs). miRNAs can be
oncogenic miRNAs (oncomiRs) or anti-oncomiRs/tumor suppressor miRNAs, and they play key roles
during colorectal carcinogenesis. However, the functions and molecular mechanisms of regulation of
miRNAs involved in inflammation-associated CRC are still anecdotal and largely unknown.
Consolidating the published results and offering perspective solutions to circumvent CRC, the current
review is focused on the role of miRNAs and their regulation in the development of CRC. We have
also discussed the model systems adapted by researchers to delineate the role of miRNAs in
inflammation-associated CRC.
Collapse
Affiliation(s)
- Sridhar Muthusami
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Ilangovan Ramachandran
- Department of Endocrinology, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, Tamil Nadu, India
| | - Sneha Krishnamoorthy
- Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641 021, Tamil Nadu, India
| | - Yuvaraj Sambandam
- Department of Surgery, Comprehensive Transplant Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Satish Ramalingam
- Department of Genetic Engineering, School of Bio-Engineering, SRM Institute of Science and Technology, Kattankulathur, Kanchipuram 603 203, Tamil Nadu, India
| | - Lurdes Queimado
- Departments of Otorhinolaryngology - Head and Neck Surgery, Cell Biology, Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Gautam Chaudhuri
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
| | | |
Collapse
|
|
24
|
Kwon YJ, Shin S, Chun YJ. Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes. Arch Pharm Res 2021; 44:63-83. [PMID: 33484438 DOI: 10.1007/s12272-021-01306-w] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 01/06/2021] [Indexed: 12/13/2022]
Abstract
Human cytochrome P450 enzymes (CYPs) play a critical role in various biological processes and human diseases. CYP1 family members, including CYP1A1, CYP1A2, and CYP1B1, are induced by aryl hydrocarbon receptors (AhRs). The binding of ligands such as polycyclic aromatic hydrocarbons activates the AhRs, which are involved in the metabolism (including oxidation) of various endogenous or exogenous substrates. The ligands that induce CYP1 expression are reported to be carcinogenic xenobiotics. Hence, CYP1 enzymes are correlated with the pathogenesis of cancers. Various endogenous substrates are involved in the metabolism of steroid hormones, eicosanoids, and other biological molecules that mediate the pathogenesis of several human diseases. Additionally, CYP1s metabolize and activate/inactivate therapeutic drugs, especially, anti-cancer agents. As the metabolism of drugs determines their therapeutic efficacy, CYP1s can determine the susceptibility of patients to some drugs. Thus, understanding the role of CYP1s in diseases and establishing novel and efficient therapeutic strategies based on CYP1s have piqued the interest of the scientific community.
Collapse
Affiliation(s)
- Yeo-Jung Kwon
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Sangyun Shin
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Young-Jin Chun
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
| |
Collapse
|
|
25
|
Cytochrome P450 CYP2E1 Suppression Ameliorates Cerebral Ischemia Reperfusion Injury. Antioxidants (Basel) 2021; 10:antiox10010052. [PMID: 33466250 PMCID: PMC7824747 DOI: 10.3390/antiox10010052] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/24/2020] [Accepted: 12/26/2020] [Indexed: 12/23/2022] Open
Abstract
Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90 min) followed by 24 h of reperfusion to induce focal I/R injury as an acute stage model. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Furthermore, the role of CYP2E1 on the blood-brain barrier (BBB) integrity was investigated by measuring 20-hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p < 0.005). Moreover, reactive oxygen species (ROS) production, apoptosis, and neurodegeneration were significantly lower in the CYP2E1(−/−) I/R group (p < 0.001). The BBB damage was significantly lower in CYP2E1(−/−) mice compared to wild-type (WT) (p < 0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(−/−) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.
Collapse
|
|
26
|
Lua YH, Ong WW, Wong HK, Chew CH. Ethanol-induced CYP2E1 Expression is Reduced by Lauric Acid via PI3K Pathway in HepG2 Cells. Trop Life Sci Res 2020; 31:63-75. [PMID: 33214856 PMCID: PMC7652244 DOI: 10.21315/tlsr2020.31.3.5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The metabolism of alcohol involves cytochrome P450 2E1 (CYP2E1)-induced oxidative stress, with the association of phosphatidylinositol-3-kinases (PI3K) and nuclear factor kappa B (NFκB) signalling pathways. CYP2E1 is primarily involved in the microsomal ethanol oxidising system, which generates massive reactive oxygen species (ROS) and ultimately leads to oxidative stress and tissue damage. Lauric acid, a major fatty acid in palm kernel oil, has been shown as a potential antioxidant. Here, we aimed to evaluate the use of lauric acid as a potential antioxidant against ethanol-mediated oxidative stress by investigating its effect on CYP2E1 mRNA expression and the signalling pathway in ethanol-induced HepG2 cells. HepG2 cells were firstly treated with different concentrations of ethanol, and subsequently co-treated with different concentrations of lauric acid for 24 h. Total cellular RNA and total protein were extracted, and qPCR and Western blot was carried out. Ethanol induced the mRNA expression of CYP2E1 significantly, but lauric acid was able to downregulate the induced CYP2E1 expression in a dose-dependent manner. Similarly, Western blot analysis and densitometry analysis showed that the phosphorylated PI3K p85 (Tyr458) protein was significantly elevated in ethanol-treated HepG2 cells, but co-treatment with lauric acid repressed the activation of PI3K. However, there was no significant difference in NFκB pathway, in which the normalised NFκB p105 (Ser933) phosphorylation remained constant in any treatment conditions in this study. This suggests that ethanol induced CYP2E1 expression by activating PI3K p85 (Tyr458) pathway, but not the NFκB p105 (Ser933) pathway in HepG2 cells.
Collapse
Affiliation(s)
- Ying-Huan Lua
- Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Wei-Wah Ong
- Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Hong-Kin Wong
- Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Bandar Barat, 31900 Kampar, Perak, Malaysia
| | - Choy-Hoong Chew
- Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman, Jalan Universiti, Bandar Barat, 31900 Kampar, Perak, Malaysia
| |
Collapse
|
|
27
|
Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations. Eur J Pharmacol 2020; 886:173454. [PMID: 32763298 PMCID: PMC7402235 DOI: 10.1016/j.ejphar.2020.173454] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 07/30/2020] [Accepted: 07/30/2020] [Indexed: 01/07/2023]
Abstract
Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.
Collapse
|
|
28
|
Wang J, Yu L, Jiang H, Zheng X, Zeng S. Epigenetic Regulation of Differentially Expressed Drug-Metabolizing Enzymes in Cancer. Drug Metab Dispos 2020; 48:759-768. [PMID: 32601104 DOI: 10.1124/dmd.120.000008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/01/2020] [Indexed: 12/14/2022] Open
Abstract
Drug metabolism is a biotransformation process of drugs, catalyzed by drug-metabolizing enzymes (DMEs), including phase I DMEs and phase II DMEs. The aberrant expression of DMEs occurs in the different stages of cancer. It can contribute to the development of cancer and lead to individual variations in drug response by affecting the metabolic process of carcinogen and anticancer drugs. Apart from genetic polymorphisms, which we know the most about, current evidence indicates that epigenetic regulation is also central to the expression of DMEs. This review summarizes differentially expressed DMEs in cancer and related epigenetic changes, including DNA methylation, histone modification, and noncoding RNAs. Exploring the epigenetic regulation of differentially expressed DMEs can provide a basis for implementing individualized and rationalized medication. Meanwhile, it can promote the development of new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer. SIGNIFICANCE STATEMENT: This review summarizes the aberrant expression of DMEs in cancer and the related epigenetic regulation of differentially expressed DMEs. Exploring the epigenetic regulatory mechanism of DMEs in cancer can help us to understand the role of DMEs in cancer progression and chemoresistance. Also, it provides a basis for developing new biomarkers and targets for the diagnosis, treatment, and prognosis of cancer.
Collapse
Affiliation(s)
- Jiaqi Wang
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Huidi Jiang
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Xiaoli Zheng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (J.W., L.Y., H.J., S.Z.) and Hangzhou Cancer Institution, Hangzhou Cancer Hospital, Hangzhou, China (X.Z.)
| |
Collapse
|
|
29
|
Cervena K, Siskova A, Buchler T, Vodicka P, Vymetalkova V. Methylation-Based Therapies for Colorectal Cancer. Cells 2020; 9:E1540. [PMID: 32599894 PMCID: PMC7349319 DOI: 10.3390/cells9061540] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 02/08/2023] Open
Abstract
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
Collapse
Affiliation(s)
- Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic;
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| |
Collapse
|
|
30
|
Evangelista EA, Cho CW, Aliwarga T, Totah RA. Expression and Function of Eicosanoid-Producing Cytochrome P450 Enzymes in Solid Tumors. Front Pharmacol 2020; 11:828. [PMID: 32581794 PMCID: PMC7295938 DOI: 10.3389/fphar.2020.00828] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/20/2020] [Indexed: 12/14/2022] Open
Abstract
Oxylipins derived from the oxidation of polyunsaturated fatty acids (PUFAs) act as important paracrine and autocrine signaling molecules. A subclass of oxylipins, the eicosanoids, have a broad range of physiological outcomes in inflammation, the immune response, cardiovascular homeostasis, and cell growth regulation. Consequently, eicosanoids are implicated in the pathophysiology of various diseases, most notably cancer, where eicosanoid mediated signaling is involved in tumor development, progression, and angiogenesis. Cytochrome P450s (CYPs) are a superfamily of heme monooxygenases generally involved in the clearance of xenobiotics while a subset of isozymes oxidize PUFAs to eicosanoids. Several eicosanoid forming CYPs are overexpressed in tumors, elevating eicosanoid levels and suggesting a key function in tumorigenesis and progression of tumors in the lung, breast, prostate, and kidney. This review summarizes the current understanding of CYPs' involvement in solid tumor etiology and progression providing supporting public data for gene expression from The Cancer Genome Atlas.
Collapse
Affiliation(s)
- Eric A Evangelista
- Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, United States
| | - Christi W Cho
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States
| | - Theresa Aliwarga
- Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, United States
| | - Rheem A Totah
- Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, United States
| |
Collapse
|
|
31
|
Alsubait A, Aldossary W, Rashid M, Algamdi A, Alrfaei BM. CYP1B1 gene: Implications in glaucoma and cancer. J Cancer 2020; 11:4652-4661. [PMID: 32626511 PMCID: PMC7330686 DOI: 10.7150/jca.42669] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/06/2020] [Indexed: 12/11/2022] Open
Abstract
Glaucoma is a serious disease that can lead to irreversible loss of vision. Patients with primary congenital glaucoma may have elevated intraocular pressure. Hypertension causes damages to intraocular structures and affects the Schlemm's canal, collector channels, trabecular meshwork, and optic nerve's molecular structures. An important gene that is defective in patients with glaucoma is CYP1B1, a gene associated with optic nerve deterioration. CYP1B1is a key enzyme involved in the metabolism of exogenous and endogenous compounds. Also, it is critical in the detoxification of pre-carcinogens, such as polycyclic aromatic hydrocarbons and estrogen. It catalyzes their conversion into metabolites subsequently eliminated from the body. In malignant tumors, the CYP1B1 promoter is hypomethylated. CYP1B1 overexpression results in the conversion of estrogens to quinone forms, which bind with DNA and create a predisposition for cancer in several organs, such as the brain, breast, and ovary. Increased cytokine interleukin-6 and leptin lead to elevated CYP1B1 activity, which possibly causes cancer. In addition, the expression of aromatic hydrocarbon receptors is increased in tumor tissues, and it elevates oxidative stress and cell growth. TCGA database analysis showed increased survival at bladder and renal carcinoma when CYP1B1 expression is low. Therefore, alteration of CYP1B1 expression may suggest a therapeutic benefit for multiple diseases such as glaucoma and cancer.
Collapse
Affiliation(s)
- Arwa Alsubait
- King Abdullah International Medical Research Center (KAIMRC)/ King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), MNGHA, Saudi Arabia
| | | | - Mamoon Rashid
- King Abdullah International Medical Research Center (KAIMRC)/ King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), MNGHA, Saudi Arabia
| | | | - Bahauddeen M Alrfaei
- King Abdullah International Medical Research Center (KAIMRC)/ King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), MNGHA, Saudi Arabia
| |
Collapse
|
|
32
|
Dysbacteriosis-Derived Lipopolysaccharide Causes Embryonic Osteopenia through Retinoic-Acid-Regulated DLX5 Expression. Int J Mol Sci 2020; 21:ijms21072518. [PMID: 32260461 PMCID: PMC7177785 DOI: 10.3390/ijms21072518] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 03/30/2020] [Accepted: 04/02/2020] [Indexed: 12/01/2022] Open
Abstract
Growing evidence suggests an adverse impact of gut microbiota dysbiosis on human health. However, it remains unclear whether embryonic osteogenesis is affected by maternal gut dysbacteriosis. In this study, we observed that elevated lipopolysaccharide (LPS) levels led to skeletal developmental retardation in an established mouse model of gut microbiota dysbiosis. Using chick embryos exposed to dysbacteriosis-derived LPS, we found restriction in the development of long bones as demonstrated by Alcian blue and alizarin red staining. Micro-CT and histological analysis exhibited decreased trabecular volume, bone mineral density, and collagen production, as well as suppressed osteoblastic gene expression (Ocn, Runx2, Osx, and Dlx5) in chick embryonic phalanges following LPS treatment. Atomic force microscopy manifested decreased roughness of MC3T3-E1 cells and poorly developed matrix vesicles (MVs) in presence of LPS. The expression of the aforementioned osteoblastic genes was suppressed in MC3T3-E1 cells as well. High-throughput RNA sequencing indicated that retinoic acid (RA) may play an important role in LPS-induced osteopenia. The addition of RA suppressed Dlx5 expression in MC3T3-E1 cells, as was also seen when exposed to LPS. Quantitative PCR, Western blot, and immunofluorescent staining showed that retinoic acid receptor α (RARα) was upregulated by LPS or RA treatment, while the expression of DLX5 was downregulated. CYP1B1 expression was increased by LPS treatment in MC3T3-E1 cells, which might be attributed to the increased inflammatory factors and subsequently activated NF-κB signaling. Eventually, blocking RA signals with AGN193109 successfully restored LPS-inhibited osteoblastic gene expression. Taken together, our data reveals that maternal gut microbiota dysbiosis can interfere with bone ossification, in which Dlx5 expression regulated by RA signaling plays an important role.
Collapse
|
|
33
|
Hwang DB, Won DH, Shin YS, Kim SY, Kang BC, Lim KM, Che JH, Nam KT, Yun JW. Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility. Free Radic Biol Med 2020; 148:128-139. [PMID: 31911150 DOI: 10.1016/j.freeradbiomed.2020.01.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/21/2019] [Accepted: 01/03/2020] [Indexed: 12/28/2022]
Abstract
Clinical cisplatin use is often limited by its drug-induced liver injury (DILI). Particularly, individual differences in susceptibility to DILI can cause life-threatening medical conditions. This study aimed to uncover the inherent genetic factors determining individual variations in hepatotoxicity susceptibility. Rats were subjected to liver biopsy and a 3-week postoperative recovery period before cisplatin administration. At 2 days post-treatment with cisplatin, the rats exhibited histopathological and serum biochemical alterations in the liver, and changes in hydrogen peroxide and cytochrome P450-2E1 levels. Based on these results of liver-related biochemical markers, 32 rats were grouped into the susceptible (top five) and resistant (bottom five) groups. Using RNA-sequencing, we compared gene expressions in the liver pre-biopsied from these two groups before cisplatin treatment and found 161 differently expressed genes between the Susceptible and Resistant groups. Among them, the clock-controlled Ccrn4l responsible for 'rhythmic process' was identified as a common gene downregulated inherently prior to drug exposure in both cisplatin- and acetaminophen-sensitive animals. Additionally, low Ccrn4l levels before cisplatin treatment in the Susceptible group were maintained even after treatment, with decreased antioxidants, increased nitration, and apoptosis. The relationship of Ccrn4l with catalase and mitochondrial RNAs in the liver was confirmed by correlation of their hepatic levels among individuals and similar patterns of circadian variation in their mRNA expression. Remarkably, Ccrn4l knockdown promoted cisplatin-induced mitochondrial dysfunction in WB-F344 cells with antioxidant catalase and apoptosis-related Bax changes. Inherent individual hepatic Ccrn4l level might be a novel factor affecting cisplatin-induced hepatotoxicity susceptibility, possibly through regulation of mitochondrial and antioxidant functions.
Collapse
Affiliation(s)
- Da-Bin Hwang
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Dong-Hoon Won
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Yoo-Sub Shin
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Shin-Young Kim
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Byeong-Cheol Kang
- Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, 03760, South Korea
| | - Jeong-Hwan Che
- Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Jun-Won Yun
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea.
| |
Collapse
|
|
34
|
Impaired Metabolic Pathways Related to Colorectal Cancer Progression and Therapeutic Implications. IRANIAN JOURNAL OF PUBLIC HEALTH 2020; 49:56-67. [PMID: 32309224 PMCID: PMC7152626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Risk of colorectal cancer (CRC) is defined by genetic predisposition and environmental factors that often co-occur and interact, resulting in diversiform biological reactions. The present study attempted to investigate transcriptome alteration and adaptation associated with CRC progression. METHODS The study consisted of patients who presented at Memorial Sloan-Kettering Cancer Center, Guangzhou, China with a colonic neoplasm in 1992-2004. Microarray GSE41258 of the study was acquired from Gene Expression Omnibus and 253 included microarrays were categorized by groups of normal colon, early primary tumor, lymph node metastases primary tumor, advanced primary tumor and distant metastases. Short Time-series Expression Miner (STEM) was applied to discover tumor grade-dependent gene expression patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to explore functional enrichment of differential expression genes (DEGs). RESULTS Overall, 2870 significant DEGs were screened out on all groups. Six significant grade-dependent gene expression patterns were statistically significant. DEGs in all significant patterns were mainly assembled in GO terms of metastases and deterioration of tumor, epithelial proteins and cytokines, and protein binding and bridging. DEGs in profile 0 down-regulated with higher tumor grade, prominently enriched in KEGG pathways of metabolism. CONCLUSION Besides many well-known colorectal cancer-related pathways, DEGs of profiles especially those down-regulated with CRC progression, clustered in various metabolic pathways including starch and sucrose metabolism, fatty acid metabolism, nitrogen metabolism, as well as xenobiotics biotransformation that link to tumorigenesis, demonstrating the impairment of physiological metabolic pathways in the context of tumor progression. These results gave a high potential for therapeutic strategies.
Collapse
|
|
35
|
Malik DES, David RM, Gooderham NJ. Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells. Arch Toxicol 2019; 93:3005-3020. [PMID: 31515600 DOI: 10.1007/s00204-019-02558-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/02/2019] [Indexed: 12/15/2022]
Abstract
Breast cancer is the most commonly diagnosed malignancy in females, the etiology being multifactorial and includes the role of lifestyle exposure to DNA-damaging chemicals such as dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Both compounds require cytochrome P450 (CYP)-mediated metabolic activation to DNA-damaging species, and both induce transcriptional responses through the nuclear receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The objective of this work was to investigate the molecular toxicology and local activation of BaP and PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24 h) of cells with BaP (10 nM-10 µM) and PhIP (100 nM-100 µM) significantly induced genetic damage (micronuclei formation) in a dose-dependent manner in both cell lines. This effect was potentiated in the presence of human IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6 treatment failed to induce micronuclei frequency above the control levels in these cells. Compared to BaP or PhIP treatment alone, IL-6 plus BaP or PhIP selectively induced CYP1B1 significantly in both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically CYP1B1 via miR27b, is responsible for this effect.
Collapse
Affiliation(s)
- Durr-E-Shahwar Malik
- Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK
| | - Rhiannon M David
- Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK
- Genetic Toxicology, Discovery Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - Nigel J Gooderham
- Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK.
| |
Collapse
|
|
36
|
Zhu Y, Mordaunt CE, Yasui DH, Marathe R, Coulson RL, Dunaway KW, Jianu JM, Walker CK, Ozonoff S, Hertz-Picciotto I, Schmidt RJ, LaSalle JM. Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study. Hum Mol Genet 2019; 28:2659-2674. [PMID: 31009952 PMCID: PMC6687952 DOI: 10.1093/hmg/ddz084] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/25/2019] [Accepted: 04/15/2019] [Indexed: 12/20/2022] Open
Abstract
DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies. A total of 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typically developing controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing and correlated with expression differences in brain. Methylation at CYP2E1 associated with both ASD diagnosis and genotype within the DMR. In contrast, methylation at IRS2 was unaffected by within DMR genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.
Collapse
Affiliation(s)
- Yihui Zhu
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Charles E Mordaunt
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Dag H Yasui
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Ria Marathe
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Rochelle L Coulson
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Keith W Dunaway
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Julia M Jianu
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| | - Cheryl K Walker
- Department of Obstetrics & Gynecology, School of Medicine, MIND Institute, University of California, Davis, 95616, USA
| | - Sally Ozonoff
- MIND Institute, University of California, Davis, CA, USA
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of California, Davis, CA, USA
| | - Irva Hertz-Picciotto
- MIND Institute, University of California, Davis, CA, USA
- Department of Public Health Sciences, University of California, Davis, CA, USA
| | - Rebecca J Schmidt
- MIND Institute, University of California, Davis, CA, USA
- Department of Public Health Sciences, University of California, Davis, CA, USA
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA
- Genome Center, University of California, Davis, CA, USA
- MIND Institute, University of California, Davis, CA, USA
| |
Collapse
|
|
37
|
Trousil S, Lee P, Edwards RJ, Maslen L, Lozan-Kuehne JP, Ramaswami R, Aboagye EO, Clarke S, Liddle C, Sharma R. Altered cytochrome 2E1 and 3A P450-dependent drug metabolism in advanced ovarian cancer correlates to tumour-associated inflammation. Br J Pharmacol 2019; 176:3712-3722. [PMID: 31236938 DOI: 10.1111/bph.14776] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/10/2019] [Accepted: 05/16/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND PURPOSE Previous work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer-related inflammation on multiple CYP enzymes using a validated drug cocktail. EXPERIMENTAL APPROACH Patients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C-reactive protein and cytokine analysis. KEY RESULTS CYP2E1 activity was markedly up-regulated in cancer (6-hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL-6, IL-8, and TNF-α. Repression of CYP3A correlated with raised levels of serum C-reactive protein, IL-6, IL-8, and TNF-α. CONCLUSIONS AND IMPLICATIONS CYP enzyme activity is differentially affected by the presence of tumour-associated inflammation, affecting particularly CYP2E1- and CYP3A-mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.
Collapse
Affiliation(s)
- Sebastian Trousil
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Patrizia Lee
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Robert J Edwards
- Division of Experimental Medicine, Imperial College London, London, UK
| | - Lynn Maslen
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Ramya Ramaswami
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Eric O Aboagye
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Stephen Clarke
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Christopher Liddle
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead, Westmead, NSW, Australia
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, London, UK
| |
Collapse
|
|
38
|
Yang ZH, Dang YQ, Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J Gastroenterol 2019; 25:2863-2877. [PMID: 31249445 PMCID: PMC6589733 DOI: 10.3748/wjg.v25.i23.2863] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.
Collapse
Affiliation(s)
- Zhen-Hua Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Digestive Endoscopy Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Qi Dang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| |
Collapse
|
|
39
|
Li D, Tolleson WH, Yu D, Chen S, Guo L, Xiao W, Tong W, Ning B. Regulation of cytochrome P450 expression by microRNAs and long noncoding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2019; 37:180-214. [PMID: 31305208 PMCID: PMC6737535 DOI: 10.1080/10590501.2019.1639481] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Environmental exposures to hazardous chemicals are associated with a variety of human diseases and disorders, including cancers. Phase I metabolic activation and detoxification reactions catalyzed by cytochrome P450 enzymes (CYPs) affect the toxicities of many xenobiotic compounds. Proper regulation of CYP expression influences their biological effects. Noncoding RNAs (ncRNAs) are involved in regulating CYP expression, and ncRNA expression is regulated in response to environmental chemicals. The mechanistic interactions between ncRNAs and CYPs associated with the toxicity and carcinogenicity of environmental chemicals are described in this review, focusing on microRNA-dependent CYP regulation. The role of long noncoding RNAs in regulating CYP expression is also presented and new avenues of research concerning this regulatory mechanism are described.
Collapse
Affiliation(s)
- Dongying Li
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - William H Tolleson
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Dianke Yu
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Si Chen
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Lei Guo
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Wenming Xiao
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Weida Tong
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| | - Baitang Ning
- a National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA) , Jefferson , AR , USA
| |
Collapse
|
|
40
|
Malik DES, David RM, Gooderham NJ. Mechanistic evidence that benzo[a]pyrene promotes an inflammatory microenvironment that drives the metastatic potential of human mammary cells. Arch Toxicol 2018; 92:3223-3239. [PMID: 30155724 PMCID: PMC6132703 DOI: 10.1007/s00204-018-2291-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 08/16/2018] [Indexed: 12/21/2022]
Abstract
Benzo[a]pyrene (B(a)P) is a major cancer-causing contaminant present in food such as cooked meats and cereals, and is ubiquitous in the environment in smoke derived from the combustion of organic material. Exposure to B(a)P is epidemiologically linked with the incidence of breast cancer. Although B(a)P is recognized as a complete genotoxic carcinogen, thought to act primarily via CYP-mediated metabolic activation to DNA-damaging species, there is also evidence that B(a)P exposure elicits other biological responses that promote development of the cancer phenotype. Here in mechanistic studies using human mammary cells MCF-7 and MDA-MB-231, we have explored mechanisms whereby B(a)P (10- 8 to 10- 5M) promotes inflammation pathways via TNF-α and NFκB leading to IL-6 upregulation, microRNA (Let7a, miR21 and miR29b) dysregulation and activation of VEGF. The miRNA dysregulation is associated with altered expression of inflammation mediators and increased migration and invasive potential of human mammary cancer cells. Our data suggest that mammary cell exposure to B(a)P results in perturbation of inflammation mediators and dysregulation of tumorigenic miRNAs, leading to an inflammation microenvironment that facilitates migration and invasion of mammary epithelial cells. These properties of B(a)P, together with its well-established metabolic activation to DNA-damaging species, offer mechanistic insights into its carcinogenic mode of action.
Collapse
Affiliation(s)
- Durr-E-Shahwar Malik
- Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK
| | - Rhiannon M David
- Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK
- Genetic Toxicology, Drug Safety and Metabolism, MSAS Unit, AstraZeneca, Cambridge, UK
| | - Nigel J Gooderham
- Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK.
| |
Collapse
|
|
41
|
Xie L, He Y, Zhou X, Li X, Jin X, Wang X, Shi D. Porcine interleukin-6 enhances the expression of CYP2C33 through a constitutive androstane receptor/retinoid X receptor-mediated pathway. Xenobiotica 2018; 49:257-264. [DOI: 10.1080/00498254.2018.1438686] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Lixia Xie
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Yucheng He
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Xiaoqiao Zhou
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Xiaowen Li
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Xiue Jin
- Hubei Provincial Institute of Veterinary Drug Control, Wuhan, People’s Republic of China
| | - Xiliang Wang
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| | - Deshi Shi
- State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
- Key Laboratory of Preventive Veterinary Medicine in Hubei Province, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China
| |
Collapse
|
|
42
|
Yun J, Park MH, Son DJ, Nam KT, Moon DB, Ju JH, Hwang OK, Choi JS, Kim TH, Jung YS, Hwang DY, Han SB, Yoon DY, Hong JT. IL-32 gamma reduces lung tumor development through upregulation of TIMP-3 overexpression and hypomethylation. Cell Death Dis 2018; 9:306. [PMID: 29467412 PMCID: PMC5833366 DOI: 10.1038/s41419-018-0375-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 12/19/2022]
Abstract
The low expression of tissue inhibitor of metalloproteinase 3 (TIMP-3) is important in inflammatory responses. Therefore, inhibition of TIMP-3 may promote tumor development. Our study showed that expression of TIMP-3 was elevated in lL-32γ mice lung tissues. In this study, we investigated whether IL-32γ mice inhibited lung tumor development through overexpression of TIMP-3 and its methylation. To explore the possible underlying mechanism, lung cancer cells were transfected with IL-32γ cDNA plasmid. A marked increase in TIMP-3 expression was caused by promoter methylation. Mechanistic studies indicated that TIMP-3 overexpression reduced NF-κB activity, which led to cell growth inhibition in IL-32γ transfected lung cancer cells. We also showed that IL-32γ inhibits expression of DNA (cytosine-5-)-methyltransferase 1 (DNMT1). Moreover, IL-32γ inhibits the binding of DNMT1 to TIMP-3 promoter, but this effect was reversed by the treatment of DNA methyltransferase inhibitor (5-Aza-CdR) and NF-κB inhibitor (PS1145), suggesting that a marked increase in TIMP-3 expression was caused by inhibition of promoter hypermethylation via decreased DNMT1 expression through the NF-κB pathway. In an in vivo carcinogen induced lung tumor model, tumor growth was inhibited in IL-32γ overexpressed mice with elevated TIMP-3 expression and hypomethylation accompanied with reduced NF-κB activity. Moreover, in the lung cancer patient tissue, the expression of IL-32 and TIMP-3 was dramatically decreased at a grade-dependent manner compared to normal lung tissue. In summary, IL-32γ may increase TIMP-3 expression via hypomethylation through inactivation of NF-κB activity, and thereby reduce lung tumor growth.
Collapse
Affiliation(s)
- Jaesuk Yun
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea.,Department of Pharmacy, Wonkwang University, #460 Iksan-daero, Iksan-si, Jeonbuk, 54538, Republic of Korea
| | - Mi Hee Park
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Dong Ju Son
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Kyung Tak Nam
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Dae Bong Moon
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Jung Heun Ju
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Ok Kyung Hwang
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Jeong Soon Choi
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Tae Hoon Kim
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Young Suk Jung
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Dae Yeon Hwang
- Department of Biomaterial Science, Pusan National University, Miryang, Kyungnam, 50463, Republic of Korea
| | - Sang Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea
| | - Do-Young Yoon
- Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Gwangjin-gu, Seoul, 05029, Republic of Korea.
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Osongsaengmyeong1-ro 194-21, Heungduk-gu, Cheongju, Chungbuk, 28160, Republic of Korea.
| |
Collapse
|
|
43
|
Alhouayek M, Gouveia-Figueira S, Hammarström ML, Fowler CJ. Involvement of CYP1B1 in interferon γ-induced alterations of epithelial barrier integrity. Br J Pharmacol 2018; 175:877-890. [PMID: 29232759 DOI: 10.1111/bph.14122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 11/24/2017] [Accepted: 11/24/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro-inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFNγ (10 ng·mL-1 ). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS IFNγ disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1α mRNA expression. CYP1B1 induction is inhibited by the NF-κB inhibitor ammonium pyrrolidinedithiocarbamate (100 μM) but not by the HIF1α inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (50 μM). Inhibition of CYP1B1 with the selective inhibitor 2,4,3',5'-tetramethoxystilbene (100 nM) partly reverses the effects of IFNγ on epithelial permeability. CONCLUSIONS AND IMPLICATIONS These data suggest that increased expression of CYP1B1 is involved in the effects of IFNγ on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFNγ and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation.
Collapse
Affiliation(s)
- Mireille Alhouayek
- Department of Pharmacology and Clinical Neuroscience, Pharmacology Unit, Umeå University, Umeå, Sweden.,Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Bruxelles, Belgium
| | - Sandra Gouveia-Figueira
- Department of Chemistry, Umeå University, Umeå, Sweden.,Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden
| | | | - Christopher J Fowler
- Department of Pharmacology and Clinical Neuroscience, Pharmacology Unit, Umeå University, Umeå, Sweden
| |
Collapse
|
|
44
|
Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer. Arch Toxicol 2018; 92:1639-1655. [PMID: 29362861 PMCID: PMC5882637 DOI: 10.1007/s00204-018-2160-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 01/17/2018] [Indexed: 02/06/2023]
Abstract
Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10-7-10-4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10-3-10-1 M) with PhIP (10-7-10-4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.
Collapse
|
|
45
|
Cancer chemoprevention revisited: Cytochrome P450 family 1B1 as a target in the tumor and the microenvironment. Cancer Treat Rev 2017; 63:1-18. [PMID: 29197745 DOI: 10.1016/j.ctrv.2017.10.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/30/2017] [Accepted: 10/31/2017] [Indexed: 02/08/2023]
Abstract
Cancer chemoprevention is the use of synthetic, natural or biological agents to prevent or delay the development or progression of malignancies. Intriguingly, many phytochemicals with anti-inflammatory and anti-angiogenic effects, recently proposed as chemoprevention strategies, are inhibitors of Cytochrome P450 family 1B1 (CYP1B1), an enzyme overexpressed in a wide variety of tumors and associated with angiogenesis. In turn, pro-inflammatory cytokines were reported to boost CYP1B1 expression, suggesting a key role of CYP1B1 in a positive loop of inflammatory angiogenesis. Other well-known pro-tumorigenic activities of CYP1B1 rely on metabolic bioactivation of xenobiotics and steroid hormones into their carcinogenic derivatives. In contrast to initial in vitro observations, in vivo studies demonstrated a protecting role against cancer for the other CYP1 family members (CYP1A1 and CYP1A2), suggesting that the specificity of CYP1 family inhibitors should be carefully taken into account for developing potential chemoprevention strategies. Recent studies also proposed a role of CYP1B1 in multiple cell types found within the tumor microenvironment, including fibroblasts, endothelial and immune cells. Overall, our review of the current literature suggests a positive loop between inflammatory cytokines and CYP1B1, which in turn may play a key role in cancer angiogenesis, acting on both cancer cells and the tumor microenvironment. Strategies aiming at specific CYP1B1 inhibition in multiple cell types may translate into clinical chemoprevention and angioprevention approaches.
Collapse
|
|
46
|
Li F, Wei L, Li S, Liu J. Indoleamine-2,3-dioxygenase and Interleukin-6 associated with tumor response to neoadjuvant chemotherapy in breast cancer. Oncotarget 2017; 8:107844-107858. [PMID: 29296206 PMCID: PMC5746108 DOI: 10.18632/oncotarget.22253] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/02/2017] [Indexed: 02/06/2023] Open
Abstract
Purpose Indoleamine-2,3-dioxygenase (IDO) and Interleukin-6 (IL-6) contribute to poor therapeutic effects, tumor relapse and aggressive tumor growth. IDO and IL-6 incorporate a positive feedback signal loop to maintain IDO and IL-6 constitutive expression and facilitate tumor progression. Results IDO expression was associated with IL-6 expression and plasma IL-6 level (P<0.05). Concentrating on clinicopathological features prior neoadjuvant chemotherapy, both IDO expression and plasma IL-6 level were associated with clinical T stage and N stage (P<0.05). IL-6 expression was associated with clinical T stage (P=0.016). The co-expression of IDO/IL-6 was correlated with clinical T, N stage and estrogen receptor (ER) status (P<0.05). IDO, IL-6 expression, clinical T stage, pathological T stage, ER status and Luminal type were correlated with clinical response to neoadjuvant chemotherapy (P<0.05). Multivariate analysis showed that IDO expression were correlated with clinical response to neoadjuvant chemotherapy (P=0.034). IL-6 expression and pathological T stage were correlated with pCR (P<0.05). In the multivariate analysis, postoperative pathological T stage associated with pCR (P=0.041). In the prognostic analysis, only clinical T stage was significant correlated with overall survival (P=0.003). Materials and Methods 46 breast cancer patients received neoadjuvant chemotherapy enrolled in this study. Immunohistochemistry was applied for evaluating IDO and IL-6 expression in biopsy tissues prior neoadjuvant chemotherapy. Immunofluorescence was applied to observe the co-localization of IDO and IL-6. Serum IL-6 level was examined via ELISA. The associations between IDO, IL-6, Serum IL-6 level and clinicopathological features, response to neoadjuvant chemotherapy were analyzed. Conclusion IDO and IL-6 expression associated with advanced breast cancer and poor response to neoadjuvant chemotherapy.
Collapse
Affiliation(s)
- Fangxuan Li
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Lijuan Wei
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Shixia Li
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Juntian Liu
- Department of Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| |
Collapse
|
|
47
|
Kim T, Wahyudi LD, Gonzalez FJ, Kim JH. Nuclear Receptor PPARα Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKKβ-Deficient Mice. Biomol Ther (Seoul) 2017; 25:504-510. [PMID: 28190320 PMCID: PMC5590794 DOI: 10.4062/biomolther.2016.218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/15/2016] [Accepted: 12/06/2016] [Indexed: 11/05/2022] Open
Abstract
Inhibitor of nuclear factor kappa-B kinase beta (IKKβ) plays a critical role in cell proliferation and inflammation in various cells by activating NF-κB signaling. However, the interrelationship between peroxisome proliferator-activated receptor α (PPARα) and IKKβ in cell proliferation is not clear. In this study, we investigated the possible role of PPARα in the hepatic cell death in the absence of IKKβ gene using liver-specific Ikkb-null (IkkbF/F-AlbCre) mice. To examine the function of PPARα activation in hepatic cell death, wild-type (IkkbF/F) and IkkbF/F-AlbCre mice were treated with PPARα agonist Wy-14,643 (0.1% w/w chow diet) for two weeks. As a result of Wy-14,643 treatment, apoptotic markers including caspase-3 cleavage, poly (ADP-ribose) polymerase (PARP) cleavage and TUNEL-positive staining were significantly decreased in the IkkbF/F-AlbCre mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and IkkbF/F-AlbCre mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that IKKβ-derived hepatic apoptosis could be altered by PPARα activation in conjunction with activation of NF-κB and STAT3 signaling.
Collapse
Affiliation(s)
- Taehyeong Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Lilik Duwi Wahyudi
- Department of Pharmacology and Graduate School of Convergence Medical Science, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Jung-Hwan Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.,Department of Pharmacology and Graduate School of Convergence Medical Science, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
| |
Collapse
|
|
48
|
Pérez-Ramírez C, Cañadas-Garre M, Alnatsha A, Molina MÁ, Robles AI, Villar E, Delgado JR, Faus-Dáder MJ, Calleja-Hernández MÁ. Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer. Surg Oncol 2017; 26:278-285. [PMID: 28807247 DOI: 10.1016/j.suronc.2017.05.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/12/2017] [Accepted: 05/19/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Surgery is the standard treatment for early-stage NSCLC, and platinum-based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naïve EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. METHODS A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. RESULTS Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes. CONCLUSIONS Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients.
Collapse
Affiliation(s)
- Cristina Pérez-Ramírez
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain; Department of Biochemistry, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain.
| | - Marisa Cañadas-Garre
- Centre for Public Health, Queen's University of Belfast c/o Regional Genetics Centre, Level A, Tower Block, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, United Kingdom.
| | - Ahmed Alnatsha
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, Spain; Department of Molecular Medicine, Faculty of Medicine, University of Tübingen, Geissweg 5, 72076 Tübingen, Germany.
| | - Miguel Ángel Molina
- Pangaea Biotech, S.L., Hospital Universitario Quirón Dexeus, C/ Sabino Arana, 5-19, 08028 Barcelona, Spain.
| | - Ana I Robles
- National Cancer Institute, 37 Convent Dr, 37/3060D, Bethesda, MD, United States.
| | - Eduardo Villar
- Pathology Service, UGC Anatomía Patológica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain.
| | - Juan Ramón Delgado
- Medical Oncology Service, UGC Oncología Médica, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain.
| | - María José Faus-Dáder
- Department of Biochemistry, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain.
| | - Miguel Ángel Calleja-Hernández
- Department of Pharmacology, Faculty of Pharmacy, University of Granada, Campus Universitario de Cartuja, s/n, 18071 Granada, Spain.
| |
Collapse
|
|
49
|
Ding L, Ni J, Yang F, Huang L, Deng H, Wu Y, Ding X, Tang J. Promising therapeutic role of miR-27b in tumor. Tumour Biol 2017; 39:1010428317691657. [PMID: 28351320 DOI: 10.1177/1010428317691657] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs are small nonprotein-encoding RNAs ranging from 18 to 25 nucleotides in size and regulate multiple biological pathways via directly targeting a variety of associated genes in cancers. MicroRNA-27b is a highly conserved MicroRNA throughout vertebrates and there are two homologs (hsa-miR-27a and hsa-miR-27b) in humans. MicroRNA-27b is an intragenic microRNA located on chromosome 9q22.1 within the C9orf3 gene, clustering with miR-23b and miR-24-1 in human. As a frequently dysregulated microRNA in human cancers, microRNA-27b could function as a tumor suppressor or an oncogenic microRNA. More and more studies indicate that microRNA-27b is involved in affecting various biological processes, such as angiogenesis, proliferation, metastasis, and drug resistance, and thus may act as a promising therapeutic target in human cancers. In this review, we discuss the role of microRNA-27b in detail and offer novel insights into molecular targeting therapy for cancers.
Collapse
Affiliation(s)
- Li Ding
- 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China.,2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Jie Ni
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China.,3 The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, P.R. China
| | - Fan Yang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Lingli Huang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Heng Deng
- 4 The Graduate School, AnHui University of Traditional Chinese Medicine, Hefei, P.R. China
| | - Yang Wu
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China
| | - Xuansheng Ding
- 1 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China
| | - Jinhai Tang
- 2 Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, P.R. China.,5 Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China
| |
Collapse
|
|
50
|
Serum inflammatory markers and colorectal cancer risk and survival. Br J Cancer 2017; 116:1358-1365. [PMID: 28376082 PMCID: PMC5482738 DOI: 10.1038/bjc.2017.96] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 01/31/2017] [Accepted: 03/17/2017] [Indexed: 12/26/2022] Open
Abstract
Background: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markers Design: A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n=325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes. Results: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06–1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03–1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01–1.41). Conclusions: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.
Collapse
|