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Tzoumpa S, Sevenet N, Bejar-Ardiles CL, Villette B, Zumelzu C, Benamouzig R, Caux F, Maubec E. Multiple basal cell carcinomas revealing a biallelic MUTYH gene mutation in a 39-year-old male patient. J Eur Acad Dermatol Venereol 2023; 37:e327-e329. [PMID: 36151995 DOI: 10.1111/jdv.18592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/13/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Sofia Tzoumpa
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Nicolas Sevenet
- Department of Genetics, Bergonié Institute, Bordeaux, France
| | - Claudia-Luisa Bejar-Ardiles
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Béatrice Villette
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Coralie Zumelzu
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Robert Benamouzig
- Department of Gastroenterology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Frédéric Caux
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France
| | - Eve Maubec
- Department of Dermatology, Avicenne University Hospital, AP-HP, Sorbonne-Paris-Nord University, Bobigny, France.,UMRS-1124, Campus Paris Saint-Germain-des-Prés, Paris University, Paris, France
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Baptista MS, Cadet J, Greer A, Thomas AH. Photosensitization Reactions of Biomolecules: Definition, Targets and Mechanisms. Photochem Photobiol 2021; 97:1456-1483. [PMID: 34133762 DOI: 10.1111/php.13470] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/13/2021] [Indexed: 02/07/2023]
Abstract
Photosensitization reactions have been demonstrated to be largely responsible for the deleterious biological effects of UV and visible radiation, as well as for the curative actions of photomedicine. A large number of endogenous and exogenous photosensitizers, biological targets and mechanisms have been reported in the past few decades. Evolving from the original definitions of the type I and type II photosensitized oxidations, we now provide physicochemical frameworks, classifications and key examples of these mechanisms in order to organize, interpret and understand the vast information available in the literature and the new reports, which are in vigorous growth. This review surveys in an extended manner all identified photosensitization mechanisms of the major biomolecule groups such as nucleic acids, proteins, lipids bridging the gap with the subsequent biological processes. Also described are the effects of photosensitization in cells in which UVA and UVB irradiation triggers enzyme activation with the subsequent delayed generation of superoxide anion radical and nitric oxide. Definitions of photosensitized reactions are identified in biomolecules with key insights into cells and tissues.
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Affiliation(s)
| | - Jean Cadet
- Département de Médecine Nucléaire et de Radiobiologie, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Alexander Greer
- Department of Chemistry, Brooklyn College, Brooklyn, NY, USA.,Ph.D. Program in Chemistry, The Graduate Center of the City University of New York, New York, NY, USA
| | - Andrés H Thomas
- Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata (UNLP), CCT La Plata-CONICET, La Plata, Argentina
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Raetz AG, Banda DM, Ma X, Xu G, Rajavel AN, McKibbin PL, Lebrilla CB, David SS. The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites. J Biol Chem 2020; 295:3692-3707. [PMID: 32001618 DOI: 10.1074/jbc.ra119.010497] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 01/22/2020] [Indexed: 11/06/2022] Open
Abstract
Higher expression of the human DNA repair enzyme MUTYH has previously been shown to be strongly associated with reduced survival in a panel of 24 human lymphoblastoid cell lines exposed to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The molecular mechanism of MUTYH-enhanced MNNG cytotoxicity is unclear, because MUTYH has a well-established role in the repair of oxidative DNA lesions. Here, we show in mouse embryonic fibroblasts (MEFs) that this MNNG-dependent phenotype does not involve oxidative DNA damage and occurs independently of both O6-methyl guanine adduct cytotoxicity and MUTYH-dependent glycosylase activity. We found that blocking of abasic (AP) sites abolishes higher survival of Mutyh-deficient (Mutyh -/-) MEFs, but this blockade had no additive cytotoxicity in WT MEFs, suggesting the cytotoxicity is due to MUTYH interactions with MNNG-induced AP sites. We found that recombinant mouse MUTYH tightly binds AP sites opposite all four canonical undamaged bases and stimulated apurinic/apyrimidinic endonuclease 1 (APE1)-mediated DNA incision. Consistent with these observations, we found that stable expression of WT, but not catalytically-inactive MUTYH, enhances MNNG cytotoxicity in Mutyh -/- MEFs and that MUTYH expression enhances MNNG-induced genomic strand breaks. Taken together, these results suggest that MUTYH enhances the rapid accumulation of AP-site intermediates by interacting with APE1, implicating MUTYH as a factor that modulates the delicate process of base-excision repair independently of its glycosylase activity.
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Affiliation(s)
- Alan G Raetz
- Department of Chemistry, University of California, Davis, California 95616
| | - Douglas M Banda
- Department of Chemistry, University of California, Davis, California 95616
| | - Xiaoyan Ma
- Department of Chemistry, University of California, Davis, California 95616
| | - Gege Xu
- Department of Chemistry, University of California, Davis, California 95616
| | - Anisha N Rajavel
- Department of Chemistry, University of California, Davis, California 95616
| | - Paige L McKibbin
- Department of Chemistry, University of California, Davis, California 95616
| | - Carlito B Lebrilla
- Department of Chemistry, University of California, Davis, California 95616
| | - Sheila S David
- Department of Chemistry, University of California, Davis, California 95616.
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Ni F, Tang H, Wang C, Wang Z, Yu F, Chen B, Sun L. Berzosertib (VE-822) inhibits gastric cancer cell proliferation via base excision repair system. Cancer Manag Res 2019; 11:8391-8405. [PMID: 31571995 PMCID: PMC6750847 DOI: 10.2147/cmar.s217375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
Background Current investigations suggest that the Base Excision Repair (BER) system may change DNA repair capacity and affect clinical gastric cancer progression such as overall survival. However, the prognostic value of BER system members in gastric cancer remains unclear. Methods We explored the prognostic correlation between 7 individual BER genes, including uracil-DNA glycosylase (UNG), Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Methyl-CpG binding domain 4 (MBD4), thymine DNA glycosylase (TDG), 8-oxoguanine DNA glycosylase (OGG1), MutY DNA glycosylase (MUTYH) and Nei like DNA glycosylase 1 (NEIL1), expression and overall survival (OS) in different clinical data, such as Lauren classification, pathological stages, human epidermal growth factor receptor-2 (HER2) expression status, treatment strategy, gender and differentiation degree in gastric cancer patients, using Kaplan-Meier plotter (KM plotter) online database. Based on the bioinformatics analysis, we utilized Berzosertib (VE-822) to inhibit DNA damage repair in cancer cells compared to solvent control group via real-time cellular analysis (RTCA), flow cytometry, colony formation and migration assay. Finally, we utilized reverse transcription-polymerase chain reaction (RT-PCR) to confirm the expression of BER members between normal and two gastric cancer cells or solvent and VE-822 treated groups. Results Our work revealed that high UNG mRNA expression was correlated with high overall survival probability; however, high SMUG1, MBD4, TDG, OGG1, MUTYH and NEIL1 mRNA expression showed relatively low overall survival probability in all GC patients. Additionally, UNG was associated with high overall survival probability in intestinal and diffuse types, but SMUG1 and NEIL1 showed opposite results. Further, VE-822 pharmacological experiment suggested that inhibition of DNA damage repair suppressed gastric cancer cells’ proliferation and migration ability via inducing apoptosis. Further, real-time polymerase chain reaction results proposed the inhibition of gastric cancer cells by VE-822 may be through UNG, MUTYH and OGG-1 of BER system. Conclusion We comprehensively analyze the prognostic value of the BER system (UNG, SMUG1, MBD4, TDG, OGG1, MUTYH and NEIL1) based on bioinformatics analysis and experimental confirmation. BER members are associated with distinctive prognostic significance and maybe new valuable prognostic indicators in gastric cancer.
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Affiliation(s)
- Fubiao Ni
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Hengjie Tang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Cheng Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Zixiang Wang
- First College of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Fangyi Yu
- First College of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Bicheng Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Linxiao Sun
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, Zhejiang Provincial Top Key Discipline in Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
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Raetz AG, David SS. When you're strange: Unusual features of the MUTYH glycosylase and implications in cancer. DNA Repair (Amst) 2019; 80:16-25. [PMID: 31203172 DOI: 10.1016/j.dnarep.2019.05.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 05/23/2019] [Accepted: 05/29/2019] [Indexed: 02/06/2023]
Abstract
MUTYH is a base-excision repair glycosylase that removes adenine opposite 8-oxoguanine (OG). Variants of MUTYH defective in functional activity lead to MUTYH-associated polyposis (MAP), which progresses to cancer with very high penetrance. Whole genome and whole exome sequencing studies have found MUTYH deficiencies in an increasing number of cancer types. While the canonical OG:A repair activity of MUTYH is well characterized and similar to bacterial MutY, here we review more recent evidence that MUTYH has activities independent of OG:A repair and appear centered on the interdomain connector (IDC) region of MUTYH. We summarize evidence that MUTYH is involved in rapid DNA damage response (DDR) signaling, including PARP activation, 9-1-1 and ATR signaling, and SIRT6 activity. MUTYH alters survival and DDR to a wide variety of DNA damaging agents in a time course that is not consistent with the formation of OG:A mispairs. Studies that suggest MUTYH inhibits the repair of alkyl-DNA damage and cyclopyrimidine dimers (CPDs) is reviewed, and evidence of a synthetic lethal interaction with mismatch repair (MMR) is summarized. Based on these studies we suggest that MUTYH has evolved from an OG:A mispair glycosylase to a multifunctional scaffold for DNA damage response signaling.
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Affiliation(s)
- Alan G Raetz
- Department of Chemistry, University of California, Davis, Davis, CA, USA.
| | - Sheila S David
- Department of Chemistry, University of California, Davis, Davis, CA, USA.
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Di Mascio P, Martinez GR, Miyamoto S, Ronsein GE, Medeiros MHG, Cadet J. Singlet Molecular Oxygen Reactions with Nucleic Acids, Lipids, and Proteins. Chem Rev 2019; 119:2043-2086. [DOI: 10.1021/acs.chemrev.8b00554] [Citation(s) in RCA: 369] [Impact Index Per Article: 61.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Paolo Di Mascio
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP Brazil
| | - Glaucia R. Martinez
- Departamento de Bioquímica e Biologia Molecular, Setor de Ciências Biológicas, Universidade Federal do Paraná, 81531-990 Curitiba, PR, Brazil
| | - Sayuri Miyamoto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP Brazil
| | - Graziella E. Ronsein
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP Brazil
| | - Marisa H. G. Medeiros
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, CP 26077, CEP 05508-000, São Paulo, SP Brazil
| | - Jean Cadet
- Département de Médecine Nucléaire et Radiobiologie, Faculté de Médecine des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, J1H 5N4 Québec, Canada
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Visnes T, Grube M, Hanna BMF, Benitez-Buelga C, Cázares-Körner A, Helleday T. Targeting BER enzymes in cancer therapy. DNA Repair (Amst) 2018; 71:118-126. [PMID: 30228084 DOI: 10.1016/j.dnarep.2018.08.015] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Base excision repair (BER) repairs mutagenic or genotoxic DNA base lesions, thought to be important for both the etiology and treatment of cancer. Cancer phenotypic stress induces oxidative lesions, and deamination products are responsible for one of the most prevalent mutational signatures in cancer. Chemotherapeutic agents induce genotoxic DNA base damage that are substrates for BER, while synthetic lethal approaches targeting BER-related factors are making their way into the clinic. Thus, there are three strategies by which BER is envisioned to be relevant in cancer chemotherapy: (i) to maintain cellular growth in the presence of endogenous DNA damage in stressed cancer cells, (ii) to maintain viability after exogenous DNA damage is introduced by therapeutic intervention, or (iii) to confer synthetic lethality in cancer cells that have lost one or more additional DNA repair pathways. Here, we discuss the potential treatment strategies, and briefly summarize the progress that has been made in developing inhibitors to core BER-proteins and related factors.
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Affiliation(s)
- Torkild Visnes
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden; Department of Biotechnology and Nanomedicine, SINTEF Industry, N-7034 Trondheim, Norway
| | - Maurice Grube
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
| | - Bishoy Magdy Fekry Hanna
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
| | - Carlos Benitez-Buelga
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
| | - Armando Cázares-Körner
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden
| | - Thomas Helleday
- Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, S-171 76 Stockholm, Sweden; Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2RX, UK.
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Schaich MA, Smith MR, Cloud AS, Holloran SM, Freudenthal BD. Structures of a DNA Polymerase Inserting Therapeutic Nucleotide Analogues. Chem Res Toxicol 2017; 30:1993-2001. [PMID: 28862449 PMCID: PMC6494084 DOI: 10.1021/acs.chemrestox.7b00173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Members of the nucleoside analogue class of cancer therapeutics compete with canonical nucleotides to disrupt numerous cellular processes, including nucleotide homeostasis, DNA and RNA synthesis, and nucleotide metabolism. Nucleoside analogues are triphosphorylated and subsequently inserted into genomic DNA, contributing to the efficacy of therapeutic nucleosides in multiple ways. In some cases, the altered base acts as a mutagen, altering the DNA sequence to promote cellular death; in others, insertion of the altered nucleotide triggers DNA repair pathways, which produce lethal levels of cytotoxic intermediates such as single and double stranded DNA breaks. As a prerequisite to many of these biological outcomes, the modified nucleotide must be accommodated in the DNA polymerase active site during nucleotide insertion. Currently, the molecular contacts that mediate DNA polymerase insertion of modified nucleotides remain unknown for multiple therapeutic compounds, despite decades of clinical use. To determine how modified bases are inserted into duplex DNA, we used mammalian DNA polymerase β (pol β) to visualize the structural conformations of four therapeutically relevant modified nucleotides, 6-thio-2'-deoxyguanosine-5'-triphosphate (6-TdGTP), 5-fluoro-2'-deoxyuridine-5'-triphosphate (5-FdUTP), 5-formyl-deoxycytosine-5'-triphosphate (5-FodCTP), and 5-formyl-deoxyuridine-5'-triphosphate (5-FodUTP). Together, the structures reveal a pattern in which the modified nucleotides utilize Watson-Crick base pairing interactions similar to that of unmodified nucleotides. The nucleotide modifications were consistently positioned in the major groove of duplex DNA, accommodated by an open cavity in pol β. These results provide novel information for the rational design of new therapeutic nucleoside analogues and a greater understanding of how modified nucleotides are tolerated by polymerases.
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Affiliation(s)
| | | | | | | | - Bret D. Freudenthal
- Corresponding Author 4015 Wahl Hall West, Laboratory of Genome Maintenance and Structural Biology, Department of Biochemistry and Molecular Biology, and Department of Cancer Biology, University of Kansas Medical Center Kansas City, Kansas 66160. Phone: 913-588-5560,
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Markkanen E. Not breathing is not an option: How to deal with oxidative DNA damage. DNA Repair (Amst) 2017; 59:82-105. [PMID: 28963982 DOI: 10.1016/j.dnarep.2017.09.007] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 09/20/2017] [Indexed: 02/07/2023]
Abstract
Oxidative DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to C:G→A:T transversion mutations. Cells have evolved a variety of pathways to mitigate the mutational potential of 8-oxo-G that include i) mechanisms to avoid incorporation of oxidized nucleotides into DNA through nucleotide pool sanitisation enzymes (by MTH1, MTH2, MTH3 and NUDT5), ii) base excision repair (BER) of 8-oxo-G in DNA (involving MUTYH, OGG1, Pol λ, and other components of the BER machinery), and iii) faithful bypass of 8-oxo-G lesions during replication (using a switch between replicative Pols and Pol λ). In the following, the fate of 8-oxo-G in mammalian cells is reviewed in detail. The differential origins of 8-oxo-G in DNA and its consequences for genetic stability will be covered. This will be followed by a thorough discussion of the different mechanisms in place to cope with 8-oxo-G with an emphasis on Pol λ-mediated correct bypass of 8-oxo-G during MUTYH-initiated BER as well as replication across 8-oxo-G. Furthermore, the multitude of mechanisms in place to regulate key proteins involved in 8-oxo-G repair will be reviewed. Novel functions of 8-oxo-G as an epigenetic-like regulator and insights into the repair of 8-oxo-G within the cellular context will be touched upon. Finally, a discussion will outline the relevance of 8-oxo-G and the proteins involved in dealing with 8-oxo-G to human diseases with a special emphasis on cancer.
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Affiliation(s)
- Enni Markkanen
- Institute of Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University of Zürich, Winterthurerstr. 260, 8057 Zürich, Switzerland.
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The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis. Oncotarget 2016; 6:19671-84. [PMID: 26109431 PMCID: PMC4637313 DOI: 10.18632/oncotarget.4284] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/05/2015] [Indexed: 12/19/2022] Open
Abstract
MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8-oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress. Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC). We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS). Mutyh−/− mice were more sensitive than wild-type (WT) animals to AOM/DSS toxicity and accumulated DNA 8-oxoG in their gastrointestinal tract. AOM/DSS-induced colonic adenomas were significantly more numerous in Mutyh−/− than in WT animals, and frequently showed a tubulo-villous feature along with high-grade dysplasia and larger size lesions. This condition resulted in a greater propensity to develop adenocarcinomas. The colon of untreated Mutyh−/− mice expressed higher basal levels of pro-inflammatory cytokines GM-CSF and IFNγ, and treatment with AOM/DSS induced an early decrease in circulating CD4+ and CD8+ T lymphocytes and an increase in myeloid-derived suppressor cells (MDSCs). Adenomas from Mutyh−/− mice had a greater infiltrate of Foxp3+ T regulatory cells, granulocytes, macrophages, MDSCs and strong expression of TGF-β-latency-associated peptide and IL6. Our findings indicate that MUTYH loss is associated with an increase in CRC risk, which involves immunosuppression and altered inflammatory response. We propose that the AOM/DSS initiation/promotion protocol in Mutyh−/− mice provides a good model for MAP.
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