|
1
|
Colarusso C, Terlizzi M, Di Caprio S, Falanga A, D’Andria E, d’Emmanuele di Villa Bianca R, Sorrentino R. Role of the AIM2 Inflammasome in Cancer: Potential Therapeutic Strategies. Biomedicines 2025; 13:395. [PMID: 40002808 PMCID: PMC11852973 DOI: 10.3390/biomedicines13020395] [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: 12/24/2024] [Revised: 01/31/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Absent in melanoma 2 (AIM2) is a member of the innate immune sensors that recognizes cytosolic nucleic acids, leading to inflammasome assembly. In recent years, several studies in the oncology field have highlighted the presence of cytoplasmic double-stranded DNA (dsDNA) following necrosis and/or genomic instability, which is typical of malignant transformation. The recognition of dsDNA by the AIM2 inflammasome either in cancer cells or in immune cells can further exacerbate inflammatory processes on the basis of cancer progression. In this context, the role of AIM2 in cancer is still controversial in that some authors assume that AIM2 activation has pro-tumor activities, while others define it as anti-tumor. This discrepancy may be due to the nature of the cells where AIM2 is expressed or the histology of the tumor. This review aims to provide an overview of the controversial role of AIM2 in cancer, taking into consideration the pharmacological tools currently available to modulate AIM2 activity in cancer.
Collapse
Affiliation(s)
- Chiara Colarusso
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| | - Michela Terlizzi
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| | - Simone Di Caprio
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| | - Anna Falanga
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| | - Emmanuel D’Andria
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| | | | - Rosalinda Sorrentino
- Department of Pharmacy (DIFARMA), University of Salerno, 84084 Fisciano, SA, Italy; (C.C.); (M.T.); (S.D.C.); (A.F.); (E.D.)
| |
Collapse
|
|
2
|
Dawson RE, Jenkins BJ. The Role of Inflammasome-Associated Innate Immune Receptors in Cancer. Immune Netw 2024; 24:e38. [PMID: 39513025 PMCID: PMC11538610 DOI: 10.4110/in.2024.24.e38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 11/15/2024] Open
Abstract
Dysregulated activation of the innate immune system is a critical driver of chronic inflammation that is associated with at least 30% of all cancers. Innate immunity can also exert tumour-promoting effects (e.g. proliferation) directly on cancer cells in an intrinsic manner. Conversely, innate immunity can influence adaptive immunity-based anti-tumour immune responses via Ag-presenting dendritic cells that activate natural killer and cytotoxic T cells to eradicate tumours. While adaptive anti-tumour immunity has underpinned immunotherapy approaches with immune checkpoint inhibitors and chimeric Ag receptor-T cells, the clinical utility of innate immunity in cancer is underexplored. Innate immune responses are governed by pattern recognition receptors, which comprise several families, including Toll-like, nucleotide-binding oligomerization domain-containing (NOD)-like and absent-in-melanoma 2 (AIM2)-like receptors. Notably, a subset of NOD-like and AIM2-like receptors can form large multiprotein "inflammasome" complexes which control maturation of biologically active IL-1β and IL-18 cytokines. Over the last decade, it has emerged that inflammasomes can coordinate contrasting pro- and anti-tumour responses in cancer and non-cancer (e.g. immune, stromal) cells. Considering the importance of inflammasomes to the net output of innate immune responses, here we provide an overview and discuss recent advancements on the diverse role of inflammasomes in cancer that have underpinned their potential targeting in diverse malignancies.
Collapse
Affiliation(s)
- Ruby E. Dawson
- South Australian immunoGENomics Cancer Institute (SAiGENCI), The University of Adelaide, Adelaide, SA 5000, Australia
| | - Brendan J. Jenkins
- South Australian immunoGENomics Cancer Institute (SAiGENCI), The University of Adelaide, Adelaide, SA 5000, Australia
| |
Collapse
|
|
3
|
Cui JZ, Chew ZH, Lim LHK. New insights into nucleic acid sensor AIM2: The potential benefit in targeted therapy for cancer. Pharmacol Res 2024; 200:107079. [PMID: 38272334 DOI: 10.1016/j.phrs.2024.107079] [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] [Received: 11/06/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024]
Abstract
The AIM2 inflammasome represents a multifaceted oligomeric protein complex within the innate immune system, with the capacity to perceive double-stranded DNA (dsDNA) and engage in diverse physiological reactions and disease contexts, including cancer. While originally conceived as a discerning DNA sensor, AIM2 has demonstrated its capability to discern various nucleic acid variations, encompassing RNA and DNA-RNA hybrids. Through its interaction with nucleic acids, AIM2 orchestrates the assembly of a complex involving multiple proteins, aptly named the AIM2 inflammasome, which facilitates the enzymatic cleavage of proinflammatory cytokines, namely pro-IL-1β and pro-IL-18. This process, in turn, underpins its pivotal biological role. In this review, we provide a systematic summary and discussion of the latest advancements in AIM2 sensing various types of nucleic acids. Additionally, we discuss the modulation of AIM2 activation, which can cause cell death, including pyroptosis, apoptosis, and autophagic cell death. Finally, we fully illustrate the evidence for the dual role of AIM2 in different cancer types, including both anti-tumorigenic and pro-tumorigenic functions. Considering the above information, we uncover the therapeutic promise of modulating the AIM2 inflammasome in cancer treatment.
Collapse
Affiliation(s)
- Jian-Zhou Cui
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS-Cambridge Immunophenotyping Centre, Life Science Institute, National University of Singapore, Singapore.
| | - Zhi Huan Chew
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Lina H K Lim
- Translational Immunology Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| |
Collapse
|
|
4
|
Liu W, Peng J, Xiao M, Cai Y, Peng B, Zhang W, Li J, Kang F, Hong Q, Liang Q, Yan Y, Xu Z. The implication of pyroptosis in cancer immunology: Current advances and prospects. Genes Dis 2023; 10:2339-2350. [PMID: 37554215 PMCID: PMC10404888 DOI: 10.1016/j.gendis.2022.04.019] [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: 01/12/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 11/18/2022] Open
Abstract
Pyroptosis is a regulated cell death pathway involved in numerous human diseases, especially malignant tumors. Recent studies have identified multiple pyroptosis-associated signaling molecules, like caspases, gasdermin family and inflammasomes. In addition, increasing in vitro and in vivo studies have shown the significant linkage between pyroptosis and immune regulation of cancers. Pyroptosis-associated biomarkers regulate the infiltration of tumor immune cells, such as CD4+ and CD8+ T cells, thus strengthening the sensitivity to therapeutic strategies. In this review, we explained the relationship between pyroptosis and cancer immunology and focused on the significance of pyroptosis in immune regulation. We also proposed the future application of pyroptosis-associated biomarkers in basic research and clinical practices to address malignant behaviors. Exploration of the underlying mechanisms and biological functions of pyroptosis is critical for immune response and cancer immunotherapy.
Collapse
Affiliation(s)
- Wei Liu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Orthopedic Surgery, The Second Hospital University of South China, Hengyang, Hunan 421001, China
| | - Jinwu Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
| | - Muzhang Xiao
- Department of Burn and Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yuan Cai
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Bi Peng
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Wenqin Zhang
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
| | - Jianbo Li
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
| | - Fanhua Kang
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
| | - Qianhui Hong
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
| | - Qiuju Liang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yuanliang Yan
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhijie Xu
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- Department of Pathology, Xiangya Changde Hospital, Changde, Hunan 415000, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| |
Collapse
|
|
5
|
Chew ZH, Cui J, Sachaphibulkij K, Tan I, Kar S, Koh KK, Singh K, Lim HM, Lee SC, Kumar AP, Gasser S, Lim LHK. Macrophage IL-1β contributes to tumorigenesis through paracrine AIM2 inflammasome activation in the tumor microenvironment. Front Immunol 2023; 14:1211730. [PMID: 37449203 PMCID: PMC10338081 DOI: 10.3389/fimmu.2023.1211730] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/08/2023] [Indexed: 07/18/2023] Open
Abstract
Intracellular recognition of self and non-self -nucleic acids can result in the initiation of effective pro-inflammatory and anti-tumorigenic responses. We hypothesized that macrophages can be activated by tumor-derived nucleic acids to induce inflammasome activation in the tumor microenvironment. We show that tumor conditioned media (CM) can induce IL-1β production, indicative of inflammasome activation in primed macrophages. This could be partially dependent on caspase 1/11, AIM2 and NLRP3. IL-1β enhances tumor cell proliferation, migration and invasion while coculture of tumor cells with macrophages enhances the proliferation of tumor cells, which is AIM2 and caspase 1/11 dependent. Furthermore, we have identified that DNA-RNA hybrids could be the nucleic acid form which activates AIM2 inflammasome at a higher sensitivity as compared to dsDNA. Taken together, the tumor-secretome stimulates an innate immune pathway in macrophages which promotes paracrine cancer growth and may be a key tumorigenic pathway in cancer. Broader understanding on the mechanisms of nucleic acid recognition and interaction with innate immune signaling pathway will help us to better appreciate its potential application in diagnostic and therapeutic benefit in cancer.
Collapse
Affiliation(s)
- Zhi Huan Chew
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| | - Jianzhou Cui
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Karishma Sachaphibulkij
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Isabelle Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Shreya Kar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kai Kiat Koh
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Kritika Singh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Hong Meng Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Soo Chin Lee
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore
| | - Stephan Gasser
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Roche Pharma Research and Early Development, Roche Innovation Center, Roche Glycart AG, Schlieren, Switzerland
| | - Lina H. K. Lim
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore
- Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
6
|
Zhang Z, Li X, Wang Y, Wei Y, Wei X. Involvement of inflammasomes in tumor microenvironment and tumor therapies. J Hematol Oncol 2023; 16:24. [PMID: 36932407 PMCID: PMC10022228 DOI: 10.1186/s13045-023-01407-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/08/2023] [Indexed: 03/19/2023] Open
Abstract
Inflammasomes are macromolecular platforms formed in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns, whose formation would cause maturation of interleukin-1 (IL-1) family members and gasdermin D (GSDMD), leading to IL-1 secretion and pyroptosis respectively. Several kinds of inflammasomes detecting different types of dangers have been found. The activation of inflammasomes is regulated at both transcription and posttranscription levels, which is crucial in protecting the host from infections and sterile insults. Present findings have illustrated that inflammasomes are involved in not only infection but also the pathology of tumors implying an important link between inflammation and tumor development. Generally, inflammasomes participate in tumorigenesis, cell death, metastasis, immune evasion, chemotherapy, target therapy, and radiotherapy. Inflammasome components are upregulated in some tumors, and inflammasomes can be activated in cancer cells and other stromal cells by DAMPs, chemotherapy agents, and radiation. In some cases, inflammasomes inhibit tumor progression by initiating GSDMD-mediated pyroptosis in cancer cells and stimulating IL-1 signal-mediated anti-tumor immunity. However, IL-1 signal recruits immunosuppressive cell subsets in other cases. We discuss the conflicting results and propose some possible explanations. Additionally, we also summarize interventions targeting inflammasome pathways in both preclinical and clinical stages. Interventions targeting inflammasomes are promising for immunotherapy and combination therapy.
Collapse
Affiliation(s)
- Ziqi Zhang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xue Li
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yang Wang
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yuquan Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xiawei Wei
- grid.13291.380000 0001 0807 1581Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| |
Collapse
|
|
7
|
Qin Y, Pan L, Qin T, Ruan H, Zhang Y, Zhang Y, Li J, Yang J, Li W. Pan-cancer analysis of AIM2 inflammasomes with potential implications for immunotherapy in human cancer: A bulk omics research and single cell sequencing validation. Front Immunol 2022; 13:998266. [PMID: 36248785 PMCID: PMC9559585 DOI: 10.3389/fimmu.2022.998266] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/15/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundThe absent in melanoma 2 (AIM2) inflammasome is a multi-protein platform that recognizes aberrant cytoplasmic double-stranded DNA(dsDNA) and induces cytokine maturation, release, and pyroptosis. Some studies found that the AIM2 inflammasome was a double-edged sword in many cancers. However, there have been fewer studies on AIM2 inflammasomes in pan-cancer.MethodsGene expression was analyzed using The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) database. Immunohistochemistry (IHC) was used to validate the expression of the AIM2. We used the survival curve to explore the prognostic significance of the AIM2 inflammasomes in pan-cancer. Mutations and methylation of AIM2 inflammasome-related genes (AIM2i-RGs) were also comprehensively analyzed. Single sample gene set enrichment analysis was used to calculate the AIM2 inflammasomes score and explore the correlation of the AIM2 inflammasomes score with immune-related genes and immune infiltrations. The function of AIM2 inflammasomes in pan-cancer was analyzed at the single-cell level. Single-cell transcriptome sequencing (scRNA-seq) data was used to assess the activation state of the AIM2 inflammasomes in the tumor microenvironment.ResultsWe found that AIM2i-RGs were aberrantly expressed in tumors and were strongly associated with prognosis. In pan-cancer, the expression of AIM2i-RGs was positively associated with copy number variation and negatively associated with methylation. In AIM2i-RGs, missense mutations were the predominant type of single nucleotide polymorphism. Moreover, we found that the drugs dimethyloxallyl glycine (DMOG) and Z-LNle-CHO may be sensitive to the AIM2 inflammasomes. The AIM2 inflammasomes score was significantly and positively correlated with the tumor immunity score and the stroma score. In most tumors, the AIM2 inflammasomes score was significantly and positively correlated with CD8+ T cell abundance in the tumor microenvironment. Additionally, the AIM2 inflammasomes score was significantly correlated with immune checkpoint genes in pan-cancer as well as immune checkpoint therapy-related markers including tumor mutational burden (TMB), microsatellite instability(MSI), and tumor immune dysfunction and exclusion(TIDE). scRNA-seq analysis suggested that AIM2 inflammasomes differ significantly among different cells in the tumor microenvironment. IHC confirmed low expression of AIM2 in colorectal cancer.DiscussionAIM2 inflammasomes may be a new target for future tumor therapy It is likely involved in tumor development, and its high expression may serve as a predictor of tumor immunotherapy efficacy.
Collapse
Affiliation(s)
- Yan Qin
- Department of Health Management, The People’s Hospital of Guangxi Zhuang Autonomous Region & Research center of Health Management, Guangxi Academy of Medical Sciences, Nanning, China
| | - Liuxian Pan
- Department of Health Management, The People’s Hospital of Guangxi Zhuang Autonomous Region & Research center of Health Management, Guangxi Academy of Medical Sciences, Nanning, China
| | - Tianyu Qin
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Hanyi Ruan
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yujie Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Zhang
- Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jianli Li
- Department of Health Management, The People’s Hospital of Guangxi Zhuang Autonomous Region & Research center of Health Management, Guangxi Academy of Medical Sciences, Nanning, China
| | - Jianrong Yang
- Department of Health Management, The People’s Hospital of Guangxi Zhuang Autonomous Region & Research center of Health Management, Guangxi Academy of Medical Sciences, Nanning, China
- *Correspondence: Wei Li, ; Jianrong Yang,
| | - Wei Li
- Department of Health Management, The People’s Hospital of Guangxi Zhuang Autonomous Region & Research center of Health Management, Guangxi Academy of Medical Sciences, Nanning, China
- *Correspondence: Wei Li, ; Jianrong Yang,
| |
Collapse
|
|
8
|
Wang J, Gao J, Huang C, Jeong S, Ko R, Shen X, Chen C, Zhong W, Zou Y, Yu B, Shen C. Roles of AIM2 Gene and AIM2 Inflammasome in the Pathogenesis and Treatment of Psoriasis. Front Genet 2022; 13:929162. [PMID: 36118867 PMCID: PMC9481235 DOI: 10.3389/fgene.2022.929162] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/22/2022] [Indexed: 11/17/2022] Open
Abstract
Psoriasis is an immune-mediated chronic inflammatory skin disease caused by a combination of environmental incentives, polygenic genetic control, and immune regulation. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene for psoriasis. AIM2 inflammasome formed from the combination of AIM2, PYD-linked apoptosis-associated speck-like protein (ASC) and Caspase-1 promotes the maturation and release of inflammatory cytokines such as IL-1β and IL-18, and triggers an inflammatory response. Studies showed the genetic and epigenetic associations between AIM2 gene and psoriasis. AIM2 gene has an essential role in the occurrence and development of psoriasis, and the inhibitors of AIM2 inflammasome will be new therapeutic targets for psoriasis. In this review, we summarized the roles of the AIM2 gene and AIM2 inflammasome in pathogenesis and treatment of psoriasis, hopefully providing a better understanding and new insight into the roles of AIM2 gene and AIM2 inflammasome in psoriasis.
Collapse
Affiliation(s)
- Jieyi Wang
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
- School of Clinical Medicine, Health Science Center, Shenzhen University, Shenzhen, Guangdong, China
| | - Jing Gao
- Department of Dermatology, The Second Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Anhui Provincial Institute of Translational Medicine, Hefei, Anhui, China
| | - Cong Huang
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
| | - Sohyun Jeong
- Marcus Institute for Aging Research at Hebrew SeniorLife, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
| | - Randy Ko
- Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
| | - Xue Shen
- Department of Dermatology, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Chaofeng Chen
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
| | - Weilong Zhong
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
| | - Yanfen Zou
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
| | - Bo Yu
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
- School of Clinical Medicine, Health Science Center, Shenzhen University, Shenzhen, Guangdong, China
| | - Changbing Shen
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University—The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, China
| |
Collapse
|
|
9
|
Man SM, Jenkins BJ. Context-dependent functions of pattern recognition receptors in cancer. Nat Rev Cancer 2022; 22:397-413. [PMID: 35355007 DOI: 10.1038/s41568-022-00462-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/01/2022] [Indexed: 02/07/2023]
Abstract
The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation. The past two decades have seen innate immune pattern recognition receptors (PRRs) emerge as critical regulators of the immune response to microbial infection and host tissue damage. More recently, it has become apparent that in many cancer types, PRRs play a central role in modulating a vast array of tumour-inhibiting and tumour-promoting cellular responses both in immune cells within the tumour microenvironment and directly in cancer cells. Herein, we provide a comprehensive overview of the fast-evolving field of PRRs in cancer, and discuss the potential to target PRRs for drug development and biomarker discovery in a wide range of oncology settings.
Collapse
Affiliation(s)
- Si Ming Man
- Division of Immunity, Inflammation and Infection, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
- Department of Molecular and Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia.
| |
Collapse
|
|
10
|
AIM2 Promotes Gastric Cancer Cell Proliferation via the MAPK Signaling Pathway. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:8756844. [PMID: 35432843 PMCID: PMC9010154 DOI: 10.1155/2022/8756844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/28/2022] [Accepted: 03/10/2022] [Indexed: 11/18/2022]
Abstract
Background Gastric cancer (GC) is a highly prevalent tumor type. The dysregulated expression of melanoma deficiency factor 2 (AIM2) has been observed in a range of tumor types. Herein, we explore the role of AIM2 in the regulation of GC progression. Methods Gastric cancer cells BGC-823 and MGC-803 in logarithmic growth phase were divided into blank group (control), Control group (NC) and SH-AIM2 group, respectively. Control group and SH-AIM2 group were transfected with AIM2 NC and SH-AIM2, respectively. Nude mice were divided into blank group (control) and SH-AIM2 group, and the treatment methods were the same as above. Differential AIM2 expression in GC tissues was assessed via bioinformatics analyses, after which western blotting was used for analyzing the AIM2 levels in tumor and paracancerous tissues from five stomach cancer patients. In addition, qPCR and protein imprinting were used to assess AIM2 expression levels in GC cells, and AIM2 knockdown was conducted in MGC-803 and BGC-823cells, after which colony formation and EdU incorporation assay were utilized to assess cell proliferation. The oncogenic role of AIM2 was then assessed in mice and validated through immunohistochemical analyses. Results GC tissues and cell lines exhibited marked AIM2 overexpression. AIM2 knockdown significantly impaired GC cell proliferation and migration, as confirmed through in vitro assays. In vivo experiments showed that both the increment ability and invasion and migration ability of AIM2 knockdown group were significantly lower than that of control and NC the change of AIM2 protein level would affect the change of MAPK pathway related protein level. Conclusions AIM2 knockdown markedly suppresses the proliferation, migration, as well as invasion of GC cells via the inhibition of MAPK signaling, thereby slowing tumor progression. Overall, these results suggest that further analyses of AIM2 may offer clinically valuable insights that can aid in the treatment of human GC.
Collapse
|
|
11
|
Chou WC, Rampanelli E, Li X, Ting JPY. Impact of intracellular innate immune receptors on immunometabolism. Cell Mol Immunol 2022; 19:337-351. [PMID: 34697412 PMCID: PMC8891342 DOI: 10.1038/s41423-021-00780-y] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/17/2021] [Indexed: 12/21/2022] Open
Abstract
Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K-AKT-mTOR and LKB1-AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.
Collapse
Affiliation(s)
- Wei-Chun Chou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
| | - Elena Rampanelli
- Amsterdam UMC (University Medical Center, location AMC), Department of Experimental Vascular Medicine, AGEM (Amsterdam Gastroenterology Endocrinology Metabolism) Institute, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - Xin Li
- Comparative Immunology Research Center, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
| |
Collapse
|
|
12
|
Fan X, Jiao L, Jin T. Activation and Immune Regulation Mechanisms of PYHIN Family During Microbial Infection. Front Microbiol 2022; 12:809412. [PMID: 35145495 PMCID: PMC8822057 DOI: 10.3389/fmicb.2021.809412] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/09/2021] [Indexed: 11/29/2022] Open
Abstract
The innate immune system defenses against pathogen infections via patten-recognition receptors (PRRs). PRRs initiate immune responses by recognizing pathogen-associated molecular patterns (PAMPs), including peptidoglycan, lipopolysaccharide, and nucleic acids. Several nucleic acid sensors or families have been identified, such as RIG-I-like receptors (RLRs), Toll-like receptors (TLRs), cyclic GMP-AMP synthase (cGAS), and PYHIN family receptors. In recent years, the PYHIN family cytosolic DNA receptors have increased attention because of their important roles in initiating innate immune responses. The family members in humans include Absent in melanoma 2 (AIM2), IFN-γ inducible protein 16 (IFI16), interferon-inducible protein X (IFIX), and myeloid cell nuclear differentiation antigen (MNDA). The PYHIN family members are also identified in mice, including AIM2, p202, p203, p204, and p205. Herein, we summarize recent advances in understanding the activation and immune regulation mechanisms of the PYHIN family during microbial infection. Furthermore, structural characterizations of AIM2, IFI16, p202, and p204 provide more accurate insights into the signaling mechanisms of PYHIN family receptors. Overall, the molecular details will facilitate the development of reagents to defense against viral infections.
Collapse
Affiliation(s)
- Xiaojiao Fan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lianying Jiao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
- Institute of Molecular and Translational Medicine, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, China
- *Correspondence: Lianying Jiao,
| | - Tengchuan Jin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Center for Excellence in Molecular Cell Science, Shanghai, China
- Tengchuan Jin,
| |
Collapse
|
|
13
|
Zhu H, Zhao M, Chang C, Chan V, Lu Q, Wu H. The complex role of AIM2 in autoimmune diseases and cancers. Immun Inflamm Dis 2021; 9:649-665. [PMID: 34014039 PMCID: PMC8342223 DOI: 10.1002/iid3.443] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)-inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double-stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent-manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome-dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS-STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non-small-cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.
Collapse
Affiliation(s)
- Huan Zhu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Ming Zhao
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisCaliforniaUSA
| | - Vera Chan
- Division of Rheumatology and Clinical Immunology, Department of MedicineThe University of Hong KongHong KongChina
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
- Institute of DermatologyChinese Academy of Medical Sciences and Peking Union Medical CollegeNanjingChina
| | - Haijing Wu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| |
Collapse
|
|
14
|
Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies. Cancers (Basel) 2021; 13:cancers13123063. [PMID: 34205397 PMCID: PMC8235567 DOI: 10.3390/cancers13123063] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary A deficient mismatch repair system (dMMR) results in microsatellite instability (MSI). The MSI status of a tumor predicts the response to immune checkpoint inhibitors (ICI) that are now approved in patients with dMMR/MSI metastatic colorectal cancers. In addition to the mechanisms through which MSI can activate the immune system via particular neo-antigens, this review reports the clinical and pre-clinical strategies being developed in the case of resistance to ICI, including emerging therapies and new biomarkers. Abstract A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur in coding sequences and lead to the production of neo-antigens able to trigger an anti-tumoral immune response. This explains why non-metastatic MSI tumors are associated with high immune infiltrates and good prognosis. Metastatic MSI tumors result from tumor escape to the immune system and are associated with poor prognosis and chemoresistance. Consequently, immune checkpoint inhibitors (ICI) are highly effective and have recently been approved in dMMR/MSI metastatic colorectal cancers (mCRC). Nevertheless, some patients with dMMR/MSI mCRC have primary or secondary resistance to ICI. This review details carcinogenesis and the mechanisms through which MSI can activate the immune system. After which, we discuss mechanistic hypotheses in an attempt to explain primary and secondary resistances to ICI and emerging strategies being developed to overcome this phenomenon by targeting other immune checkpoints or through vaccination and modification of microbiota.
Collapse
|
|
15
|
Abstract
Significance: Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recent Advances: Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Critical Issues: Genomic stress is closely intertwined with antitumor immunity via mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future Directions: Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. Antioxid. Redox Signal. 34, 1128-1150.
Collapse
Affiliation(s)
- Congying Pu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Siyao Tao
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jun Xu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Min Huang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
16
|
Shah S, Qin S, Luo Y, Huang Y, Jing R, Shah JN, Chen J, Chen H, Zhong M. AIM2 Inhibits BRAF-Mutant Colorectal Cancer Growth in a Caspase-1-Dependent Manner. Front Cell Dev Biol 2021; 9:588278. [PMID: 33842454 PMCID: PMC8027362 DOI: 10.3389/fcell.2021.588278] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 02/01/2021] [Indexed: 12/09/2022] Open
Abstract
Absent in melanoma 2 (AIM2), a DNA sensor that plays an important role in natural immunity system, has been reported to participate in colorectal cancer (CRC) development. However, the functional role of AIM2 in BRAF-mutant CRC remains unclear. In this study, we first investigated AIM2 expression level in BRAF-mutant CRC tumor tissues. Overexpression of AIM2 in CRC cells was performed to investigate the effect of AIM2 on CRC cell viability, and cell death detection and caspase activity assay were performed to explore the mechanism that AIM2 impacts the growth of BRAF-mutant CRC cells. Moreover, we confirmed the antitumor effect of AIM2 in BRAF-mutant CRC cell-derived tumor xenograft (CDX) models as well as patient-derived organoids (PDOs). Herein, we reported that AIM2 expression was lower in BRAF-mutant than that in BRAF wild-type CRC tumor tissues. Restoring the expression of AIM2 in BRAF-mutant CRC cells greatly inhibits the tumor cell growth by inducing necrotic cell death. Mechanism studies revealed that AIM2-induced cell death is in a caspase-1-dependent manner. Additionally, overexpression of AIM2 significantly inhibits tumor growth and metastasis in BRAF-mutant CRC in vivo, which was further confirmed in BRAF-mutant CRC PDOs. Taken together, our data suggested that AIM2 inhibits BRAF-mutant colon cancer growth in a caspase-1-dependent manner, which may provide evidence to understand the pathogenesis of CRC with BRAF-mutant, as well as new strategies for manipulation of CRC.
Collapse
Affiliation(s)
- Shailendra Shah
- Department of Surgery, Patan Hospital, Patan Academy of Health Sciences, Lalitpur, Nepal
| | - Shaolan Qin
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Luo
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yizhou Huang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ran Jing
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jay N Shah
- Department of Surgery, Patan Hospital, Patan Academy of Health Sciences, Kathmandu, Nepal
| | - Jianjun Chen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Huimin Chen
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Zhong
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
17
|
Abstract
The innate immune system recognizes conserved pathogen-associated molecular patterns and produces inflammatory cytokines that direct downstream immune responses. The inappropriate localization of DNA within the cell cytosol or endosomal compartments indicates that a cell may either be infected by a DNA virus or bacterium, or has problems with its own nuclear integrity. This DNA is sensed by certain receptors that mediate cytokine production and, in some cases, initiate an inflammatory and lytic form of cell death called pyroptosis. Dysregulation of these DNA-sensing pathways is thought to contribute to autoimmune diseases and the development of cancer. In this review, we will discuss the DNA sensors Toll-like receptor 9 (TLR9), cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), absent in melanoma 2 (AIM2), and interferon gamma-inducible 16 (IFI16), their ligands, and their physiological significance. We will also examine the less-well-understood DEAH- and DEAD-box helicases DHX9, DHX36, DDX41, and RNA polymerase III, each of which may play an important role in DNA-mediated innate immunity.
Collapse
Affiliation(s)
- Benoit Briard
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - David E Place
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | | |
Collapse
|
|
18
|
Kumar V. The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA. Front Immunol 2021; 11:624597. [PMID: 33643304 PMCID: PMC7905024 DOI: 10.3389/fimmu.2020.624597] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.
Collapse
Affiliation(s)
- Vijay Kumar
- Children's Health Queensland Clinical Unit, School of Clinical Medicine, Faculty of Medicine, Mater Research, University of Queensland, St. Lucia, Brisbane, QLD, Australia.,School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, Brisbane, QLD, Australia
| |
Collapse
|
|
19
|
Suryavanshi SV, Kovalchuk I, Kovalchuk O. Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective. Front Immunol 2021; 11:613613. [PMID: 33584697 PMCID: PMC7876066 DOI: 10.3389/fimmu.2020.613613] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/10/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1–mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity. Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases. In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.
Collapse
Affiliation(s)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
| |
Collapse
|
|
20
|
Lozano-Ruiz B, González-Navajas JM. The Emerging Relevance of AIM2 in Liver Disease. Int J Mol Sci 2020; 21:ijms21186535. [PMID: 32906750 PMCID: PMC7555176 DOI: 10.3390/ijms21186535] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 01/18/2023] Open
Abstract
Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 β and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC).
Collapse
Affiliation(s)
- Beatriz Lozano-Ruiz
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain;
- Department of Pharmacology, Paediatrics and Organic Chemistry, University Miguel Hernández (UMH), 03550 San Juan, Alicante, Spain
| | - José M. González-Navajas
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain;
- Department of Pharmacology, Paediatrics and Organic Chemistry, University Miguel Hernández (UMH), 03550 San Juan, Alicante, Spain
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain
- Institute of Research, Development and Innovation in Healthcare Biotechnology in Elche (IDiBE), University Miguel Hernández, 03202 Elche, Alicante, Spain
- Correspondence: ; Tel.: +34-(965)-913-928
| |
Collapse
|
|
21
|
Michalak M, Katzenmaier EM, Roeckel N, Woerner SM, Fuchs V, Warnken U, Yuan YP, Bork P, Neu-Yilik G, Kulozik A, von Knebel Doeberitz M, Kloor M, Kopitz J, Gebert J. (Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A. Int J Mol Sci 2020; 21:ijms21155234. [PMID: 32718059 PMCID: PMC7432364 DOI: 10.3390/ijms21155234] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.
Collapse
Affiliation(s)
- Malwina Michalak
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Department of Pediatric Oncology, Hematology and Immunology, Children’s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
| | - Eva-Maria Katzenmaier
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
| | - Nina Roeckel
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
| | - Stefan M. Woerner
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Department of Internal Medicine I, Endocrinology and Metabolism, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Vera Fuchs
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
| | - Uwe Warnken
- Clinical Cooperation Unit Neurooncology, DKFZ (German Cancer Research Center), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;
| | - Yan P. Yuan
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany;
| | - Peer Bork
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany;
- Max-Delbrück-Centre for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
| | - Gabriele Neu-Yilik
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Department of Pediatric Oncology, Hematology and Immunology, Children’s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
| | - Andreas Kulozik
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Department of Pediatric Oncology, Hematology and Immunology, Children’s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Jürgen Kopitz
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; (M.M.); (E.-M.K.); (N.R.); (V.F.); (M.v.K.D.); (M.K.); (J.K.)
- Molecular Medicine Partnership Unit, Medical Faculty of the University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany; (S.M.W.); (P.B.); (G.N.-Y.); (A.K.)
- Clinical Cooperation Unit Applied Tumor Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221-564223
| |
Collapse
|
|
22
|
Wang B, Bhattacharya M, Roy S, Tian Y, Yin Q. Immunobiology and structural biology of AIM2 inflammasome. Mol Aspects Med 2020; 76:100869. [PMID: 32660715 DOI: 10.1016/j.mam.2020.100869] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/29/2020] [Accepted: 06/05/2020] [Indexed: 12/15/2022]
Abstract
Absent in melanoma 2 (AIM2) is a cytoplasmic sensor that upon recognizing double-stranded DNA assembles with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 to form the multi-protein complex AIM2 inflammasome. Double-stranded DNA from bacterial, viral, or host cellular origins triggers AIM2 inflammasome assembly and activation, ultimately resulting in secretion of proinflammatory cytokines and pyroptotic cell death in order to eliminate microbial infection. Many pathogens therefore evade or suppress AIM2 inflammasome to establish infection. On the other hand, AIM2 activation is tightly controlled by multiple cellular factors to prevent autoinflammation. Extensive structural studies have captured the molecular details of multiple steps in AIM2 inflammasome assembly. The structures collectively revealed a nucleated polymerization mechanism that not only pervades each step of AIM2 inflammasome assembly, but also underlies assembly of other inflammasomes and complexes in immune signaling. In this article, we briefly review the identification of AIM2 as a cytoplasmic DNA sensor, summarize the importance of AIM2 inflammasome in infections and diseases, and discuss the molecular mechanisms of AIM2 assembly, activation, and regulation using recent cellular, biochemical, and structural results.
Collapse
Affiliation(s)
- Bing Wang
- Department of Biological Science, Florida State University, Tallahassee, FL, 32301, USA
| | - Madhurima Bhattacharya
- Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, 32301, USA
| | - Sayantan Roy
- Department of Biological Science, Florida State University, Tallahassee, FL, 32301, USA
| | - Yuan Tian
- Department of Biological Science, Florida State University, Tallahassee, FL, 32301, USA
| | - Qian Yin
- Department of Biological Science, Florida State University, Tallahassee, FL, 32301, USA; Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, 32301, USA.
| |
Collapse
|
|
23
|
DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis. Int J Mol Sci 2020; 21:ijms21051668. [PMID: 32121297 PMCID: PMC7084700 DOI: 10.3390/ijms21051668] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/23/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Chronic lung inflammation is linked to the pathogenesis of IPF. DROSHA, a class 2 ribonuclease III enzyme, has an important role in the biogenesis of microRNA (miRNA). The function of miRNAs has been identified in the regulation of the target gene or protein related to inflammatory responses via degradation of mRNA or inhibition of translation. The absent-in-melanoma-2 (AIM2) inflammasome is critical for inflammatory responses against cytosolic double stranded DNA (dsDNA) from pathogen-associated molecular patterns (PAMPs) and self-DNA from danger-associated molecular patterns (DAMPs). The AIM2 inflammasome senses double strand DNA (dsDNA) and interacts with the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which recruits pro-caspase-1 and regulates the maturation and secretion of interleukin (IL)-1β and IL-18. A recent study showed that inflammasome activation contributes to lung inflammation and fibrogenesis during IPF. In the current review, we discuss recent advances in our understanding of the DROSHA-miRNA-AIM2 inflammasome axis in the pathogenesis of IPF.
Collapse
|
|
24
|
Maelfait J, Liverpool L, Rehwinkel J. Nucleic Acid Sensors and Programmed Cell Death. J Mol Biol 2020; 432:552-568. [PMID: 31786265 PMCID: PMC7322524 DOI: 10.1016/j.jmb.2019.11.016] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 11/15/2019] [Accepted: 11/15/2019] [Indexed: 02/07/2023]
Abstract
Nucleic acids derived from microorganisms are powerful triggers for innate immune responses. Proteins called RNA and DNA sensors detect foreign nucleic acids and, in mammalian cells, include RIG-I, cGAS, and AIM2. On binding to nucleic acids, these proteins initiate signaling cascades that activate host defense responses. An important aspect of this defense program is the production of cytokines such as type I interferons and IL-1β. Studies conducted over recent years have revealed that nucleic acid sensors also activate programmed cell death pathways as an innate immune response to infection. Indeed, RNA and DNA sensors induce apoptosis, pyroptosis, and necroptosis. Cell death via these pathways prevents replication of pathogens by eliminating the infected cell and additionally contributes to the release of cytokines and inflammatory mediators. Interestingly, recent evidence suggests that programmed cell death triggered by nucleic acid sensors plays an important role in a number of noninfectious pathologies. In addition to nonself DNA and RNA from microorganisms, nucleic acid sensors also recognize endogenous nucleic acids, for example when cells are damaged by genotoxic agents and in certain autoinflammatory diseases. This review article summarizes current knowledge on the links between nucleic acid sensing and cell death and explores important open questions for future studies in this area.
Collapse
Affiliation(s)
- Jonathan Maelfait
- VIB Center for Inflammation Research, 9052 Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
| | - Layal Liverpool
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
| |
Collapse
|
|
25
|
Sharma BR, Karki R, Kanneganti TD. Role of AIM2 inflammasome in inflammatory diseases, cancer and infection. Eur J Immunol 2019; 49:1998-2011. [PMID: 31372985 DOI: 10.1002/eji.201848070] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/22/2019] [Accepted: 07/31/2019] [Indexed: 12/23/2022]
Abstract
AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.
Collapse
Affiliation(s)
- Bhesh Raj Sharma
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rajendra Karki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | | |
Collapse
|
|
26
|
Zhou CB, Fang JY. The role of pyroptosis in gastrointestinal cancer and immune responses to intestinal microbial infection. Biochim Biophys Acta Rev Cancer 2019; 1872:1-10. [DOI: 10.1016/j.bbcan.2019.05.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 04/18/2019] [Accepted: 05/01/2019] [Indexed: 01/04/2023]
|
|
27
|
Yang Y, Zhang M, Jin C, Ding Y, Yang M, Wang R, Zhou Y, Zhou Y, Li T, Wang K, Hu R. Absent in melanoma 2 suppresses epithelial-mesenchymal transition via Akt and inflammasome pathways in human colorectal cancer cells. J Cell Biochem 2019; 120:17744-17756. [PMID: 31210372 DOI: 10.1002/jcb.29040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/05/2019] [Accepted: 05/07/2019] [Indexed: 11/09/2022]
Abstract
Absent in melanoma 2 (AIM2) is a critical component in natural immunity system and is closely related to cancer initiation and development. It has been shown that AIM2 inhibited colorectal cancer (CRC) development and cell proliferation. It remains unresolved how AIM2 acts on CRC metastasis. In this study, we assessed migration, invasion ability, and epithelial-mesenchymal transition (EMT) program upon AIM2 overexpression or knockdown in human CRC cells. Transwell assay demonstrated that upregulation of AIM2 reduced cell migration and invasion. Epithelial marker E-cadherin was augmented and mesenchymal markers vimentin, as well as Snail, were examined decreased by Western blot, real-time polymerase chain reaction, and immunofluorescence. Correspondingly, knockdown of AIM2 led to a reverse consequence. In addition, AIM2 regulated Akt phosphorylation and effects of AIM2 on cell invasion and EMT were recovered after administration of Akt inhibitor, suggesting that AIM2 suppressed EMT dependent on Akt pathway. In addition, caspase-1 inhibitor exposure indicated that AIM2 abrogated EMT through the inflammasome pathway as well. In summary, AIM2 suppressed EMT via Akt and inflammasome pathways in human CRC cells.
Collapse
Affiliation(s)
- Yunjia Yang
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Minda Zhang
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Chenyu Jin
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Yang Ding
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Mengdi Yang
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Rui Wang
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Yunjiang Zhou
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Yang Zhou
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Tao Li
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Keke Wang
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| | - Rong Hu
- State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
28
|
Hsa-miR-889-3p promotes the proliferation of osteosarcoma through inhibiting myeloid cell nuclear differentiation antigen expression. Biomed Pharmacother 2019; 114:108819. [DOI: 10.1016/j.biopha.2019.108819] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 03/23/2019] [Accepted: 03/26/2019] [Indexed: 01/06/2023] Open
|
|
29
|
Martínez-Cardona C, Lozano-Ruiz B, Bachiller V, Peiró G, Algaba-Chueca F, Gómez-Hurtado I, Such J, Zapater P, Francés R, González-Navajas JM. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice. Int J Cancer 2018; 143:2997-3007. [PMID: 30133699 DOI: 10.1002/ijc.31827] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/10/2018] [Accepted: 08/13/2018] [Indexed: 12/26/2022]
Abstract
Chronic liver inflammation is crucial in the pathogenesis of hepatocellular carcinoma (HCC). Activation of the inflammasome complex is a key inflammatory process that has been associated with different liver diseases, but its role in HCC development remains largely unexplored. Here we analyzed the impact of different inflammasome components, including absent in melanoma 2 (AIM2) and NOD-like receptor family pyrin domain containing 3 (NLRP3), in the development of diethylnitrosamine (DEN)-induced HCC in mice. Genetic inactivation of AIM2, but not NLRP3, reduces liver damage and HCC development in this model. AIM2 deficiency ameliorates inflammasome activation, liver inflammation and proliferative responses during HCC initiation. We also identified that AIM2 is highly expressed in Kupffer cells, and that AIM2-mediated production of IL-1β by these cells is enhanced after DEN-induced liver damage. Our data indicate that AIM2 promotes inflammation during carcinogenic liver injury and that it contributes to genotoxic HCC development in mice, thereby recognizing AIM2 as a potential therapeutic target in this disease.
Collapse
Affiliation(s)
- Claudia Martínez-Cardona
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Pharmacology, University Miguel Hernández, Elche, Spain
| | - Beatriz Lozano-Ruiz
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Victoria Bachiller
- Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Gloria Peiró
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Pathology Department, Hospital General Universitario de Alicante, Alicante, Spain
| | - Francisco Algaba-Chueca
- Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Isabel Gómez-Hurtado
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José Such
- Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Pedro Zapater
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Pharmacology, University Miguel Hernández, Elche, Spain
| | - Rubén Francés
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Department of Clinical Medicine, University Miguel Hernández, Elche, Spain
| | - José Manuel González-Navajas
- Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO), Hospital General Universitario de Alicante, Alicante, Spain.,Biomedical Research Network for Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,The Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Sino-French Hoffman Institute, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
30
|
Ramachandran RA, Lupfer C, Zaki H. The Inflammasome: Regulation of Nitric Oxide and Antimicrobial Host Defence. Adv Microb Physiol 2018; 72:65-115. [PMID: 29778217 DOI: 10.1016/bs.ampbs.2018.01.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nitric oxide (NO) is a gaseous signalling molecule that plays diverse physiological functions including antimicrobial host defence. During microbial infection, NO is synthesized by inducible NO synthase (iNOS), which is expressed by host immune cells through the recognition of microbial pattern molecules. Therefore, sensing pathogens or their pattern molecules by pattern recognition receptors (PRRs), which are located at the cell surface, endosomal and phagosomal compartment, or in the cytosol, is key in inducing iNOS and eliciting antimicrobial host defence. A group of cytosolic PRRs is involved in inducing NO and other antimicrobial molecules by forming a molecular complex called the inflammasome. Assembled inflammasomes activate inflammatory caspases, such as caspase-1 and caspase-11, which in turn process proinflammatory cytokines IL-1β and IL-18 into their mature forms and induce pyroptotic cell death. IL-1β and IL-18 play a central role in immunity against microbial infection through activation and recruitment of immune cells, induction of inflammatory molecules, and regulation of antimicrobial mediators including NO. Interestingly, NO can also regulate inflammasome activity in an autocrine and paracrine manner. Here, we discuss molecular mechanisms of inflammasome formation and the inflammasome-mediated regulation of host defence responses during microbial infections.
Collapse
Affiliation(s)
| | | | - Hasan Zaki
- UT Southwestern Medical Center, Dallas, TX, United States.
| |
Collapse
|
|
31
|
Loss of AIM2 expression promotes hepatocarcinoma progression through activation of mTOR-S6K1 pathway. Oncotarget 2017; 7:36185-36197. [PMID: 27167192 PMCID: PMC5094992 DOI: 10.18632/oncotarget.9154] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/19/2016] [Indexed: 01/04/2023] Open
Abstract
Absent in melanoma (AIM2) is a member of the interferon-inducible HIN-200 protein family and is recently recognized to play an important dual role in both innate immunity and tumor pathology. However, the role of AIM2 in the development of hepatocellular carcinoma (HCC) remains to be clarified. Here we showed that AIM2 expression was significantly decreased in liver cancer tissues, and loss of its expression was significantly correlated with more advanced tumor progression. Exogenous overexpression of AIM2 in HCC cells suppressed mammalian target of rapamycin (mTOR)-S6K1 pathway and further inhibited proliferation, colony formation and invasion of HCC cells. On the contrary, block of AIM2 in HCC cells induced (mTOR)-S6K1 pathway activation and thus promoted HCC progression. Treatment with mTOR pathway inhibitor rapamycin further verified its contribution to HCC progression in AIM2 absent HCC cells. Thus, these data suggested that AIM2 played a critical role as a tumor suppressor and might serve as a potential therapeutic target for future development of AIM2-based gene therapy for human liver cancer. This study also paves a new avenue to treat AIM2-deficient cancer by suppression of mTOR.
Collapse
|
|
32
|
Lugrin J, Martinon F. The AIM2 inflammasome: Sensor of pathogens and cellular perturbations. Immunol Rev 2017; 281:99-114. [DOI: 10.1111/imr.12618] [Citation(s) in RCA: 178] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Jérôme Lugrin
- Service of Adult Intensive Care Medicine; Lausanne University Hospital; Epalinges Switzerland
| | - Fabio Martinon
- Department of Biochemistry; University of Lausanne; Epalinges Switzerland
| |
Collapse
|
|
33
|
Inflammasomes and intestinal inflammation. Mucosal Immunol 2017; 10:865-883. [PMID: 28401932 DOI: 10.1038/mi.2017.19] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/19/2017] [Indexed: 02/04/2023]
Abstract
The inflammasome is a cytosolic multi-protein innate immune rheostat, sensing a variety of endogenous and environmental stimuli, and regulating homeostasis or damage control. In the gastrointestinal tract, inflammasomes orchestrate immune tolerance to microbial and potentially food-related signals or drive the initiation of inflammatory responses to invading pathogens. When inadequately regulated, intestinal inflammasome activation leads to a perpetuated inflammatory response leading to immune pathology and tissue damage. In this review, we present the main features of the predominant types of inflammasomes participating in intestinal homeostasis and inflammation. We then discuss current controversies and open questions related to their functions and implications in disease, highlighting how pathological inflammasome over-activation or impaired function impact gut homeostasis, the microbiome ecosystem, and the propensity to develop gut-associated diseases. Collectively, understanding of the molecular basis of intestinal inflammasome signaling may be translated into clinical manipulation of this fundamental pathway as a potential immune modulatory therapeutic intervention.
Collapse
|
|
34
|
He L, Chen Y, Wu Y, Xu Y, Zhang Z, Liu Z. Nucleic acid sensing pattern recognition receptors in the development of colorectal cancer and colitis. Cell Mol Life Sci 2017; 74:2395-2411. [PMID: 28224203 PMCID: PMC11107753 DOI: 10.1007/s00018-017-2477-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Revised: 01/02/2017] [Accepted: 01/26/2017] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths that is often associated with inflammation initiated by activation of pattern recognition receptors (PRRs). Nucleic acid sensing PRRs are one of the major subsets of PRRs that sense nucleic acid (DNA and RNA), mainly including some members of Toll-like receptors (TLR3, 7, 8, 9), AIM2-like receptors (AIM2, IFI16), STING, cGAS, RNA polymerase III, and DExD/H box nucleic acid helicases (such as RIG-I like receptors (RIG-I, MDA5, LPG2), DDX1, 3, 5, 7, 17, 21, 41, 60, and DHX9, 36). Activation of these receptors eventually leads to the release of cytokines and activation of immune cells, which are well known to play crucial roles in host defense against intracellular bacterial and virus infection. However, the functions of these nucleic acid sensing PRRs in the other diseases such as CRC and colitis remain largely unknown. Recent studies indicated that nucleic acid sensing PRRs contribute to CRC and/or colitis development, and therapeutic modulation of nucleic acid sensing PRRs may reduce the risk of CRC development. However, until now, a comprehensive review on the role of nucleic acid sensing PRRs in CRC and colitis is still lacking. This review provided an overview of the roles as well as the mechanisms of these nucleic acid sensing PRRs (AIM2, STING, cGAS, RIG-I and its downstream molecules, DDX3, 5, 6,17, and DHX9, 36) in CRC and colitis, which may aid the diagnosis, therapy, and prognostic prediction of CRC and colitis.
Collapse
Affiliation(s)
- Liangmei He
- Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Yayun Chen
- Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Yuanbing Wu
- Gannan Medical University, Ganzhou, Jiangxi, 341000, China
| | - Ying Xu
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China
| | - Zixiang Zhang
- The First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, Jiangxi, China.
| | - Zhiping Liu
- School of Basic Medicine, Gannan Medical University, Ganzhou, 341000, Jiangxi, China.
| |
Collapse
|
|
35
|
Chen J, Wang Z, Yu S. AIM2 regulates viability and apoptosis in human colorectal cancer cells via the PI3K/Akt pathway. Onco Targets Ther 2017; 10:811-817. [PMID: 28243117 PMCID: PMC5315344 DOI: 10.2147/ott.s125039] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Absent in melanoma 2 (AIM2) plays an important role in innate immunity as a DNA sensor in the cytoplasm by triggering the assembly of an AIM2 inflammasome that results in caspase-1-mediated inflammatory responses and cell death. In recent years, studies have indicated that AIM2 can suppress cancer cell proliferation, and mutations in the gene encoding AIM2 are frequently identified in patients with colorectal cancer (CRC). However, the mechanism by which AIM2 restricts tumor growth remains unclear. We reconstructed AIM2 expression in HCT116 CRC cells by lentivirus transfection. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, we demonstrated that expression of AIM2 inhibited the viability and increased the apoptosis rate of CRC cells, and cell cycle analysis suggested that AIM2 blocked cell cycle transition from G1 to S phase. Western blot analysis showed that AIM2 promoted apoptosis in CRC cells by suppressing the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. Our data suggest that AIM2 plays a critical role as a tumor suppressor and might serve as a potential therapeutic target in CRC.
Collapse
Affiliation(s)
- Jianjun Chen
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhenjun Wang
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Sanshui Yu
- Department of General Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| |
Collapse
|
|
36
|
Vanhove W, Peeters PM, Cleynen I, Van Assche G, Ferrante M, Vermeire S, Arijs I. Review Article. Absent in melanoma 2 (AIM2) in the intestine: diverging actions with converging consequences. ACTA ACUST UNITED AC 2017. [DOI: 10.1515/infl-2017-0001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AbstractThe intestinal mucosa is a difficult environment to maintain homeostasis as it is constantly challenged by microbial and food antigens. Maintaining an intact epithelial barrier, a continuous turnover of intestinal epithelial cells and normobiosis of the gut microbiota are essential components to prevent intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Inflammasomes are critical immune regulators that are involved in all of these processes. They are multiprotein complexes able to assemble upon interaction with a noxious stimulus that will subsequently lead to caspase-1 activation. Activated caspase-1 will orchestrate the maturation and release of proinflammatory cytokines IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. Both cytokine release and pyroptosis are initiated after detection of molecular patterns by a distinct inflammasome sensor protein. Absent in melanoma 2 (AIM2) is such an inflammasome sensor that specifically responds to the presence of double stranded DNA (dsDNA) in the cytoplasm, leading to the recruitment and activation of caspase-1. Recent studies revealed additional roles of AIM2 in controlling epithelial cell proliferation, tight junction expression and the microbiome. Therefore, AIM2 plays a significant role in maintaining intestinal homeostasis. This review focuses on the multifunctional role of AIM2 in intestinal homeostasis by regulating intestinal immunity and preventing colorectal cancer development.
Collapse
|
|
37
|
Choubey D. Absent in melanoma 2 proteins in the development of cancer. Cell Mol Life Sci 2016; 73:4383-4395. [PMID: 27328971 PMCID: PMC11108365 DOI: 10.1007/s00018-016-2296-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 06/04/2016] [Accepted: 06/16/2016] [Indexed: 12/19/2022]
Abstract
Recent studies utilizing chemical-induced colitis-associated and sporadic colon cancer in mouse models indicated a protective role for absent in melanoma 2 (Aim2) in colon epithelial cells. Accordingly, mutations in the human AIM2 gene have been found in colorectal cancer (CRC), and reduced expression of AIM2 in CRC is associated with its progression. Furthermore, the overexpression of AIM2 protein in human cancer cell lines inhibits cell proliferation. Interferon-inducible Aim2 and AIM2 are members of the PYHIN (PYRIN and HIN domain-containing) protein family and share ~57 % amino acid identity. The family also includes murine p202, human PYRIN-only protein 3, and IFI16, which negatively regulate Aim2/AIM2 functions. Because the CRC incidence and mortality rates are higher among men compared with women and the expression of Aim2/AIM2 proteins and their regulators is dependent upon age, gender, and sex hormones, we discuss the potential roles of Aim2/AIM2 in the development of cancer. An improved understanding of the biological functions of the AIM2 in the development of CRC will likely identify new therapeutic approaches to treat patients.
Collapse
Affiliation(s)
- Divaker Choubey
- Research Service, Cincinnati VA Medical Center, 3200 Vine Street, ML-151, Cincinnati, OH, 45220, USA.
- Department of Environmental Health, University of Cincinnati, 160 Panzeca Way, P. O. Box-670056, Cincinnati, OH, 45267, USA.
| |
Collapse
|
|
38
|
Chuong EB, Elde NC, Feschotte C. Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet 2016; 18:71-86. [PMID: 27867194 DOI: 10.1038/nrg.2016.139] [Citation(s) in RCA: 833] [Impact Index Per Article: 92.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Transposable elements (TEs) are a prolific source of tightly regulated, biochemically active non-coding elements, such as transcription factor-binding sites and non-coding RNAs. Many recent studies reinvigorate the idea that these elements are pervasively co-opted for the regulation of host genes. We argue that the inherent genetic properties of TEs and the conflicting relationships with their hosts facilitate their recruitment for regulatory functions in diverse genomes. We review recent findings supporting the long-standing hypothesis that the waves of TE invasions endured by organisms for eons have catalysed the evolution of gene-regulatory networks. We also discuss the challenges of dissecting and interpreting the phenotypic effect of regulatory activities encoded by TEs in health and disease.
Collapse
Affiliation(s)
- Edward B Chuong
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84103, USA
| | - Nels C Elde
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84103, USA
| | - Cédric Feschotte
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84103, USA
| |
Collapse
|
|
39
|
Hu GQ, Song PX, Li N, Chen W, Lei QQ, Yu SX, Zhang XJ, Du CT, Deng XM, Han WY, Yang YJ. AIM2 contributes to the maintenance of intestinal integrity via Akt and protects against Salmonella mucosal infection. Mucosal Immunol 2016; 9:1330-9. [PMID: 26838050 DOI: 10.1038/mi.2015.142] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 11/16/2015] [Indexed: 02/04/2023]
Abstract
The mechanism regulating the gastrointestinal epithelial barrier remains poorly understood. We herein demonstrate that Absent in melanoma-2 (AIM2) contributes to the maintenance of intestinal barrier integrity and defense against bacterial infection. AIM2-deficient mice displayed an increased susceptibility to mucosal but not systemic infection by Salmonella typhimurium, indicating a protective role for AIM2 in the gastrointestinal tract. In a Salmonella colitis model, compared with wild-type mice, AIM2(-/-) mice exhibited more severe body weight loss, intestinal damage, intestinal inflammation, and disruption of basal and activated epithelial cell turnover. In vivo and in vitro data showed that AIM2 restricted the early epithelial paracellular invasion of Salmonella and decreased epithelial permeability. The decreased epithelial barrier in AIM2(-/-) mice might be attributed to the altered expression of tight junction proteins that contribute to epithelial integrity. AIM2 promoted the expression of tight junction proteins through Akt activation. Together, these results suggest that AIM2 is required for maintaining the integrity of the epithelial barrier.
Collapse
Affiliation(s)
- G-Q Hu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - P-X Song
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - N Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - W Chen
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - Q-Q Lei
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - S-X Yu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - X-J Zhang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - C-T Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - X-M Deng
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - W-Y Han
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| | - Y-J Yang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine & The First Hospital, Jilin University, Changchun, China
| |
Collapse
|
|
40
|
Man SM, Karki R, Kanneganti TD. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur J Immunol 2015; 46:269-80. [PMID: 26626159 DOI: 10.1002/eji.201545839] [Citation(s) in RCA: 239] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 11/13/2015] [Accepted: 11/26/2015] [Indexed: 12/15/2022]
Abstract
Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory cytokines pro-IL-1β and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus, and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer, and autoimmunity.
Collapse
Affiliation(s)
- Si Ming Man
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rajendra Karki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | | |
Collapse
|
|
41
|
Han Y, Chen Z, Hou R, Yan D, Liu C, Chen S, Li X, Du W. Expression of AIM2 is correlated with increased inflammation in chronic hepatitis B patients. Virol J 2015; 12:129. [PMID: 26290184 PMCID: PMC4545983 DOI: 10.1186/s12985-015-0360-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Accepted: 08/14/2015] [Indexed: 12/12/2022] Open
Abstract
Background The absent in melanoma 2 (AIM2), a cytosolic dsDNA inflammasome, can be activated by viral DNA to trigger caspase-1. Its role in immunopathology of chronic hepatitis B and C virus (HBV, HCV) infection is still largely unclear. In this study, the expression AIM2, and its downstream cytokines, caspase-1, IL-18 and IL-1β, in liver tissue of patients with chronic hepatitis B and C (CHB, CHC) were investigated. Methods A total of 70 patients diagnosed with chronic hepatitis were enrolled, including 47 patients with CHB and 23 patients with CHC. A liver biopsy was taken from each patient, and immunohistochemistry was used to detect the expression of AIM2 and inflammatory factors caspase-1, IL-18, and IL-1β in the biopsy specimens. The relationship between AIM2 expression and these inflammatory factors was analyzed. Results The expression of AIM2 in CHB patients (89.4 %) was significantly higher than in CHC patients (8.7 %), and among the CHB patients, the expression of AIM2 was significantly higher in the high HBV replication group (HBV DNA ≥ 1 × 105copies/mL) than in the low HBV replication group (HBV DNA < 1 × 105copies/mL). The expression of AIM2 was also correlated with HBV-associated inflammatory activity in CHB patients statistically. Additionally, AIM2 levels were positively correlated with the expression of caspase-1, IL-1β and IL-18 in CHB patients, which implied that the AIM2 expression is directly correlated with the inflammatory activity associated with CHB. Conclusions AIM2 upregulation may be a component of HBV immunopathology. The underlying mechanism and possible signal pathway warrant further study.
Collapse
Affiliation(s)
- Yongtao Han
- Deparment of Pharmacy, Qilu Hospital, Shandong University, Jinan, China.
| | - Ziping Chen
- Digestive Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
| | - Ruiping Hou
- Department of Infectious Disease, Hospital of Laiwu Affiliated to Taishan Medical College, Laiwu, China.
| | - Daojie Yan
- Digestive Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
| | - Changhong Liu
- Digestive Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
| | - Shijun Chen
- Department of Liver Disease, Jinan Infectious Disease Hospital, Shandong University, Jinan, China.
| | - Xiaobo Li
- Center of Translational Medicine, Harbin Medical University, Harbin, Heilongjiang Province, 150086, China.
| | - Wenjun Du
- Digestive Department, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China. .,Digestive Department, Shandong Provincial Qianfoshan Hospital, School of Medicine, Shandong University, Jingshi Road 16766#, Jinan, 250014, China.
| |
Collapse
|
|
42
|
Wilson JE, Petrucelli AS, Chen L, Koblansky AA, Truax AD, Oyama Y, Rogers AB, Brickey WJ, Wang Y, Schneider M, Mühlbauer M, Chou WC, Barker BR, Jobin C, Allbritton NL, Ramsden DA, Davis BK, Ting JPY. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med 2015; 21:906-13. [PMID: 26107252 DOI: 10.1038/nm.3908] [Citation(s) in RCA: 235] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 06/18/2015] [Indexed: 12/11/2022]
Abstract
The inflammasome activates caspase-1 and the release of interleukin-1β (IL-1β) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1β and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K-related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers.
Collapse
Affiliation(s)
- Justin E Wilson
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Alex S Petrucelli
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Liang Chen
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - A Alicia Koblansky
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Agnieszka D Truax
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Yoshitaka Oyama
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Arlin B Rogers
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA
| | - W June Brickey
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Yuli Wang
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Monika Schneider
- The American Association of Immunologists, Bethesda, Maryland, USA
| | - Marcus Mühlbauer
- 1] Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, Florida, USA. [2] Department of Infectious Diseases &Pathology, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Wei-Chun Chou
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Brianne R Barker
- Department of Biology, Drew University, Madison, New Jersey, USA
| | - Christian Jobin
- 1] Department of Medicine, Division of Gastroenterology, University of Florida College of Medicine, Gainesville, Florida, USA. [2] Department of Infectious Diseases &Pathology, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Nancy L Allbritton
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Dale A Ramsden
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Beckley K Davis
- Department of Biology, Franklin &Marshall College, Lancaster, Pennsylvania, USA
| | - Jenny P Y Ting
- 1] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
| |
Collapse
|
|
43
|
Man SM, Zhu Q, Zhu L, Liu Z, Karki R, Malik A, Sharma D, Li L, Malireddi RKS, Gurung P, Neale G, Olsen SR, Carter RA, McGoldrick DJ, Wu G, Finkelstein D, Vogel P, Gilbertson RJ, Kanneganti TD. Critical Role for the DNA Sensor AIM2 in Stem Cell Proliferation and Cancer. Cell 2015; 162:45-58. [PMID: 26095253 DOI: 10.1016/j.cell.2015.06.001] [Citation(s) in RCA: 265] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 05/04/2015] [Accepted: 05/29/2015] [Indexed: 12/18/2022]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
Collapse
Affiliation(s)
- Si Ming Man
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Qifan Zhu
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Liqin Zhu
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Zhiping Liu
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Biochemistry and Molecular Biology, School of Basic Medicines, Gannan Medical University, Ganzhou, Jiangxi 341000, China
| | - Rajendra Karki
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Ankit Malik
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Deepika Sharma
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Liyuan Li
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | | | - Prajwal Gurung
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Geoffrey Neale
- Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Scott R Olsen
- Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Robert A Carter
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Daniel J McGoldrick
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Gang Wu
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - David Finkelstein
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Peter Vogel
- Animal Resources Center and the Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Richard J Gilbertson
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | | |
Collapse
|
|
44
|
Kurz C, Hakimi M, Kloor M, Grond-Ginsbach C, Gross-Weissmann ML, Böckler D, von Knebel Doeberitz M, Dihlmann S. Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review. Mol Med 2015; 21:479-86. [PMID: 26070012 DOI: 10.2119/molmed.2014.00258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 06/09/2015] [Indexed: 11/06/2022] Open
Abstract
Somatic DNA alterations are known to occur in atherosclerotic carotid artery lesions; however, their significance is unknown. The accumulation of microsatellite mutations in coding DNA regions may reflect a deficiency of the DNA mismatch repair (MMR) system. Alternatively, accumulation of these coding microsatellite mutations may indicate that they contribute to the pathology. To discriminate between these two possibilities, we compared the mutation frequencies in coding microsatellites (likely functionally relevant) with those in noncoding microsatellites (likely neutral). Genomic DNA was isolated from carotid endarterectomy (CEA) specimens of 26 patients undergoing carotid surgery and from 15 nonatherosclerotic control arteries. Samples were analyzed by DNA fragment analysis for instability at three noncoding (BAT25, BAT26, CAT25) and five coding (AIM2, ACVR2, BAX, CASP5, TGFBR2) microsatellite loci, with proven validity for detection of microsatellite instability in neoplasms. We found an increased frequency of coding microsatellite mutations in CEA specimens compared with control specimens (34.6 versus 0%; p = 0.0013). Five CEA specimens exhibited more than one frameshift mutation, and ACVR2 and CASP5 were affected most frequently (5/26 and 6/26). Moreover, the rate of coding microsatellite alterations (15/130) differed significantly from that of noncoding alterations (0/78) in CEA specimens (p = 0.0013). In control arteries, no microsatellite alterations were observed, neither in coding nor in noncoding microsatellite loci. In conclusion, the specific accumulation of coding mutations suggests that these mutations play a role in the pathogenesis of atherosclerotic carotid lesions, since the absence of mutations in noncoding microsatellites argues against general microsatellite instability, reflecting MMR deficiency.
Collapse
Affiliation(s)
- Carolin Kurz
- Department of Neurology, Technical University Munich, Munich, Germany
| | - Maani Hakimi
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Kloor
- Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Marie-Luise Gross-Weissmann
- General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.,Pathologie Heidelberg, Heidelberg, Germany
| | - Dittmar Böckler
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | | | - Susanne Dihlmann
- Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
45
|
Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters. PLoS One 2015; 10:e0121980. [PMID: 25816162 PMCID: PMC4376900 DOI: 10.1371/journal.pone.0121980] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 02/05/2015] [Indexed: 12/22/2022] Open
Abstract
Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.
Collapse
|
|
46
|
Komori HK, Hart T, LaMere SA, Chew PV, Salomon DR. Defining CD4 T cell memory by the epigenetic landscape of CpG DNA methylation. THE JOURNAL OF IMMUNOLOGY 2015; 194:1565-79. [PMID: 25576597 DOI: 10.4049/jimmunol.1401162] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Memory T cells are primed for rapid responses to Ag; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpGs) mapped by deep sequencing of T cell activation in human naive and memory CD4 T cells. Four hundred sixty-six CpGs (132 genes) displayed differential methylation between naive and memory cells. Twenty-one genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 of 21 genes encode proteins closely studied in T cells, whereas 15 genes represent novel targets for further study. Eighty-four genes demonstrated differential methylation between memory and naive cells that correlated to differential gene expression following activation, of which 39 exhibited reduced methylation in memory cells coupled with increased gene expression upon activation compared with naive cells. These reveal a class of primed genes more rapidly expressed in memory compared with naive cells and putatively regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells that correlates with activation-induced gene expression.
Collapse
Affiliation(s)
- H Kiyomi Komori
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
| | - Traver Hart
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
| | - Sarah A LaMere
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
| | - Pamela V Chew
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
| | - Daniel R Salomon
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037
| |
Collapse
|
|
47
|
Dihlmann S, Tao S, Echterdiek F, Herpel E, Jansen L, Chang-Claude J, Brenner H, Hoffmeister M, Kloor M. Lack of Absent in Melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival in colorectal cancer patients. Int J Cancer 2014; 135:2387-96. [PMID: 24729378 DOI: 10.1002/ijc.28891] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 03/10/2014] [Accepted: 03/28/2014] [Indexed: 12/31/2022]
Abstract
Functional studies on colorectal cancer cells indicated a protective role of the interferon-inducible dsDNA sensor Absent in Melanoma 2 (AIM2) in cancer progression. Given that a high mutation rate and lack of AIM2 expression was previously detected in a subset of colorectal cancers, we here investigated the association of AIM2 expression in tumor cells and patient prognosis (5-year follow-up). A tissue microarray analysis of 476 matched tissue pairs (colorectal tumor and adjacent normal colon epithelium) was performed by two independent observers. Samples from 62 patients were excluded because of missing follow-up information or due to neo-adjuvant therapy before tissue sampling. Out of the remaining 414 tissue pairs, 279 (67.4%) displayed reduced AIM2 expression in cancer cells when compared to epithelial cells of their normal counterpart. Thirty-eight patients (9.18%) had completely lost AIM2 expression in tumor cells. After adjustment for sex, age, cancer stage, tumor site, tumor grade and chemotherapy, complete lack of AIM2 expression was associated with an up to 3-fold increase in overall mortality (HR=2.40; 95% CI=1.44-3.99) and disease specific mortality (HR=3.14; 95% CI=1.75-5.65) in comparison to AIM2-positive tumor samples. Our results demonstrate that lack of AIM2 expression is closely associated with poor outcome in colorectal cancer. The data thus strongly substantiate a protective role of AIM2 against progression of colorectal tumors. Further studies are required to assess whether lack of AIM2 expression may be used as a biomarker for the identification of colorectal cancer patients with poor prognosis.
Collapse
Affiliation(s)
- Susanne Dihlmann
- Department of Vascular and Endovascular Surgery, University of Heidelberg, Heidelberg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol 2014; 20:4230-4243. [PMID: 24764661 PMCID: PMC3989959 DOI: 10.3748/wjg.v20.i15.4230] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/30/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.
Collapse
|
|
49
|
Sun C, Liu C, Dong J, Li D, Li W. Effects of the myeloid cell nuclear differentiation antigen on the proliferation, apoptosis and migration of osteosarcoma cells. Oncol Lett 2014; 7:815-819. [PMID: 24520299 PMCID: PMC3919948 DOI: 10.3892/ol.2014.1811] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 09/25/2013] [Indexed: 11/05/2022] Open
Abstract
Despite improvements over the past two decades, the outcome for patients with advanced osteosarcoma remains poor. Targeted therapies have emerged as promising treatment options for various malignancies. However, effective targeted cancer therapies require the identification of key molecules in the pathogenesis of cancer. The aim of this study was to evaluate the value of the myeloid cell nuclear differentiation antigen (MNDA), a member of the interferon-inducible p200 (IFI-200) family, as a therapeutic target for osteosarcoma by analyzing the baseline expression of MNDA in human osteosarcoma cells and determining the effect of MNDA overexpression on the proliferation and apoptosis profiles and migration/invasion ability in osteosarcoma cells. To this end, MNDA mRNA abundance in wild-type sarcoma osteogenic (Saos-2) cells was analyzed using reverse transcription-polymerase chain reaction, proliferation/apoptosis profiles and migration/invasion capacity in Saos-2 cells overexpressing a green fluorescence protein (GFP)-human MNDA fusion protein. Saos-2 cells found to be overexpressing GFP alone were assessed by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometric analysis and Matrigel Transwell migration assay. The results demonstrated that MNDA mRNA was significantly less abundant in wild-type Saos-2 cells compared with human monocyte-like U-937 cells and MNDA overexpression effectively inhibited proliferation, induced apoptosis and reduced migration/invasiveness in Saos-2 cells compared with GFP overexpression alone. Preliminary observations suggested that MNDA potentially serves as a novel therapeutic target for osteosarcoma.
Collapse
Affiliation(s)
- Chengliang Sun
- Department of Orthopaedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Chuanju Liu
- Department of Orthopaedic Surgery and Cell Biology, New York University School of Medicine, New York, NY 10003, USA
| | - Jun Dong
- Department of Orthopaedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Dong Li
- Department of Orthopaedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Wei Li
- Department of Orthopaedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| |
Collapse
|
|
50
|
Ponomareva L, Liu H, Duan X, Dickerson E, Shen H, Panchanathan R, Choubey D. AIM2, an IFN-inducible cytosolic DNA sensor, in the development of benign prostate hyperplasia and prostate cancer. Mol Cancer Res 2013; 11:1193-202. [PMID: 23864729 DOI: 10.1158/1541-7786.mcr-13-0145] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Close links have been noted between chronic inflammation of the prostate and the development of human prostatic diseases such as benign prostate hyperplasia (BPH) and prostate cancer. However, the molecular mechanisms that contribute to prostatic inflammation remain largely unexplored. Recent studies have indicated that the IFN-inducible AIM2 protein is a cytosolic DNA sensor in macrophages and keratinocytes. Upon sensing DNA, AIM2 recruits the adaptor ASC and pro-CASP1 to assemble the AIM2 inflammasome. Activation of the AIM2 inflammasome cleaves pro-interleukin (IL)-1β and pro-IL-18 and promotes the secretion of IL-1β and IL-18 proinflammatory cytokines. Given that human prostatic infections are associated with chronic inflammation, the development of BPH is associated with an accumulation of senescent cells with a proinflammatory phenotype, and the development of prostate cancer is associated with the loss of IFN signaling, the role of AIM2 in mediating the formation of prostatic diseases was investigated. It was determined that IFNs (α, β, or γ) induced AIM2 expression in human prostate epithelial cells and cytosolic DNA activated the AIM2 inflammasome. Steady-state levels of the AIM2 mRNA were higher in BPH than in normal prostate tissue. However, the levels of AIM2 mRNA were significantly lower in clinical tumor specimens. Accordingly, constitutive levels of AIM2 mRNA and protein were lower in a subset of prostate cancer cells as compared with BPH cells. Further, the cytosolic DNA activated the AIM2 inflammasome in the androgen receptor-negative PC3 prostate cancer cell line, suggesting that AIM2-mediated events are independent of androgen receptor status. IMPLICATIONS The AIM2 inflammasome has a fundamental role in the generation of human prostatic diseases.
Collapse
Affiliation(s)
- Larissa Ponomareva
- Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, PO Box 670056, Cincinnati, OH 45267.
| | | | | | | | | | | | | |
Collapse
|