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Ulhe A, Raina P, Chaudhary A, Kaul-Ghanekar R. Alpha-linolenic acid-mediated epigenetic reprogramming of cervical cancer cell lines. Epigenetics 2025; 20:2451551. [PMID: 39895102 PMCID: PMC11792827 DOI: 10.1080/15592294.2025.2451551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 11/25/2024] [Accepted: 01/02/2025] [Indexed: 02/04/2025] Open
Abstract
Cervical cancer, the fourth most common cancer globally and the second most prevalent cancer among women in India, is primarily caused by Human Papilloma Virus (HPV). The association of diet with cancer etiology and prevention has been well established and nutrition has been shown to regulate cancer through modulation of epigenetic markers. Dietary fatty acids, especially omega-3, reduce the risk of cancer by preventing or reversing the progression through a variety of cellular targets, including epigenetic regulation. In this work, we have evaluated the potential of ALA (α linolenic acid), an ω-3 fatty acid, to regulate cervical cancer through epigenetic mechanisms. The effect of ALA was evaluated on the regulation of histone deacetylases1, DNA methyltransferases 1, and 3b, and global DNA methylation by ELISA. RT-PCR was utilized to assess the expression of tumor regulatory genes (hTERT, DAPK, RARβ, and CDH1) and their promoter methylation in HeLa (HPV18-positive), SiHa (HPV16-positive) and C33a (HPV-negative) cervical cancer cell lines. ALA increased DNA demethylase, HMTs, and HATs while decreasing global DNA methylation, DNMT, HDMs, and HDACs mRNA expression/activity in all cervical cancer cell lines. ALA downregulated hTERT oncogene while upregulating the mRNA expression of TSGs (Tumor Suppressor Genes) CDH1, RARβ, and DAPK in all the cell lines. ALA reduced methylation in the 5' CpG island of CDH1, RARβ, and DAPK1 promoters and reduced global DNA methylation in cervical cancer cell lines. These results suggest that ALA regulates the growth of cervical cancer cells by targeting epigenetic markers, shedding light on its potential therapeutic role in cervical cancer management.
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Affiliation(s)
- Amrita Ulhe
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Prerna Raina
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Analytical Department (ADT), Lupin Limited, Pune, India
| | - Amol Chaudhary
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Ruchika Kaul-Ghanekar
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Symbiosis Centre for Research and Innovation (SCRI); Symbiosis International Deemed University (SIU), Pune, India
- Cancer Research Lab, Symbiosis School of Biological Sciences (SSBS), Symbiosis International Deemed University (SIU), Pune, India
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Chen Z, Wang X, Tan M, Hu W, Wang J, Jin Z. Overexpressed Rv0222 in M. smegmatis suppresses host innate immunity by downregulating miR-9 target SIRT1. Microb Pathog 2025; 204:107525. [PMID: 40180236 DOI: 10.1016/j.micpath.2025.107525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 03/30/2025] [Accepted: 04/01/2025] [Indexed: 04/05/2025]
Abstract
Tuberculosis (TB) remains one of the most fatal infectious diseases, the pathogenic bacterium Mycobacterium tuberculosis (Mtb) has a thick wall to resist the invasion of extracellular substances and secretes a variety of virulence proteins to antagonize host innate immunity. Rv0222, a protein encoded by the gene Rv0222 in the RD4 region of Mtb, is a critical virulence factor in the pathogenicity of Mtb. However, the mechanism of its regulation of miRNAs during bacterial infection is unclear. We used Rv0222 gene and Mycobacterium smegmatis (M. smegmatis), which is highly homologous to Mtb, to construct Rv0222 recombinant M. smegmatis Ms_Rv0222. Ms_Rv0222 induced down-regulation of miR-9 expression and up-regulation of SIRT1 in RAW264.7 cells and mice post-infection. Up-regulation of SIRT1 caused down-regulation of p65 activity and decreased the expression of pro-inflammatory cytokine, which increased the intracellular survival of M. smegmatis. Si-SIRT1 induced up-regulation of p65 activity and increased the expression of pro-inflammatory cytokine, then decreased the intracellular survival of M. smegmatis. This study reveals that Mtb Rv0222 mediates the suppression of host innate immunity by miR-9 and its target SIRT1, and may provide a potential site for the development of new anti-TB drugs targeting Rv0222.
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Affiliation(s)
- Zonghai Chen
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China; Laboratory of Infection and Immunity, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China.
| | - Xianghu Wang
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Ming Tan
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Wenxu Hu
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Jinsuan Wang
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
| | - Zixuan Jin
- School of Medicine, Taizhou University, Taizhou, Zhejiang, China
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Fu K, Yang X, Zhang M, Yin R. The role of innate immunity triggered by HPV infection in promoting cervical lesions. J Mol Med (Berl) 2025:10.1007/s00109-025-02553-w. [PMID: 40411606 DOI: 10.1007/s00109-025-02553-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 04/26/2025] [Accepted: 05/05/2025] [Indexed: 05/26/2025]
Abstract
Innate immunity is the immune system that organisms possess from birth. It is primarily responsible for the rapid, nonspecific recognition of pathogens when they invade, activating the host's immune response to eliminate. Cervical cancer is one of the most well-known tumors caused by human papillomavirus (HPV) infection. As the first line of defense against pathogens, innate immunity plays a crucial role in the response to HPV invasion, and there has been significant research in this area in recent years. The findings suggest that innate immune responses not only contribute to the clearance of HPV but may also facilitate the spread of the virus and the carcinogenic transformation of cervical epithelial cells. In this review, we comprehensively examine the activation of innate immune responses during HPV infection, the mechanisms by which HPV evades these immune defenses, and the role of innate immunity in promoting cervical intraepithelial neoplasia. Additionally, we explore the characteristics of innate immune responses within the tumor microenvironment of cervical cancer. Furthermore, we summarize recent advances in understanding the various mechanisms by which innate immune responses can be activated, with a focus on potential therapeutic implications. By reviewing the latest research, this article aims to provide valuable insights and stimulate further investigation into the role of innate immunity in HPV-associated cervical lesions, potentially leading to more effective strategies for prevention and treatment in the future.
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Affiliation(s)
- Kaiyu Fu
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
- Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xin Yang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Mengpei Zhang
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China
- Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rutie Yin
- Department of Obstetrics and Gynecology, West China Second University Hospital of Sichuan University, Chengdu, China.
- Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
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4
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Ding D, Liu H, Zhang L, Zhang G, Wei Y, Zhang W, Yang X, Li M, Yin G, Guo W, Chen X, Huang Z, Gao R. AIM2 promotes the progression of HNSCC via STAT1 mediated transcription and IL-17/MAPK signaling. Cell Signal 2025; 127:111545. [PMID: 39638137 DOI: 10.1016/j.cellsig.2024.111545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 11/10/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Chronic inflammation has been recognized as one of the hallmarks of head and neck squamous cell carcinoma (HNSCC), Absent In Melanoma 2(AIM2) has emerged as important regulators of chronic inflammatory, and participated in initiation, progression of kinds of human cancers. Nonetheless, the biological functions and underlying mechanisms of AIM2 in HNSCC remain inadequately understood. Based on the bioinformatics analysis of public databases, we identified elevated AIM2 expression in HNSCC, which positively correlates with disease stage and HPV infection, thereby possessing both diagnostic and prognostic significance. Immunohistochemistry on clinical samples revealed that AIM2 expression was frequently upregulated in cancerous tissues compared to paracancerous tissues, exhibiting a significant association with Ki-67 expression. Modulating AIM2 expression in HNSCC cell lines through transfection with inhibitors or mimics demonstrated that ectopic AIM2 expression enhances cell growth, migration, tumorigenesis, and metastasis both in vitro and in vivo. A dual luciferase reporter assay indicated that the transcription factor STAT1 can bind directly to the AIM2 promoter region and activate its transcription. The STAT1 inhibitor, fludarabine, reduces AIM2 expression and subsequently diminishes cell proliferation. Mechanistically, AIM2 exerts its tumor-promoting effects through the IL-17-MAPK signaling pathway. Collectively, our data demonstrate that AIM2, transcriptionally activated by STAT1, exhibits oncogenic functions by promoting the IL-17-MAPK signaling pathway, suggesting that AIM2 may be a new intervention targets for the diagnostic and treatment of HNSCC.
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Affiliation(s)
- Dong Ding
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China; NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China; Departments of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui Province 230001, PR China
| | - Hongfei Liu
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China
| | - Liping Zhang
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Guoxin Zhang
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Yumin Wei
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Wenlong Zhang
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Xingjiu Yang
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Mengyuan Li
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China
| | - Gaofei Yin
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China
| | - Wei Guo
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China
| | - Xiaohong Chen
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China.
| | - Zhigang Huang
- Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, PR China.
| | - Ran Gao
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, PR China; Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Chinese Academy of Medical Sciences&Peking Union Medical College, Beijing 100021, PR China.
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Shiri Aghbash P, Rasizadeh R, Sadri Nahand J, Bannazadeh Baghi H. The role of immune cells and inflammasomes in Modulating cytokine responses in HPV-Related cervical cancer. Int Immunopharmacol 2025; 145:113625. [PMID: 39637578 DOI: 10.1016/j.intimp.2024.113625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/26/2024] [Accepted: 11/10/2024] [Indexed: 12/07/2024]
Abstract
One of the most frequent cancers associated with gynecological malignancies is cervical cancer. Nearly 99% of cervical tumor lesions are produced by prolonged infection with hr-HPV and almost 70% of cases are related to HPV-16 and HPV-18. The human immune system has a crucial role in defending against infections caused by HPV infection. As an illustration, elevation in neutrophils reduces T cell antitumor activity, which in turn results in the development of malignancies and subsequently inhibits immune system function. HPV-infected cells, also, express a significant number of genes related to pro-inflammatory mediators including IL-1β. Moreover, inflammasomes, which are multi-protein complexes, owing the production of the pro-inflammatory cytokines including IL-1β and IL-18 in response to viral infections. In other words, these multi-protein complexes have a crucial role in tumor immunity regulation through the secretion of pro-inflammatory cytokines and induction of antigen presentation and maturation by APCs including dendritic cells. In this study, we attempted to investigate the inflammasome's general role in the initiation and advancement of cervical cancer, as well as a summary of the pathways connected to the possible participation of inflammasomes in the pathological process of cervical carcinoma and immune cell engagement. Novel strategy techniques that target the inflammatory reaction of tumor-related antigens may be created with an understanding of inflammasome-dependent pathways to accomplish tumor immunotherapy and cervical tumor treatment.
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Affiliation(s)
- Parisa Shiri Aghbash
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reyhaneh Rasizadeh
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Xu C, Jing W, Liu C, Yuan B, Zhang X, Liu L, Zhang F, Chen P, Liu Q, Wang H, Du X. Cytoplasmic DNA and AIM2 inflammasome in RA: where they come from and where they go? Front Immunol 2024; 15:1343325. [PMID: 39450183 PMCID: PMC11499118 DOI: 10.3389/fimmu.2024.1343325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Rheumatoid arthritis is a chronic autoimmune disease of undetermined etiology characterized by symmetric synovitis with predominantly destructive and multiple joint inflammation. Cytoplasmic DNA sensors that recognize protein molecules that are not themselves or abnormal dsDNA fragments play an integral role in the generation and perpetuation of autoimmune diseases by activating different signaling pathways and triggering innate immune signaling pathways and host defenses. Among them, melanoma deficiency factor 2 (AIM2) recognizes damaged DNA and double-stranded DNA and binds to them to further assemble inflammasome, initiating the innate immune response and participating in the pathophysiological process of rheumatoid arthritis. In this article, we review the research progress on the source of cytoplasmic DNA, the mechanism of assembly and activation of AIM2 inflammasome, and the related roles of other cytoplasmic DNA sensors in rheumatoid arthritis.
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Affiliation(s)
- Conghui Xu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Weiyao Jing
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Cui Liu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Bo Yuan
- Department of Acupuncture and Pain, Affiliated Hospital of Gansu University of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Xinghua Zhang
- Department of Acupuncture, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Limei Liu
- Department of Zheng's Acupuncture, Affiliated Hospital of Gansu University of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Fengfan Zhang
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Ping Chen
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Qiang Liu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Haidong Wang
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Xiaozheng Du
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
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Zhang CH, Lu DC, Liu Y, Wang L, Sethi G, Ma Z. The role of extracellular vesicles in pyroptosis-mediated infectious and non-infectious diseases. Int Immunopharmacol 2024; 138:112633. [PMID: 38986299 DOI: 10.1016/j.intimp.2024.112633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 06/22/2024] [Accepted: 07/02/2024] [Indexed: 07/12/2024]
Abstract
Pyroptosis, a lytic and pro-inflammatory cell death, is important in various pathophysiological processes. Host- and bacteria-derived extracellular vesicles (EVs), as natural nanocarriers messengers, are versatile mediators of intercellular communication between different types of cells. Recently, emerging research has suggested that EVs exhibit multifaceted roles in disease progression by manipulating pyroptosis. This review focuses on new findings concerning how EVs shape disease progression in infectious and non-infectious diseases by regulating pyroptosis. Understanding the characteristics and activity of EVs-mediated pyroptotic death may conducive to the discovery of novel mechanisms and more efficient therapeutic targets in infectious and non-infectious diseases.
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Affiliation(s)
- Cai-Hua Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China; Department of Oncology, People's Hospital Affiliated to Chongqing Three Gorges Medical College, Chongqing 404100, China
| | - Ding-Ci Lu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China
| | - Ying Liu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore; Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, 117599 Singapore.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600 Singapore; NUS Centre for Cancer Research (N2CR), National University of Singapore, 117599 Singapore.
| | - Zhaowu Ma
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.
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Xie S, Wang C, Liu X, Li C, Yu J, Ma S, Li Q, Du W. Hepatocellular carcinoma and AIM2: Therapeutic potential through regulation of autophagy and macrophage polarization. Immun Inflamm Dis 2024; 12:e70002. [PMID: 39222064 PMCID: PMC11367919 DOI: 10.1002/iid3.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 06/27/2024] [Accepted: 08/08/2024] [Indexed: 09/04/2024] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) poses a significant challenge to global health. Its pathophysiology involves interconnected processes, including cell proliferation, autophagy, and macrophage polarization. However, the role of Absent in Melanoma 2 (AIM2) in HCC remains elusive. METHODS The expression of AIM2 in Huh-7 and Hep3B cell lines was manipulated and cell proliferation, autophagy, apoptosis, and migration/invasion, together with the polarization of M2 macrophages, were evaluated. The markers of autophagy pathway, LC3B, Beclin-1, and P62, underwent examination through Western blot analysis. An autophagy inhibitor, 3-MA, was used to measured the role of autophagy in HCC. Finally, the effect of AIM2 overexpression on HCC was further evaluated using a subcutaneous tumor model in nude mice. RESULTS Our results established that AIM2 overexpression inhibits HCC cell proliferation, migration, and invasion while promoting apoptosis and autophagy. Conversely, knockdown of AIM2 engendered opposite effects. AIM2 overexpression was correlated with reduced M2 macrophage polarization. The autophagy inhibitor substantiated AIM2's role in autophagy and identified its downstream impact on cell proliferation, migration, invasion, and macrophage polarization. In the in vivo model, overexpression of AIM2 led to the inhibition of HCC tumor growth. CONCLUSION The findings underscore AIM2's crucial function in modulating major biological processes in HCC, pointing to its potential as a therapeutic target. This study inaugurally demonstrated that AIM2 activates autophagy and influences macrophage polarization, playing a role in liver cancer progression.
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Affiliation(s)
- Shuangshuang Xie
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Cuiyun Wang
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Xiaoyan Liu
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Cheng Li
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Jinhong Yu
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Shumin Ma
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Qiang Li
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
| | - Wenjun Du
- Department of liver diseases, Shandong public health clinical centerShandong universityJinanShandongChina
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Gusakov K, Kalinkovich A, Ashkenazi S, Livshits G. Nature of the Association between Rheumatoid Arthritis and Cervical Cancer and Its Potential Therapeutic Implications. Nutrients 2024; 16:2569. [PMID: 39125448 PMCID: PMC11314534 DOI: 10.3390/nu16152569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/02/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024] Open
Abstract
It is now established that patients with rheumatoid arthritis (RA) have an increased risk of developing cervical cancer (CC) or its precursor, cervical intraepithelial neoplasia (CIN). However, the underlying mechanisms of this association have not been elucidated. RA is characterized by unresolved chronic inflammation. It is suggested that human papillomavirus (HPV) infection in RA patients exacerbates inflammation, increasing the risk of CC. The tumor microenvironment in RA patients with CC is also marked by chronic inflammation, which aggravates the manifestations of both conditions. Gut and vaginal dysbiosis are also considered potential mechanisms that contribute to the chronic inflammation and aggravation of RA and CC manifestations. Numerous clinical and pre-clinical studies have demonstrated the beneficial effects of various nutritional approaches to attenuate chronic inflammation, including polyunsaturated fatty acids and their derivatives, specialized pro-resolving mediators (SPMs), probiotics, prebiotics, and certain diets. We believe that successful resolution of chronic inflammation and correction of dysbiosis, in combination with current anti-RA and anti-CC therapies, is a promising therapeutic approach for RA and CC. This approach could also reduce the risk of CC development in HPV-infected RA patients.
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Affiliation(s)
- Kirill Gusakov
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
| | - Alexander Kalinkovich
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel;
| | - Shai Ashkenazi
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
| | - Gregory Livshits
- Department of Morphological Sciences, Adelson School of Medicine, Ariel University, Ariel 4077625, Israel; (K.G.); (S.A.)
- Department of Anatomy and Anthropology, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv 6905126, Israel;
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10
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Wang Y, Li D, Xun J, Wu Y, Wang HL. Construction of prognostic markers for gastric cancer and comprehensive analysis of pyroptosis-related long non-coding RNAs. World J Gastrointest Surg 2024; 16:2281-2295. [PMID: 39087128 PMCID: PMC11287702 DOI: 10.4240/wjgs.v16.i7.2281] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/22/2024] [Accepted: 06/14/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND China's most frequent malignancy is gastric cancer (GC), which has a very poor survival rate, and the survival rate for patients with advanced GC is dismal. Pyroptosis has been connected to the genesis and development of cancer. The function of pyroptosis-related long non-coding RNAs (PRLs) in GC, on the other hand, remains uncertain. AIM To explore the construction and comprehensive analysis of the prognostic characteristics of long non-coding RNA (lncRNA) related to pyroptosis in GC patients. METHODS The TCGA database provided us with 352 stomach adenocarcinoma samples, and we obtained 28 pyroptotic genes from the Reactome database. We examined the correlation between lncRNAs and pyroptosis using the Pearson correlation coefficient. Prognosis-related PRLs were identified through univariate Cox analysis. A predictive signature was constructed using stepwise Cox regression analysis, and its reliability and independence were assessed. To facilitate clinical application, a nomogram was created based on this signature. we analyzed differences in immune cell infiltration, immune function, and checkpoints between the high-risk group (HRG) and low-risk group (LRG). RESULTS Five hundred and twenty-three PRLs were screened from all lncRNAs (absolute correlation coefficient > 0.4, P < 0.05). Nine PRLs were included in the risk prediction signature that was created through stepwise Cox regression analysis. We determined the risk score for GC patients and employed the median value as the dividing line between HRG and LRG. The ability of the risk signature to predict the overall survival (OS) of GC is demonstrated by the Kaplan-Meier analysis, risk curve, receiver operating characteristic curve, and decision curve analysis curve. The risk signature was shown to be an independent prognostic factor for OS in both univariate and multivariate Cox regression analyses. HRG showed a more efficient local immune response or modulation compared to LRG, as indicated by the predicted signal pathway analysis and examination of immune cell infiltration, function, and checkpoints (P < 0.05). CONCLUSION In general, we have created a brand-new prognostic signature using PRLs, which may provide ideas for immunotherapy in patients with GC.
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Affiliation(s)
- Yu Wang
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Di Li
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Jing Xun
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Yu Wu
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Hong-Lei Wang
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
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11
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Pan B, Liu C, Su J, Xia C. Activation of AMPK inhibits cervical cancer growth by hyperacetylation of H3K9 through PCAF. Cell Commun Signal 2024; 22:306. [PMID: 38831454 PMCID: PMC11145780 DOI: 10.1186/s12964-024-01687-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 05/28/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Dysregulation in histone acetylation, a significant epigenetic alteration closely associated with major pathologies including cancer, promotes tumorigenesis, inactivating tumor-suppressor genes and activating oncogenic pathways. AMP-activated protein kinase (AMPK) is a cellular energy sensor that regulates a multitude of biological processes. Although a number of studies have identified the mechanisms by which AMPK regulates cancer growth, the underlying epigenetic mechanisms remain unknown. METHODS The impact of metformin, an AMPK activator, on cervical cancer was evaluated through assessments of cell viability, tumor xenograft model, pan-acetylation analysis, and the role of the AMPK-PCAF-H3K9ac signaling pathway. Using label-free quantitative acetylproteomics and chromatin immunoprecipitation-sequencing (ChIP) technology, the activation of AMPK-induced H3K9 acetylation was further investigated. RESULTS In this study, we found that metformin, acting as an AMPK agonist, activates AMPK, thereby inhibiting the proliferation of cervical cancer both in vitro and in vivo. Mechanistically, AMPK activation induces H3K9 acetylation at epigenetic level, leading to chromatin remodeling in cervical cancer. This also enhances the binding of H3K9ac to the promoter regions of multiple tumor suppressor genes, thereby promoting their transcriptional activation. Furthermore, the absence of PCAF renders AMPK activation incapable of inducing H3K9 acetylation. CONCLUSIONS In conclusion, our findings demonstrate that AMPK mediates the inhibition of cervical cancer growth through PCAF-dependent H3K9 acetylation. This discovery not only facilitates the clinical application of metformin but also underscores the essential role of PCAF in AMPK activation-induced H3K9 hyperacetylation.
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Affiliation(s)
- Botao Pan
- Foshan Women and Children Hospital, Foshan, 528000, China
| | - Can Liu
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 515150, China
| | - Jiyan Su
- Foshan Women and Children Hospital, Foshan, 528000, China
| | - Chenglai Xia
- Foshan Women and Children Hospital, Foshan, 528000, China.
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 515150, China.
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12
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Wu J, Sun X, Jiang P. Metabolism-inflammasome crosstalk shapes innate and adaptive immunity. Cell Chem Biol 2024; 31:884-903. [PMID: 38759617 DOI: 10.1016/j.chembiol.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/19/2024]
Abstract
Inflammasomes are a central component of innate immunity and play a vital role in regulating innate immune response. Activation of inflammasomes is also indispensable for adaptive immunity, modulating the development and response of adaptive immunity. Recently, increasing studies have shown that metabolic alterations and adaptations strongly influence and regulate the differentiation and function of the immune system. In this review, we will take a holistic view of how inflammasomes bridge innate and adaptive (especially T cell) immunity and how inflammasomes crosstalk with metabolic signals during the immune responses. And, special attention will be paid to the metabolic control of inflammasome-mediated interactions between innate and adaptive immunity in disease. Understanding the metabolic regulatory functions of inflammasomes would provide new insights into future research directions in this area and may help to identify potential targets for inflammasome-associated diseases and broaden therapeutic avenues.
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Affiliation(s)
- Jun Wu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian, China; State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Xuan Sun
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Peng Jiang
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
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13
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Bhatti R, Sato PY. Exploring the role of pyroptosis in the pathogenicity of heart disease. Front Physiol 2024; 15:1357285. [PMID: 38645692 PMCID: PMC11026861 DOI: 10.3389/fphys.2024.1357285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 03/25/2024] [Indexed: 04/23/2024] Open
Abstract
Cell death is an essential cellular mechanism that ensures quality control and whole-body homeostasis. Various modes of cell death have been studied and detailed. Unbalanced cell death can lead to uncontrolled cell proliferation (i.e., tumors) or excessive loss of cells (i.e., ischemia injury tissue loss). Thus, it is imperative for modes of cell death to be balanced and controlled. Here, we will focus on a recent mode of cell death called pyroptosis. While extensive studies have shown the role of this route of cell death in macrophages and monocytes, evidence for pyroptosis have expanded to encompass other pathologies, including cancer and cardiac diseases. Herein, we provide a brief review on pyroptosis and discuss current gaps in knowledge and scientific advances in cardiac pyroptosis in recent years. Lastly, we provide conclusions and prospective on the relevance to various cardiac diseases.
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Affiliation(s)
| | - Priscila Y. Sato
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, United States
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14
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Zhang L, Wang J, Guo Y, Yue H, Zhang M. The construction, validation and promotion of the nomogram prognosis prediction model of UCEC, and the experimental verification of the expression and knockdown of the key gene GPX4. Heliyon 2024; 10:e24415. [PMID: 38312660 PMCID: PMC10835249 DOI: 10.1016/j.heliyon.2024.e24415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/29/2023] [Accepted: 01/08/2024] [Indexed: 02/06/2024] Open
Abstract
Background Adequate prognostic prediction of Uterine Corpus Endometrial Carcinoma (UCEC) is crucial for informing clinical decision-making. However, there is a scarcity of research on the utilization of a nomogram prognostic evaluation model that incorporates pyroptosis-related genes (PRGs) in UCEC. Methods By analyzing data from UCEC patients in the TCGA database, four PRGs associated with prognosis were identified. Subsequently, a "risk score" was developed using these four PRGs and LASSO. Ordinary and web-based dynamic nomogram prognosis prediction models were constructed. The discrimination, calibration, clinical benefit, and promotional value of the selected GPX4 were validated. The expression level of GPX4 in UCEC cell lines was subsequently verified. The effects of GPX4 knock-down on the malignant biological behavior of UCEC cells were assessed. Results Four key PRGs and a "risk score" were identified, with the "risk score" calculated as (-0.4323) * GPX4 + (0.2385) * GSDME + (0.0525) * NLRP2 + (-0.3299) * NOD2. The nomogram prognosis prediction model, incorporating the "risk score," "age," and "FIGO stage," demonstrated moderate predictive performance (AUC >0.7), good calibration, and clinical significance for 1, 3, and 5-year survival. The web-based dynamic nomogram demonstrated significant promotional value (https://shibaolu.shinyapps.io/DynamicNomogramForUCEC/). UCEC cells exhibited abnormally elevated expression of GPX4, and the knockdown of GPX4 effectively suppressed malignant biological activities, including proliferation and migration, while inducing apoptosis. The findings from tumorigenic experiments conducted on nude mice further validated the results obtained from cellular experiments. Conclusion Following validation, the nomogram prognosis prediction model, which relies on four pivotal PRGs, demonstrated a high degree of accuracy in forecasting the precise probability of prognosis for patients with UCEC. Additionally, the web-based dynamic nomogram exhibited considerable potential for promotion. Notably, the key gene GPX4 exhibited characteristics of a potential oncogene in UCEC, as it facilitated malignant biological behavior and impeded apoptosis.
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Affiliation(s)
- Lindong Zhang
- Department of Gynecology, The Third Affiliated Hospital of Zhengzhou University, 7 Rehabilitation Front Street, Zhengzhou, 450052, China
| | - Jialin Wang
- Department of Orthopedics, Xuanwu Hospital, Capital Medical University, Beijing, 100000, China
| | - Yan Guo
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, No. 7 Weiwu Street, Zhengzhou, 450003, China
| | - Haodi Yue
- Department of Center for Clinical Single Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, No. 7 Weiwu Street, Zhengzhou, 450003, China
| | - Mengjun Zhang
- Department of Gynecology, The Third Affiliated Hospital of Zhengzhou University, 7 Rehabilitation Front Street, Zhengzhou, 450052, China
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15
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Yang YC, Jiang Q, Yang KP, Wang L, Sethi G, Ma Z. Extracellular vesicle-mediated ferroptosis, pyroptosis, and necroptosis: potential clinical applications in cancer therapy. Cell Death Discov 2024; 10:23. [PMID: 38216595 PMCID: PMC10786909 DOI: 10.1038/s41420-024-01799-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 12/15/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024] Open
Abstract
Extracellular vesicles (EVs) have gained increasing recognition as significant regulators of intercellular communication in various physiological and pathological processes. These vesicles play a pivotal role in cancer progression by facilitating the transfer of diverse cargoes, including lipids, proteins, and nucleic acids. Regulated cell death (RCD), the orderly and autonomous death of cells, is controlled by a variety of biomacromolecules and, in turn, influences various biological processes and cancer progression. Recent studies have demonstrated that EV cargoes regulate diverse oncogenes and tumor suppressors to mediate different nonapoptotic forms of RCD, notably ferroptosis, pyroptosis, and necroptosis. Nevertheless, comprehensive exploration of EV-mediated nonapoptotic RCD forms in the context of cancer has not been performed. This review summarizes the progress regarding the biological functions and underlying mechanisms of EVs in mediating nonapoptotic RCD by delivery of cargoes to regulate tumor progression. Additionally, the review delves into the potential clinical applications of EV-mediated cell death and its significance in the areas of cancer diagnosis and therapy.
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Affiliation(s)
- Yi-Chi Yang
- School of Basic Medicine, Yangtze University, Health Science Center, Yangtze University, 434023, Jingzhou, Hubei, China
| | - Qian Jiang
- Honghu Hospital of Traditional Chinese Medicine, 433200, Honghu, China
- Digestive Disease Research Institution of Yangtze University, Yangtze University, 434023, Jingzhou, China
| | - Ke-Ping Yang
- Department of Cardiology, Jingzhou Hospital Affiliated to Yangtze University, 434023, Jingzhou, China
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, 117599, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, 117599, Singapore.
| | - Zhaowu Ma
- School of Basic Medicine, Yangtze University, Health Science Center, Yangtze University, 434023, Jingzhou, Hubei, China.
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16
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Singh T, Bhattacharya M, Mavi AK, Gulati A, Rakesh, Sharma NK, Gaur S, Kumar U. Immunogenicity of cancer cells: An overview. Cell Signal 2024; 113:110952. [PMID: 38084844 DOI: 10.1016/j.cellsig.2023.110952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 12/18/2023]
Abstract
The immune system assumes a pivotal role in the organism's capacity to discern and obliterate malignant cells. The immunogenicity of a cancer cell pertains to its proficiency in inciting an immunological response. The prowess of immunogenicity stands as a pivotal determinant in the triumph of formulating immunotherapeutic methodologies. Immunotherapeutic strategies include immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and on vaccines. Immunogenic cell death (ICD) epitomizes a form of cellular demise that incites an immune response against dying cells. ICD is characterized by the liberation of distinct specific molecules that activate the immune system, thereby leading to the identification and elimination of dying cells by immunocytes. One of the salient characteristics inherent to the ICD phenomenon resides in the vigorous liberation of adenosine triphosphate (ATP) by cellular entities dedicated to embarking upon the process of programmed cell death, yet refraining from complete apoptotic demise. ICD is initiated by a sequence of molecular events that occur during cell death. These occurrences encompass the unveiling or discharge of molecules such as calreticulin, high-mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) from dying cells. These molecules act as "eat me" signals, which are recognized by immune cells, thereby prompting the engulfment and deterioration of expiring cells by phagocytes including various pathways such as Necroptosis, Apoptosis, and pyroptosis. Here, we review our current understanding of the pathophysiological importance of the immune responses against dying cells and the mechanisms underlying their activation. Overall, the ICD represents an important mechanism by which the immune system recognizes and eliminates dying cells, including cancer cells. Understanding the molecular events that underlie ICD bears the potential to engender innovative cancer therapeutics that harness the power of the immune system to combat cancer.
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Affiliation(s)
- Tanya Singh
- Department of Microbiology, Ram Lal Anand College, University of Delhi, Delhi 110021, India
| | - Madhuri Bhattacharya
- Department of Microbiology, Ram Lal Anand College, University of Delhi, Delhi 110021, India
| | - Anil Kumar Mavi
- Department of Botany, Sri Aurobindo College, University of Delhi, Delhi 110017, India.
| | - Anita Gulati
- Department of Zoology, Deen Dayal Upadhyaya College, University of Delhi, Delhi 110078, India
| | - Rakesh
- Janki Devi Memorial College, University of Delhi, Delhi 110060, India
| | - Naresh Kumar Sharma
- Department of Medical Microbiology & Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Sonal Gaur
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Umesh Kumar
- School of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH9, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh 201015, India.
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17
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You HM, Wang L, Meng HW, Huang C, Fang GY, Li J. Pyroptosis: shedding light on the mechanisms and links with cancers. Front Immunol 2023; 14:1290885. [PMID: 38016064 PMCID: PMC10651733 DOI: 10.3389/fimmu.2023.1290885] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/20/2023] [Indexed: 11/30/2023] Open
Abstract
Pyroptosis, a novel form of programmed cell death (PCD) discovered after apoptosis and necrosis, is characterized by cell swelling, cytomembrane perforation and lysis, chromatin DNA fragmentation, and the release of intracellular proinflammatory contents, such as Interleukin (IL) 8, IL-1β, ATP, IL-1α, and high mobility group box 1 (HMGB1). Our understanding of pyroptosis has increased over time with an increase in research on the subject: gasdermin-mediated lytic PCD usually, but not always, requires cleavage by caspases. Moreover, new evidence suggests that pyroptosis induction in tumor cells results in a strong inflammatory response and significant cancer regression, which has stimulated great interest among scientists for its potential application in clinical cancer therapy. It's worth noting that the side effects of chemotherapy and radiotherapy can be triggered by pyroptosis. Thus, the intelligent use of pyroptosis, the double-edged sword for tumors, will enable us to understand the genesis and development of cancers and provide potential methods to develop novel anticancer drugs based on pyroptosis. Hence, in this review, we systematically summarize the molecular mechanisms of pyroptosis and provide the latest available evidence supporting the antitumor properties of pyroptosis, and provide a summary of the various antitumor medicines targeting pyroptosis signaling pathways.
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Affiliation(s)
- Hong-mei You
- Department of Pharmacy, Hangzhou Women’s Hospital, Hangzhou, China
| | - Ling Wang
- Department of Pharmacy, Shangyu People’s Hospital of Shaoxing, Shaoxing, China
| | - Hong-wu Meng
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Guo-ying Fang
- Department of Pharmacy, Hangzhou Women’s Hospital, Hangzhou, China
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
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18
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Lo Cigno I, Calati F, Girone C, Borgogna C, Venuti A, Boldorini R, Gariglio M. SIRT1 is an actionable target to restore p53 function in HPV-associated cancer therapy. Br J Cancer 2023; 129:1863-1874. [PMID: 37838812 PMCID: PMC10667542 DOI: 10.1038/s41416-023-02465-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 09/26/2023] [Accepted: 10/04/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND Our aim was to evaluate the efficacy and anti-cancer action of a precision medicine approach involving a novel SIRT1-dependent pathway that, when disrupted, leads to the restoration of a functional p53 in human papillomavirus (HPV)-transformed cells. METHODS The anticancer potential of inhibiting SIRT1 was evaluated by examining the effects of the specific SIRT1 inhibitor EX527 (also known as Selisistat) or genetic silencing, either individually or in conjunction with standard chemotherapeutic agents, on a range of HPV+ cancer cells and a preclinical mouse model of HPV16-induced cancer. RESULTS We show that SIRT1 inhibition restores a transcriptionally active K382-acetylated p53 in HPV+ but not HPV- cell lines, which in turn promotes G0/G1 cell cycle arrest and inhibits clonogenicity specifically in HPV+ cells. Additionally, EX527 treatment increases the sensitivity of HPV+ cells to sublethal doses of standard genotoxic agents. The enhanced sensitivity to cisplatin as well as p53 restoration were also observed in an in vivo tumorigenicity assay using syngeneic C3.43 cells harbouring an integrated HPV16 genome, injected subcutaneously into C57BL/6J mice. CONCLUSIONS Our findings uncover an essential role of SIRT1 in HPV-driven oncogenesis, which may have direct translational implications for the treatment of this type of cancer.
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Affiliation(s)
- Irene Lo Cigno
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Federica Calati
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Carlo Girone
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Cinzia Borgogna
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy
| | - Aldo Venuti
- HPV Unit, UOSD Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Renzo Boldorini
- Pathology Unit, Department of Health Sciences, Eastern Piedmont University, Novara, Italy
| | - Marisa Gariglio
- Virology Unit, Department of Translational Medicine, Eastern Piedmont University, Novara, Italy.
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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] [Download PDF] [Figures] [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.
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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
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20
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Wang J, Hua S, Bao H, Yuan J, Zhao Y, Chen S. Pyroptosis and inflammasomes in cancer and inflammation. MedComm (Beijing) 2023; 4:e374. [PMID: 37752941 PMCID: PMC10518439 DOI: 10.1002/mco2.374] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 08/20/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023] Open
Abstract
Nonprogrammed cell death (NPCD) and programmed cell death (PCD) are two types of cell death. Cell death is significantly linked to tumor development, medication resistance, cancer recurrence, and metastatic dissemination. Therefore, a comprehensive understanding of cell death is essential for the treatment of cancer. Pyroptosis is a kind of PCD distinct from autophagy and apoptosis in terms of the structure and function of cells. The defining features of pyroptosis include the release of an inflammatory cascade reaction and the expulsion of lysosomes, inflammatory mediators, and other cellular substances from within the cell. Additionally, it displays variations in osmotic pressure both within and outside the cell. Pyroptosis, as evidenced by a growing body of research, is critical for controlling the development of inflammatory diseases and cancer. In this paper, we reviewed the current level of knowledge on the mechanism of pyroptosis and inflammasomes and their connection to cancer and inflammatory diseases. This article presents a theoretical framework for investigating the potential of therapeutic targets in cancer and inflammatory diseases, overcoming medication resistance, establishing nanomedicines associated with pyroptosis, and developing risk prediction models in refractory cancer. Given the link between pyroptosis and the emergence of cancer and inflammatory diseases, pyroptosis-targeted treatments may be a cutting-edge treatment strategy.
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Affiliation(s)
- Jie‐Lin Wang
- Department of Obstetrics and GynecologyGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of Gynecologic Oncology Research OfficeGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Sheng‐Ni Hua
- Department of Radiation OncologyZhuhai Peoples HospitalZhuhai Hospital Affiliated with Jinan UniversityZhuhaiChina
| | - Hai‐Juan Bao
- Department of Obstetrics and GynecologyGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of Gynecologic Oncology Research OfficeGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Jing Yuan
- Department of Obstetrics and GynecologyGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of Gynecologic Oncology Research OfficeGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Yang Zhao
- Department of Obstetrics and GynecologyGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of Gynecologic Oncology Research OfficeGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
| | - Shuo Chen
- Department of Obstetrics and GynecologyGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
- Department of Gynecologic Oncology Research OfficeGuangzhou Key Laboratory of Targeted Therapy for Gynecologic OncologyGuangdong Provincial Key Laboratory of Major Obstetric DiseasesThe Third Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina
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21
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Ding C, Yang X, Li S, Zhang E, Fan X, Huang L, He Z, Sun J, Ma J, Zang L, Zheng M. Exploring the role of pyroptosis in shaping the tumor microenvironment of colorectal cancer by bulk and single-cell RNA sequencing. Cancer Cell Int 2023; 23:95. [PMID: 37198617 DOI: 10.1186/s12935-023-02897-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/12/2023] [Indexed: 05/19/2023] Open
Abstract
BACKGROUND Emerging studies have shown that pyroptosis plays a non-negligible role in the development and treatment of tumors. However, the mechanism of pyroptosis in colorectal cancer (CRC) remains still unclear. Therefore, this study investigated the role of pyroptosis in CRC. METHODS A pyroptosis-related risk model was developed using univariate Cox regression and LASSO Cox regression analyses. Based on this model, pyroptosis-related risk scores (PRS) of CRC samples with OS time > 0 from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database were calculated. The abundance of immune cells in CRC tumor microenvironment (TME) was predicted by single-sample gene-set enrichment analysis (ssGSEA). Then, the responses to chemotherapy and immunotherapy were predicted by pRRophetic algorithm, the tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms, respectively. Moreover, the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing dataset (PRISM) were used to explore novel drug treatment strategies of CRC. Finally, we investigated pyroptosis-related genes in the level of single-cell and validated the expression levels of these genes between normal and CRC cell lines by RT-qPCR. RESULTS Survival analysis showed that CRC samples with low PRS had better overall survival (OS) and progression-free survival (PFS). CRC samples with low PRS had higher immune-related gene expression and immune cell infiltration than those with high PRS. Besides, CRC samples with low PRS were more likely to benefit from 5-fluorouracil based chemotherapy and anti-PD-1 immunotherapy. In novel drug prediction, some compounds such as C6-ceramide and noretynodrel, were inferred as potential drugs for CRC with different PRS. Single-cell analysis revealed pyroptosis-related genes were highly expressed in tumor cells. RT-qPCR also demonstrated different expression levels of these genes between normal and CRC cell lines. CONCLUSIONS Taken together, this study provides a comprehensive investigation of the role of pyroptosis in CRC at the bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels, advances our understanding of CRC characteristics, and guides more effective treatment regimens.
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Affiliation(s)
- Chengsheng Ding
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xiao Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Shuchun Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Enkui Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xiaodong Fan
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Ling Huang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Zirui He
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Junjun Ma
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Lu Zang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China.
- Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, School of Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China.
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22
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Tang Y, Zhang C, Ye C, Tian K, Zeng J, Cheng S, Zeng W, Yang B, Liu Y, Yu Y. Construction and validation of programmed cell death-based molecular clusters for prognostic and therapeutic significance of clear cell renal cell carcinoma. Heliyon 2023; 9:e15693. [PMID: 37305457 PMCID: PMC10256830 DOI: 10.1016/j.heliyon.2023.e15693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/08/2023] [Accepted: 04/19/2023] [Indexed: 06/13/2023] Open
Abstract
As the dominant histological subtype of kidney cancer, clear cell renal cell carcinoma (ccRCC) poorly responds to conventional chemotherapy and radiotherapy. Although novel immunotherapies such as immune checkpoint inhibitors could have a durable effect in treating ccRCC patients, the limited availability of dependable biomarkers has restricted their application in clinic. In the study of carcinogenesis and cancer therapies, there has been a recent emphasis on researching programmed cell death (PCD). In the current study, we discovered the enriched and prognostic PCD in ccRCC utilizing gene set enrichment analysis (GSEA) and investigate the functional status of ccRCC patients with different PCD risks. Then, genes related to PCD that had prognostic value in ccRCC were identified for the conduction of non-negative matrix factorization to cluster ccRCC patients. Next, the tumor microenvironment, immunogenicity, and therapeutic response in different molecular clusters were analyzed. Among PCD, apoptosis and pyroptosis were enriched in ccRCC and correlated with prognosis. Patients with high PCD levels were related to poor prognosis and a rich but suppressive immune microenvironment. PCD-based molecular clusters were identified to differentiate the clinical status and prognosis of ccRCC. Moreover, the molecular cluster with high PCD levels may correlate with high immunogenicity and a favorable therapeutic response to ccRCC. Furthermore, a simplified PCD-based gene classifier was established to facilitate clinical application and used transcriptome sequencing data from clinical ccRCC samples to validate the applicability of the gene classifier. We thoroughly extended the understanding of PCD in ccRCC and constructed a PCD-based gene classifier for differentiation of the prognosis and therapeutic efficacy in ccRCC.
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Affiliation(s)
- Yanlin Tang
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Changzheng Zhang
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chujin Ye
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Kaiwen Tian
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jiayi Zeng
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shouyu Cheng
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Weinan Zeng
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Bowen Yang
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanjun Liu
- Department of Immunology, School of Basic Medical Science, Southern Medical University, Guangzhou, China
| | - Yuming Yu
- Department of Urology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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23
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Wang D, Wan X. Progress in the study of molecular mechanisms of cell pyroptosis in tumor therapy. Int Immunopharmacol 2023; 118:110143. [PMID: 37030114 DOI: 10.1016/j.intimp.2023.110143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/08/2023]
Abstract
Pyroptosis, also known as cellular inflammatory necrosis, is a programmed cell death mediated by the Gasdermin family of proteins. The mechanisms by which pyroptosis occurs are divided into the GSDMD-mediated Caspase-1 and Caspase-4/-5/-11-dependent classical inflammatory vesicle pathway and the GSDME-mediated Caspase-3 and granzyme-dependent non-classical inflammatory vesicle pathways, among others. Recent studies have shown that pyroptosis has both inhibitory and promotive effects on tumor development. Pyroptosis induction also plays a dual role in antitumor immunotherapy: on the one hand, it suppresses antitumor immunity by promoting the release of inflammatory factors, and on the other hand, it inhibits tumor cell proliferation by triggering antitumor inflammatory responses. In addition, cell scorching plays an essential role in chemotherapy. It has been found that natural drugs modulating the induction of cell scorch are necessary to treat tumors. Therefore, studying the specific mechanisms of cell pyroptosis in different tumors can provide more ideas for developing oncology drugs. In this paper, we review the molecular mechanisms of pyroptosis and the role of pyroptosis in tumor development and treatment to provide new targets for clinical tumor treatment, prognosis, and antitumor drug development.
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24
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Wang W, Sun W, Xu H, Liu Y, Wei C, Wang S, Xian S, Yan P, Zhang J, Guo H, Qin H, Lian J, Han X, Zhang J, Guo R, Zhang J, Huang Z. Bibliometric analysis and mini-review of global research on pyroptosis in the field of cancer. Apoptosis 2023:10.1007/s10495-023-01821-9. [PMID: 37071294 DOI: 10.1007/s10495-023-01821-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2023] [Indexed: 04/19/2023]
Abstract
Pyroptosis is one of the mechanisms of programmed cell death (PCD) activated by inflammasomes and involved by the caspase family and the gasdermin family. During the oncogenesis and progression of tumors, pyroptosis is crucial, and complex withal. Currently, pyroptosis is the focus topic in the research field of oncology, but there is no single bibliometric analysis systematically studying 'pyroptosis and cancer'. Our study aimed to visualize the research status of pyroptosis in oncology and excavate the hotspots and prospects in this field. Furthermore, in consideration of the professional direction of researchers, we particularly emphasized articles on pyroptosis in gynecology and formed a mini systematic review. This bibliometric work integrated and analyzed all articles from ISI Web of Science: Science Citation Index Expanded (SCI-Expanded) (dated April 25th, 2022), based on quantitative and visual mapping approaches. Systematically reviewing articles on pyroptosis in gynecology helped us complement our analysis of research advancements in this field. Including 634 articles, our study found that the number of articles on pyroptosis in cancer increased exponentially in recent years. These publications came from 45 countries and regions headed by China and the US mainly aiming at the mechanism of pyroptosis in cell biology and biochemistry molecular biology, as well as the role of pyroptosis in the development and therapeutic application of various cancers. The top 20 most cited studies on this topic mostly came from the US, followed by China and England, and half of the articles cited more than 100 times in total were published in Nature. Moreover, as for gynecologic cancer, in vitro and bioinformatics analysis were the main methodology conducting to explore roles of pyroptosis-related genes (PRGs) and formation of inflammasomes in cancer progression and prognosis. Pyroptosis has evolved into a burgeoning research field in oncology. The cellular and molecular pathway mechanism of pyroptosis, as well as the effect of pyroptosis in oncogenesis, progression, and treatment have been the hot topic of the current study and provided us the future direction as the potential opportunities and challenges. We advocate more active cooperation to improve therapeutic strategies for cancer.
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Affiliation(s)
- Wenwen Wang
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Henan Province, 450052, Zhengzhou, China
| | - Wenhuizi Sun
- Department of Obstetrics and Gynecology, Tongji Hospital, School of Medicine, Tongji University, 200065, Shanghai, China
| | - Han Xu
- Department of Obstetrics and Gynecology, East Hospital, School of Medicine, Tongji University, 200120, Shanghai, China
| | - Yao Liu
- Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
| | - Chenlu Wei
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Siqiao Wang
- Tongji University School of Medicine, 200092, Shanghai, China
| | - Shuyuan Xian
- Tongji University School of Medicine, 200092, Shanghai, China
| | - Penghui Yan
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Jiajun Zhang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Hongjun Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Hengwei Qin
- Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Jie Lian
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Xiangyu Han
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Jiaqi Zhang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China.
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Henan Province, 450052, Zhengzhou, China.
| | - Jie Zhang
- Tongji University School of Medicine, 200092, Shanghai, China.
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, 389 Xincun Road, 200065, Shanghai, China.
| | - Zongqiang Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, 450052, Zhengzhou, China.
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25
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Liu SW, Song WJ, Ma GK, Wang H, Yang L. Pyroptosis and its role in cancer. World J Clin Cases 2023; 11:2386-2395. [PMID: 37123307 PMCID: PMC10130989 DOI: 10.12998/wjcc.v11.i11.2386] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/23/2023] [Accepted: 03/14/2023] [Indexed: 04/06/2023] Open
Abstract
Programmed cell death (PCD) is mediated by specific genes that encode signals. It can balance cell survival and death. Pyroptosis is a type of inflammatory, caspase-dependent PCD mediated by gasdermin proteins, which function in pore formation, cell expansion, and plasma membrane rupture, followed by the release of intracellular contents. Pyroptosis is mediated by caspase-1/3/4/5/11 and is primarily divided into the classical pathway, which is dependent on caspase-1, and the non-classical pathway, which is dependent on caspase-4/5/11. Inflammasomes play a vital role in these processes. The various components of the pyroptosis pathway are related to the occurrence, invasion, and metastasis of tumors. Research on pyroptosis has revealed new options for tumor treatment. This article summarizes the recent research progress on the molecular mechanism of pyroptosis, the relationship between the various components of the pyroptosis pathway and cancer, and the applications and prospects of pyroptosis in anticancer therapy.
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Affiliation(s)
- Shi-Wei Liu
- Department of Joint Surgery, Dalian Medical University, Dalian 116044, Liaoning Province, China
| | - Wen-Jing Song
- Department of Oncology, The First Affiliated Hospital of Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Gui-Kai Ma
- Department of Oncology, The First Affiliated Hospital of Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Hui Wang
- Department of Oncology, The First Affiliated Hospital of Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Liang Yang
- Department of Joint Surgery, The Second Hospital of Dalian Medical University, Dalian 116023, Liaoning Province, China
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26
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Li X, Zhang H, Zheng W, Sun J, Wang L, He Z. Ozanimod-Dependent Activation of SIRT3/NF-κB/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage. Mol Neurobiol 2023; 60:1117-1131. [PMID: 36417102 DOI: 10.1007/s12035-022-03137-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/12/2022] [Indexed: 11/24/2022]
Abstract
Intracerebral hemorrhage (ICH) is characterized by poor prognosis and high mortality rates. To date, satisfactory therapeutic approaches for ICH remain limited, so it is urgently needed to develop a safer and more effective prescription. Secondary inflammatory response has been acknowledged as an aggravating factor to neurological deterioration after ICH. As a component of inflammasome sensors, absent in melanoma 2 (AIM2) plays an important role in the neuroinflammation process. Here, ozanimod, a novel selective sphingosine 1-phosphate receptor modulator, has gained much attention, which alleviates the resultant neuroinflammation and improves functional recovery derived from ICH. In this study, ozanimod improved neurological functions of ICH mice via reduction of hematoma size. Furthermore, both microglial and AIM2 inflammasome activations were reversed by ozanimod, which are confirmed by the downregulation of related inflammatory proteins and cytokines (IL-1β, IL-6, and TNF-α), coupled with the upregulation of SIRT3, by leveraging the Western blot and enzyme-linked immunosorbent assay. Additionally, we find that ozanimod decreases nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression. Notably, in vitro cell experiments induced by lipopolysaccharide confirms that the anti-inflammatory effect of ozanimod could be abolished by the SIRT3 inhibitor. In conclusion, these results indicate that ozanimod mitigates ICH-induced secondary inflammatory responses by modulating AIM2 inflammasome mediated by SIRT3/NF-κB/AIM2 pathway. This demonstrates ozanimod orchestrates ICH-induced neuroinflammation and could be a targeted therapy for improving prognosis of ICH.
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Affiliation(s)
- Xiaoxi Li
- Department of Geriatrics, the First Hospital of China Medical University, Shenyang, 110001, China
| | - Heyu Zhang
- Department of Neurology, the First Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, 510080, China
| | - Wenxu Zheng
- Department of Geriatrics, Dalian Friendship Hospital, Dalian, 116100, China
| | - Jizhou Sun
- Department of Neurosurgery, the Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
| | - Liyuan Wang
- Department of Neurology, the First Hospital of China Medical University, Shenyang, 110001, China.
| | - Zhiyi He
- Department of Neurology, the First Hospital of China Medical University, Shenyang, 110001, China.
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27
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Wu QJ, Zhang TN, Chen HH, Yu XF, Lv JL, Liu YY, Liu YS, Zheng G, Zhao JQ, Wei YF, Guo JY, Liu FH, Chang Q, Zhang YX, Liu CG, Zhao YH. The sirtuin family in health and disease. Signal Transduct Target Ther 2022; 7:402. [PMID: 36581622 PMCID: PMC9797940 DOI: 10.1038/s41392-022-01257-8] [Citation(s) in RCA: 352] [Impact Index Per Article: 117.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/10/2022] [Accepted: 11/18/2022] [Indexed: 12/30/2022] Open
Abstract
Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.
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Affiliation(s)
- Qi-Jun Wu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Tie-Ning Zhang
- grid.412467.20000 0004 1806 3501Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Huan-Huan Chen
- grid.412467.20000 0004 1806 3501Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xue-Fei Yu
- grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jia-Le Lv
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Yang Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ya-Shu Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Gang Zheng
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jun-Qi Zhao
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Fan Wei
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jing-Yi Guo
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fang-Hua Liu
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qing Chang
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yi-Xiao Zhang
- grid.412467.20000 0004 1806 3501Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Cai-Gang Liu
- grid.412467.20000 0004 1806 3501Department of Cancer, Breast Cancer Center, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu-Hong Zhao
- grid.412467.20000 0004 1806 3501Liaoning Key Laboratory of Precision Medical Research on Major Chronic Disease, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China ,grid.412467.20000 0004 1806 3501Clinical Research Center, Shengjing Hospital of China Medical University, Shenyang, China
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Pyroptosis and Its Role in Cervical Cancer. Cancers (Basel) 2022; 14:cancers14235764. [PMID: 36497244 PMCID: PMC9739612 DOI: 10.3390/cancers14235764] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/21/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022] Open
Abstract
Pyroptosis, an inflammatory programmed cell death, is characterized by the caspase-mediated pore formation of plasma membranes and the release of large quantities of inflammatory mediators. In recent years, the morphological characteristics, induction mechanism and action process of pyroptosis have been gradually unraveled. As a malignant tumor with high morbidity and mortality, cervical cancer is seriously harmful to women's health. It has been found that pyroptosis is closely related to the initiation and development of cervical cancer. In this review the mechanisms of pyroptosis and its role in the initiation, progression and treatment application of cervical cancer are summarized and discussed.
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Yan C, Niu Y, Li F, Zhao W, Ma L. System analysis based on the pyroptosis-related genes identifies GSDMC as a novel therapy target for pancreatic adenocarcinoma. J Transl Med 2022; 20:455. [PMID: 36199146 PMCID: PMC9533512 DOI: 10.1186/s12967-022-03632-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/07/2022] [Indexed: 11/12/2022] Open
Abstract
Background Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors of the digestive tract. Pyroptosis is a newly discovered programmed cell death that highly correlated with the prognosis of tumors. However, the prognostic value of pyroptosis in PAAD remains unclear. Methods A total of 178 pancreatic cancer PAAD samples and 167 normal samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The “DESeq2” R package was used to identify differntially expressed pyroptosis-related genes between normal pancreatic samples and PAAD samples. The prognostic model was established in TCGA cohort based on univariate Cox and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, which was validated in test set from Gene Expression Omnibus (GEO) cohort. Univariate independent prognostic analysis and multivariate independent prognostic analysis were used to determine whether the risk score can be used as an independent prognostic factor to predict the clinicopathological features of PAAD patients. A nomogram was used to predict the survival probability of PAAD patients, which could help in clinical decision-making. The R package "pRRophetic" was applied to calculate the drug sensitivity of each samples from high- and low-risk group. Tumor immune infiltration was investigated using an ESTIMATE algorithm. Finally, the pro‐tumor phenotype of GSDMC was explored in PANC-1 and CFPAC-1 cells. Result On the basis of univariate Cox and LASSO regression analyses, we constructed a risk model with identified five pyroptosis-related genes (IL18, CASP4, NLRP1, GSDMC, and NLRP2), which was validated in the test set. The PAAD samples were divided into high-risk and low-risk groups on the basis of the risk score's median. According to Kaplan Meier curve analysis, samples from high-risk groups had worse outcomes than those from low-risk groups. The time-dependent receiver operating characteristics (ROC) analysis revealed that the risk model could predict the prognosis of PAAD accurately. A nomogram accompanied by calibration curves was presented for predicting 1-, 2-, and 3-year survival in PAAD patients. More importantly, 4 small molecular compounds (A.443654, PD.173074, Epothilone. B, Lapatinib) were identified, which might be potential drugs for the treatment of PAAD patients. Finally, the depletion of GSDMC inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells. Conclusion In this study, we developed a pyroptosis-related prognostic model based on IL18, CASP4, NLRP1, NLRP2, and GSDMC , which may be helpful for clinicians to make clinical decisions for PAAD patients and provide valuable insights for individualized treatment. Our result suggest that GSDMC may promote the proliferation and migration of PAAD cell lines. These findings may provide new insights into the roles of pyroptosis-related genes in PAAD, and offer new therapeutic targets for the treatment of PAAD. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03632-z.
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Affiliation(s)
- Cheng Yan
- School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453000, Henan, China
| | - Yandie Niu
- School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453000, Henan, China
| | - Feng Li
- School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453000, Henan, China
| | - Wei Zhao
- School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453000, Henan, China
| | - Liukai Ma
- School of Pharmacy, Key Laboratory of Nano-Carbon Modified Film Technology of Henan Province, Diagnostic Laboratory of Animal Diseases, Xinxiang University, Xinxiang, 453000, Henan, China.
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Skelin J, Sabol I, Tomaić V. Do or Die: HPV E5, E6 and E7 in Cell Death Evasion. Pathogens 2022; 11:pathogens11091027. [PMID: 36145459 PMCID: PMC9502459 DOI: 10.3390/pathogens11091027] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/21/2022] Open
Abstract
Human papillomaviruses (HPVs) infect the dividing cells of human epithelia and hijack the cellular replication machinery to ensure their own propagation. In the effort to adapt the cell to suit their own reproductive needs, the virus changes a number of processes, amongst which is the ability of the cell to undergo programmed cell death. Viral infections, forced cell divisions and mutations, which accumulate as a result of uncontrolled proliferation, all trigger one of several cell death pathways. Here, we examine the mechanisms employed by HPVs to ensure the survival of infected cells manipulated into cell cycle progression and proliferation.
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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.
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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
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Abstract
Background Pyroptosis has been attracting much attention recently. We have briefly compared its differences and similarities with other programmed deaths and the process of its study. With further exploration of the caspase family, including caspase-1/3/4/5/8/11, new insights into the molecular pathways of action of pyroptosis have been gained. It is also closely related to the development of many cancers, which at the same time provides us with new ideas for the treatment of cancer. Scope of Review We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies. Major Conclusions Pyroptosis, a caspase-dependent cell death, causes pore formation, cell swelling, rupture of the plasma membrane, and release of all intracellular contents. The role of pyroptosis in cancer is an extremely complex issue. There is growing evidence that tumor pyroptosis has anti-tumor and pro-tumor roles. It should be discussed in different cancer periods according to the characteristics of cancer occurrence and development. In cancer treatment, pyroptosis provides us with some potential new targets. For the existing drugs, the study of pyroptosis also helps us make better use of existing drugs for anticancer treatment. Immunotherapy is a hot research direction in the field of cancer treatment.
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Affiliation(s)
- Chen Huang
- Department of Abdominal Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, China
| | - Jian Li
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Chenliang Zhang
- Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, China.
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Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation. Viruses 2022; 14:v14081764. [PMID: 36016386 PMCID: PMC9415472 DOI: 10.3390/v14081764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered.
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Zhou Y, Zheng J, Bai M, Gao Y, Lin N. Effect of Pyroptosis-Related Genes on the Prognosis of Breast Cancer. Front Oncol 2022; 12:948169. [PMID: 35957895 PMCID: PMC9357945 DOI: 10.3389/fonc.2022.948169] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/20/2022] [Indexed: 11/28/2022] Open
Abstract
Backgrounds Pyroptosis, a newly pattern of specific programmed cell death, has been reported to participate in several cancers. However, the value of pyroptosis in breast cancer (BRCA) is still not clear. Methods Herein, we analyzed the data of BRCA from both The Cancer Genome Atlas (TCGA) and GSEA MSigDB database. Based on the obtained pyroptosis-related genes (PRGs), we searched the interactions by STRING. After that, we performed clustering analysis by ConsensusClusterPlus. The PRGs with significant prognostic value were then screened through univariate cox regression and further evaluate by constructing a risk model by least absolute shrinkage and selection operator (LASSO) Cox regression. The immune and sensitivity to drugs were also predicted by comprehensive algorithms. Finally, real-time quantitative PCR (qPCR) was performed on two of the screened signature PRGs. Results A total of 49 PRGs were obtained from public database and 35 of them were significantly differentially expressed genes (DEGs). Cluster analysis was then performed to explore the relationship between DEGs with overall survival. After that, 6 optimal PRGs (GSDMC, IL-18, CHMP3, TP63, GZMB and CHMP6) were screened out to construct a prognostic signature, which divide BRCA patients into two risk groups. Risk scores were then confirmed to be independent prognostic factors in BRCA. Functional enrichment analyses showed that the signature were obviously associated with tumor-related and immune-associated pathways. 79 microenvironmental cells and 11 immune checkpoint genes were found disparate in two groups. Besides, tumor immune dysfunction and exclusion (TIDE) scores revealed that patients with higher risk scores are more sensitive to immune checkpoint blockade treatment. Patients in the low-risk group were more sensitive to Cytarabine, Docetaxel, Gefitinib, Paclitaxel, and Vinblastine. Inversely, patients in the high-risk group were more sensitive to Lapatinib. Finally, we found that, CHMP3 were down-regulated in both BRCA tissues and cell lines, while IL-18 were up-regulated. Conclusion PRGs play important roles in BRCA. Our study fills the gaps of 6 selected PRGs in BRCA, which were worthy for the further study as predict potential biomarkers and therapeutic targets.
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Affiliation(s)
- Ying Zhou
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China
- Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianfeng Zheng
- Department of Obstetrics and Gynecology, Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China
| | - Mengru Bai
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China
- Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuzhen Gao
- Department of Clinical Laboratory, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China
- Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Nengming Lin,
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Huang Y, Li R, Yang Y. Role of Pyroptosis in Gynecological Oncology and Its Therapeutic Regulation. Biomolecules 2022; 12:biom12070924. [PMID: 35883480 PMCID: PMC9313147 DOI: 10.3390/biom12070924] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 02/04/2023] Open
Abstract
With the continuous advances in molecular biotechnology, many new cell death methods have been discovered. Pyroptosis is a programmed cell death process that differs from apoptosis and autophagy in cell morphology and function. Compared with apoptosis and autophagy, pyroptosis is primarily mediated by intracellular inflammasome and gasdermin D of the gasdermin protein family and involves the release of numerous inflammatory factors. Pyroptosis has been found to be involved in the occurrence and development of infectious diseases and other diseases involving the nervous system and the cardiovascular system. Recent studies have also reported the occurrence of pyroptosis in tumor cells. Accordingly, exploring its effect on tumors has become one of the research hotspots. Herein, recent research progress on pyroptosis is reviewed, especially its role in the development of gynecological tumors. As the pathogenesis of gynecological tumor is better understood, new targets have been introduced for the prevention and clinical treatment of gynecological tumors.
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Affiliation(s)
- Yi Huang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (Y.H.); (R.L.)
| | - Ruiyun Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, China; (Y.H.); (R.L.)
| | - Yuan Yang
- The Reproductive Medicine Center, The 1st Hospital of Lanzhou University, Lanzhou 730000, China
- Correspondence:
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Li S, Li X, Zhang S, Feng Y, Jia T, Zhu M, Fang L, Gong L, Dong S, Kong X, Wang Z, Sun L. Association Between GSDMB Gene Polymorphism and Cervical Cancer in the Northeast Chinese Han Population. Front Genet 2022; 13:860727. [PMID: 35832190 PMCID: PMC9271821 DOI: 10.3389/fgene.2022.860727] [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: 01/23/2022] [Accepted: 04/26/2022] [Indexed: 11/16/2022] Open
Abstract
Objective: The purpose of this study was to investigate the relationship between GSDMB gene polymorphism and genetic susceptibility to cervical cancer in the Han population in Northeast China. Methods: In this case-control study, the genotypes and alleles of rs8067378 in the GSDMB gene were analyzed by multiplex polymerase chain reaction (PCR) and next-generation sequencing methods in 482 cervical cancer (CC) patients, 775 cervical squamous intraepithelial lesion (SIL) patients, and 495 healthy women. The potential relationships between the SNP of the GSDMB gene with SIL and CC were analyzed by multivariate logistic regression analysis combined with 10,000 permutation tests. Results: In the comparison between the SIL group and the control group, the genotype and allele distribution frequencies of rs8067378 SNP of the GSDMB gene were statistically significant (p = 0.0493 and p = 0.0202, respectively). The allele distribution frequencies of rs8067378 were also statistically significant in the comparison between high-grade cervical squamous intraepithelial lesion (HSIL) and low-grade cervical squamous intraepithelial lesion (LSIL) groups with control group ( p = 0.0483 and p = 0.0330, respectively). Logistic regression analysis showed that after adjusting for age, the rs8067378 SNP of the GSDMB gene was significantly associated with the reduced risk of SIL under the dominant model (p = 0.0213, OR = 0.764, CI = 0.607-0.961) and the additive model (p = 0.0199, OR = 0.814, and CI = 0.684-0.968), and its mutant gene G may play a role in the progression of healthy people to LSIL and even HSIL as a protective factor. However, there was no significant association between cervical cancer and its subtypes with the control group (p > 0.05). After 10,000 permutations, there was still no correlation that has provided evidence for the accuracy of our study. Conclusion: The results of this study showed that rs8067378 single nucleotide polymorphism of the GSDMB gene may reduce the risk of SIL and protect the susceptibility to cervical precancerous lesions in the Northeast Chinese Han population, but it has no significant correlation with the progression of cervical cancer.
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Affiliation(s)
- Songxue Li
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Xiaoying Li
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuang Zhang
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Feng
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianshuang Jia
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Manning Zhu
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Lei Fang
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liping Gong
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuang Dong
- Department of Ultrasound, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xianchao Kong
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhenzhen Wang
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Litao Sun
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Hangzhou, China
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Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther 2022; 7:196. [PMID: 35725836 PMCID: PMC9208265 DOI: 10.1038/s41392-022-01046-3] [Citation(s) in RCA: 526] [Impact Index Per Article: 175.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune “cold” tumors into “hot” tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.
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Affiliation(s)
- Weitong Gao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xueying Wang
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, changsha, 410008, China
| | - Yang Zhou
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Xueqian Wang
- Department of Head and Neck Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
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Li Z, Ji S, Jiang ML, Xu Y, Zhang CJ. The Regulation and Modification of GSDMD Signaling in Diseases. Front Immunol 2022; 13:893912. [PMID: 35774778 PMCID: PMC9237231 DOI: 10.3389/fimmu.2022.893912] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/11/2022] [Indexed: 11/13/2022] Open
Abstract
Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1β, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.
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Affiliation(s)
- Zihao Li
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China
| | - Senlin Ji
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China
| | - Mei-Ling Jiang
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China
| | - Yun Xu
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
| | - Cun-Jin Zhang
- Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, China
- Institute of Brain Sciences, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, China
- Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, China
- Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, China
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Yu X, Li Z, Bai R, Tang F. Transcriptional factor 3 binds to sirtuin 1 to activate the Wnt/β-catenin signaling in cervical cancer. Bioengineered 2022; 13:12516-12531. [PMID: 35587604 PMCID: PMC9275895 DOI: 10.1080/21655979.2022.2076481] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Transcriptional factor 3 (TCF3, also termed E2A), first reported to exert crucial functions during lymphocyte development, has been revealed to participate in the pathogenesis of human cancers. The aim of this work was to investigate the function of TCF3 in cervical cancer (CC) and the molecular interactions. The bioinformatics prediction suggested that TCF3 was highly expressed in CC and linked to poor prognosis. Increased TCF3 expression was identified in CC cell lines, and its downregulation reduced proliferation and migration of CC cells in vitro as well as growth of xenograft tumors in vivo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the TCF-3-related genes and genes showed differential expression between CC and normal tissues were mainly enriched in the Wnt/β-catenin pathway. TCF3 bound to sirtuin 1 (SIRT1) promoter for transcriptional activation, and SIRT1 promoted deacetylation and nuclear translocation of β-catenin in CC. SIRT1 overexpression blocked the role of TCF3 silencing and restored cell proliferation in vitro and tumor growth in vivo. Treatment with XAV-939, a β-catenin inhibitor, significantly suppressed the cell proliferation and tumor growth induced by SIRT1 overexpression. In conclusion, this study demonstrates that TCF3 augments progression of CC by activating SIRT1-mediated β-catenin signaling.
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Affiliation(s)
- Xiao Yu
- Department of Gynecological Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan, P.R. China
| | - Zhaoshuo Li
- Department of Cerebrovascular Disease, Henan Provincial People's Hospital, Henan, P.R. China
| | - Ruihua Bai
- Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan, P.R. China
| | - Fuxiang Tang
- Department of Gynecology, The Second Affiliated Hospital of Zhengzhou University, Henan, P.R. China
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Sun Y, Yang YM, Hu YY, Ouyang L, Sun ZH, Yin XF, Li N, He QY, Wang Y. Inhibition of nuclear deacetylase Sirtuin-1 induces mitochondrial acetylation and calcium overload leading to cell death. Redox Biol 2022; 53:102334. [PMID: 35636016 PMCID: PMC9142701 DOI: 10.1016/j.redox.2022.102334] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/06/2022] [Accepted: 05/08/2022] [Indexed: 12/14/2022] Open
Abstract
Sirtuin-1 (SIRT1) is a critical nuclear deacetylase that participates in a wide range of biological processes. We hereby employed quantitative acetyl-proteomics to globally reveal the landscape of SIRT1-dependent acetylation in colorectal cancer (CRC) cells stimulated by specific SIRT1 inhibitor Inauhzin (INZ). We strikingly observed that SIRT1 inhibition enhances protein acetylation levels, with the multisite-acetylated proteins (acetyl sites >4/protein) mainly enriched in mitochondria. INZ treatment increases mitochondrial fission and depolarization in CRC cells. The acetylation of mitochondrial proteins promoted by SIRT1 inhibition prevents the recruitment of ubiquitin and LC3 for mitophagic degradation. We then found that, SIRT1 inhibition increases the acetylation of mitochondrial calcium uniporter (MCU) at residue K332, resulting in mitochondrial Ca2+ overload and depolarization, and ultimately CRC apoptosis. Arginine substitution of the K332 (K332R) dramatically decreases the mitochondrial Ca2+ influx, mitochondrial membrane potential loss and ROS burst induced by INZ. This finding uncovers a non-canonical role of SIRT1 in regulating mitochondrial function and implicates a possible way for anticancer intervention through SIRT1 inhibition.
SIRT1 inhibition induces mitochondrial fission, depolarization and ROS burst. SIRT1 inhibition induces the mitochondrial acetylation. Mitochondrial acetylation prevents the recruitment of ubiquitin and LC3 for mitophagic degradation. SIRT1 inhibition increases the acetylation of MCU at residue K332, resulting in mitochondrial Ca2+ overload.
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Song K, Ma J, Gao Y, Qu Y, Ren C, Yan P, Zheng B, Yue B. Knocking down Siglec-15 in osteosarcoma cells inhibits proliferation while promoting apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway. Adv Med Sci 2022; 67:187-195. [PMID: 35398779 DOI: 10.1016/j.advms.2022.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/26/2022] [Accepted: 03/29/2022] [Indexed: 12/01/2022]
Abstract
PURPOSE Sialic acid-bound immunoglobulin lectin 15 (Siglec-15) plays a crucial role in many kinds of tumors. The relationship between Siglec-15 and the prognosis of osteosarcoma patients and its role in the apoptosis and pyroptosis of osteosarcoma cells are not sufficiently understood. Our study aimed to investigate the function of Siglec-15 in osteosarcoma cells and its effect on tumor cell proliferation, apoptosis and pyroptosis. MATERIALS AND METHODS The Siglec-15 expression in pathological sections of osteosarcoma patients was analyzed and the overall survival time related to the expression of Siglec-15 was further analyzed. Next, we detected the expression of Siglec-15 in osteosarcoma cells and downregulated the expression of Siglec-15 by small interfering RNA (siRNA). The proliferation, apoptosis and pyroptosis of osteosarcoma cells were studied by proliferation and apoptosis kits and Western blotting. Furthermore, the Siglec-15 signaling pathway was examined, which may be involved in the observed cellular effects. RESULTS We demonstrated the expression of Siglec-15 in osteosarcoma cells. SiRNA-mediated downregulation of Siglec-15 was successful. We found that knockdown of Siglec-15 in osteosarcoma cell lines significantly inhibited proliferation while promoting apoptosis. Further investigation showed that the expression of proliferation-related proteins was downregulated and that apoptosis- and pyroptosis-related proteins were upregulated. In addition, we found that Siglec-15 may inhibit proliferation while inducing apoptosis and pyroptosis via the (Signal Transducer and Activator of Transcription 3) STAT3/Bcl-2 pathway in osteosarcoma. CONCLUSIONS In this study, we demonstrated that the ablation of Siglec-15 in osteosarcoma inhibited proliferation and promoted apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway.
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Affiliation(s)
- Keliang Song
- Department of Orthopedic Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China
| | - Jinfeng Ma
- Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China; Department of Spinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yang Gao
- Medical Department, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Yan Qu
- Industrial Investment Department, Haier, Qingdao, People's Republic of China
| | - Chongmin Ren
- Department of Orthopedic Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China
| | - Peng Yan
- Department of Orthopedic Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China
| | - Bingxin Zheng
- Department of Orthopedic Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China.
| | - Bin Yue
- Department of Orthopedic Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China; Qingdao Medical College of Qingdao University, Qingdao, People's Republic of China.
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Lei S, Li H. Two Pyroptosis-Related Subtypes with Distinct Immune Microenvironment Characteristics and a Novel Signature for Predicting Immunotherapy Response and Prognosis in Uveal Melanoma. Curr Eye Res 2022; 47:930-943. [PMID: 35348009 DOI: 10.1080/02713683.2022.2048396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Shizhen Lei
- Department of Ophthalmology, Fourth Affiliated Hospital of China Medical University, Shenyang, China
| | - Haihui Li
- Department of Ophthalmology, Yan'an People's Hospital, Yan'an, China
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Lin G, Feng Q, Zhan F, Yang F, Niu Y, Li G. Generation and Analysis of Pyroptosis-Based and Immune-Based Signatures for Kidney Renal Clear Cell Carcinoma Patients, and Cell Experiment. Front Genet 2022; 13:809794. [PMID: 35281845 PMCID: PMC8908022 DOI: 10.3389/fgene.2022.809794] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Pyroptosis is a programmed cell death caused by inflammasomes, which is closely related to immune responses and tumor progression. The present study aimed to construct dual prognostic indices based on pyroptosis-associated and immune-associated genes and to investigate the impact of the biological signatures of these genes on Kidney Renal Clear Cell Carcinoma (KIRC). Materials and Methods: All the KIRC samples from the Cancer Genome Atlas (TCGA) were randomly and equally divided into the training and testing datasets. Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis were used to screen crucial pyroptosis-associated genes (PAGs), and a pyroptosis-associated genes prognostic index (PAGsPI) was constructed. Immune-associated genes (IAGs) related to PAGs were identified, and then screened through Cox and LASSO regression analyses, and an immune-associated genes prognostic index (IAGsPI) was developed. These two prognostic indices were verified by using the testing and the Gene Expression Omnibus (GEO) datasets and an independent cohort. The patients’ response to immunotherapy was analyzed. A nomogram was constructed and calibrated. qRT-PCR was used to detect the expression of PAGs and IAGs in the tumor tissues and normal tissues. Functional experiment was carried out. Results: 86 PAGs and 1,774 differentially expressed genes (DEGs) were obtained. After intersecting PAGs with DEGs, 22 differentially expressed PAGs (DEPAGs) were included in Cox and LASSO regression analyses, identifying 5 crucial PAGs. The PAGsPI was generated. Patients in the high-PAGsPI group had a poor prognosis. 82 differentially expressed IAGs (DEIAGs) were highly correlated with DEPAGs. 7 key IAGs were screened out, and an IAGsPI was generated. Patients in the high-IAGsPI group had a poor prognosis. PAGsPI and IAGsPI were verified to be robust and reliable. The results revealed patients in low-PAGsPI group and high-IAGsPI group may be more sensitive to immunotherapy. The calibrated nomogram was proved to be reliable. An independent cohort study also proved that PAGsPI and IAGsPI performed well in prognosis prediction. We found that the expression of AIM2 may affect proliferation of KIRC cells. Conclusion: PAGsPI and IAGsPI could be regarded as potential biomarkers for predicting the prognosis of patients with KIRC.
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Affiliation(s)
- Gaoteng Lin
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Qingfu Feng
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Fangfang Zhan
- Department of Neurology, The Affiliated Hospital of Putian University, Putian, China
| | - Fan Yang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yuanjie Niu
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Gang Li
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
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Lu H, Wu J, Liang L, Wang X, Cai H. Identifying a Novel Defined Pyroptosis-Associated Long Noncoding RNA Signature Contributes to Predicting Prognosis and Tumor Microenvironment of Bladder Cancer. Front Immunol 2022; 13:803355. [PMID: 35154117 PMCID: PMC8828980 DOI: 10.3389/fimmu.2022.803355] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/04/2022] [Indexed: 12/18/2022] Open
Abstract
Background Bladder cancer (BLCA) is a common malignant tumor of the urinary tract, which is the sixth most common cancer among men. Numerous studies suggested that pyroptosis and long noncoding RNAs (lncRNAs) played an essential role in the development of cancers. However, the role of pyroptosis-related lncRNAs in BLCA and their prognostic value are still unclear. Methods In this study, we constructed a signature model through least absolute shrinkage and selection operator (LASSO) Cox regression analysis and Cox univariate analysis based on The Cancer Genome Atlas (TCGA) database. The expression of 12 pyroptosis-related lncRNAs was also confirmed by qRT-PCR in BLCA cell lines. TIMER, XCELL, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT R script were applied to quantify the relative proportions of infiltrating immune cells. Correlation coefficients were computed by Spearman analyses. The Kaplan–Meier method, Cox regression model, and log-rank tests were used to evaluate the prognostic value. The R package of pRRophetic was used to predict IC50 of common chemotherapeutic agents. Results A total of 12 pyroptosis-related lncRNAs with great prognosis value were identified. The expression was investigated by qRT-PCR in four BLCA cell lines. Then, 126 cases were identified as high-risk group, and 277 cases were identified as low-risk group based on the cutoff point. Patients in the low-risk group showed a significant survival advantage. Furthermore, we found that clinical features were significantly related to the risk score. As well, based on the C-index values, a nomogram was constructed. The gene set enrichment analysis (GSEA) results showed that mitogen-activated protein kinase (MAPK) signaling, transforming growth factor (TGF)-β signaling, and WNT signaling were with important significance in the high-risk group. Moreover, we found that riskscore was positively correlated with M0 macrophages and M2 macrophages. Conclusions In conclusion, our study indicated that pyroptosis is closely connected to BLCA. The riskscore generated from the expression of 12 pyroptosis-related lncRNAs was evaluated by various clinical features including survival status, tumor microenvironment, clinicopathological characteristic, and chemotherapy. It may offer a significant basis for future studies.
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Affiliation(s)
- Hongcheng Lu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jiajin Wu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Linghui Liang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinwei Wang
- Department of Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Hongzhou Cai
- Department of Urology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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Xu T, Gu H, Zhang C, Zhang W, Liang X, Cheng X. A Novel Risk Model Identified Based on Pyroptosis-Related lncRNA Predicts Overall Survival and Associates With the Immune Landscape of GC Patients. Front Genet 2022; 13:843538. [PMID: 35198013 PMCID: PMC8859253 DOI: 10.3389/fgene.2022.843538] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 01/12/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant gastrointestinal tumors worldwide. Pyroptosis was widely reported to exert a crucial function in tumor development. In addition, pyroptosis was also proved to be associated with the immune landscape. However, whether pyroptosis-related lncRNAs are associated with the prognosis and the immune landscape of GC remains unclear. In the present study, we first constructed a novel risk model by using pyroptosis-related lncRNAs. We identified 11 pyroptosis-related lncRNAs for the establishment of the risk model. The risk model could be used to predict the survival outcome and immune landscape of GC patients. The results of survival analysis and AUC value of a time-related ROC curve proved that our risk model has an elevated efficiency and accuracy in predicting the survival outcome of patients. We also found that the risk model was also associated with the immune landscape, drug sensitivity, and tumor mutation burden of GC patients. In conclusion, our risk model plays a crucial role in the tumor immune microenvironment and could be used to predict survival outcomes of GC patients.
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Affiliation(s)
- Tingting Xu
- The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Hanxin Gu
- The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Changsong Zhang
- The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Wushuang Zhang
- The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Xiaolong Liang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Xiaoxia Cheng, ; Xiaolong Liang,
| | - Xiaoxia Cheng
- The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
- *Correspondence: Xiaoxia Cheng, ; Xiaolong Liang,
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Shen W, He J, Hou T, Si J, Chen S. Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions. Aging Dis 2022; 13:1063-1091. [PMID: 35855334 PMCID: PMC9286910 DOI: 10.14336/ad.2021.1208] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.
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Affiliation(s)
- Weiyi Shen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
| | - Jiamin He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
| | - Tongyao Hou
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Jianmin Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang, China.
- Institute of Gastroenterology, Zhejiang University, Hangzhou 310016, Zhejiang, China.
- Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China
- Correspondence should be addressed to: Dr. Shujie Chen (), Dr. Jianmin Si () and Dr. Tongyao Hou (), Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China
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Antiochos B, Trejo-Zambrano D, Fenaroli P, Rosenberg A, Baer A, Garg A, Sohn J, Li J, Petri M, Goldman DW, Mecoli C, Casciola-Rosen L, Rosen A. The DNA sensors AIM2 and IFI16 are SLE autoantigens that bind neutrophil extracellular traps. eLife 2022; 11:72103. [PMID: 35608258 PMCID: PMC9129876 DOI: 10.7554/elife.72103] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 04/17/2022] [Indexed: 01/12/2023] Open
Abstract
Background Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context. Methods AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy. Results AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Conclusions Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE. Funding These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.
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Affiliation(s)
- Brendan Antiochos
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Daniela Trejo-Zambrano
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Paride Fenaroli
- Nephrology Unit, Parma University Hospital, Department of Medicine and SurgeryParmaItaly,Johns Hopkins University School of Medicine, Division of PathologyBaltimoreUnited States
| | - Avi Rosenberg
- Johns Hopkins University School of Medicine, Division of PathologyBaltimoreUnited States
| | - Alan Baer
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Archit Garg
- Johns Hopkins University School of Medicine, Department of Biophysics and Biophysical ChemistryBaltimoreUnited States
| | - Jungsan Sohn
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States,Johns Hopkins University School of Medicine, Department of Biophysics and Biophysical ChemistryBaltimoreUnited States
| | - Jessica Li
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Michelle Petri
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Daniel W Goldman
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Christopher Mecoli
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Livia Casciola-Rosen
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States
| | - Antony Rosen
- Johns Hopkins University School of Medicine, Division of RheumatologyBaltimoreUnited States,Johns Hopkins University School of Medicine, Division of PathologyBaltimoreUnited States
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Identification of pyroptosis-related signature for cervical cancer predicting prognosis. Aging (Albany NY) 2021; 13:24795-24814. [PMID: 34837692 PMCID: PMC8660613 DOI: 10.18632/aging.203716] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/28/2021] [Indexed: 12/21/2022]
Abstract
Cervical cancer (CC) is one of the most common malignancies encountered in gynecology practice. However, there is a paucity of information about specific biomarkers that assist in the diagnosis and prognosis of CC. Pyroptosis is a form of programmed cell death whose different elements are related to the occurrence, invasion, and metastasis of tumors. However, the role of pyroptosis phenomena in the progression of CC has not yet been elucidated. This study focuses on the development of a pyroptosis-associated prognostic signature for CC using integrated bioinformatics to delineate the relationships among the signature, tumor microenvironment, and immune response of the patients. In this respect, we identified a prognostic signature that depends on eight pyroptosis-related genes (PRGs) that designate with better prognostic survival in the low-risk group (P<0.05) and where AUC values were greater than 0.7. A multi-factor Cox regression analysis indicated that such a signature could be used as an independent prognostic factor, and both the DCA and the Nomogram suggested that the proposed prognostic signature had good predictive capabilities. Interestingly, this prognostic signature can be applied to multiple tumors and thus, is versatile from a clinical point of view. In addition, there were significant differences in the tumor microenvironment and immune infiltration status between the high- and low-risk groups (P<0. 05). The core gene granzyme B (GZMB) was screened and the CC-associated regulatory axis, GZMB/ miR-378a/TRIM52-AS1, was constructed, which may promote CC progression, and further experimentation is needed to validate these results.
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Li M, Wang J, Ma H, Gao L, Zhao K, Huang T. Extracellular Vesicles Long Non-Coding RNA AGAP2-AS1 Contributes to Cervical Cancer Cell Proliferation Through Regulating the miR-3064-5p/SIRT1 Axis. Front Oncol 2021; 11:684477. [PMID: 34796103 PMCID: PMC8593909 DOI: 10.3389/fonc.2021.684477] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 05/27/2021] [Indexed: 12/16/2022] Open
Abstract
Cervical cancer is one of the most severe and prevalent female malignancies and a global health issue. The molecular mechanisms underlying cervical cancer development are poorly investigated. As a type of extracellular membrane vesicles, EVs from cancer cells are involved in cancer progression by delivering regulatory factors, such as proteins, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs). In this study, we identified an innovative function of extracellular vesicle (EV) lncRNA AGAP2-AS1 in regulating cervical cancer cell proliferation. The EVs were isolated from the cervical cancer cells and were observed by transmission electron microscopy (TEM) and were confirmed by analyzing exosome markers. The depletion of AGAP2-AS1 by siRNA significantly reduced its expression in the exosomes from cervical cancer and in the cervical cancer treated with AGAP2-AS1-knockdown exosomes. The expression of AGAP2-AS1 was elevated in the clinical cervical cancer tissues compared with the adjacent normal tissues. The depletion of EV AGAP2-AS1 reduced cell viabilities and Edu-positive cervical cancer cells, while it enhanced cervical cancer cell apoptosis. Tumorigenicity analysis in nude mice showed that the silencing of EV AGAP2-AS1 attenuated cervical cancer cell growth in vivo. Regarding the mechanism, we identified that AGAP2-AS1 increased SIRT1 expression by sponging miR-3064-5p in cervical cancer cells. The overexpression of SIRT1 or the inhibition of miR-3064-5p reversed EV AGAP2-AS1 depletion-inhibited cancer cell proliferation in vitro. Consequently, we concluded that EV lncRNA AGAP2-AS1 contributed to cervical cancer cell proliferation through regulating the miR-3064-5p/SIRT1 axis. The clinical values of EV lncRNA AGAP2-AS1 and miR-3064-5p deserve to be explored in cervical cancer diagnosis and treatments.
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Affiliation(s)
- Min Li
- Pathology Department, Jinan Second Maternal and Child Health Care Hospital, Jinan, China,*Correspondence: Min Li,
| | - Jing Wang
- The Second Children & Women’s Healthcare of Jinan City, Jinan, China
| | - Hongli Ma
- Department of Obstetrics, Tai’an City Central Hospital, Tai’an, China
| | - Li Gao
- Department of Obstetrics, Tai’an City Central Hospital, Tai’an, China
| | - Kunxiang Zhao
- Department of Obstetrics and Gynecology, Pengquan Community Health Service Center, Jinan, China
| | - Tingting Huang
- Department of Obstetrics, Tai’an City Central Hospital, Tai’an, China
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50
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Duan J, Yin M, Shao Y, Zheng J, Nie S. Puerarin induces platinum-resistant epithelial ovarian cancer cell apoptosis by targeting SIRT1. J Int Med Res 2021; 49:3000605211040762. [PMID: 34590923 PMCID: PMC8489779 DOI: 10.1177/03000605211040762] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 07/30/2021] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE Previous investigations indicated the anticancer activity of puerarin. The current study aimed to evaluate the effect and molecular mechanisms of puerarin in chemotherapy-resistant ovarian cancer cells. METHODS We examined the effects of puerarin in platinum-resistant epithelial ovarian cancer cells in vitro and in vivo. We also analyzed the molecular mechanism underlying Wnt/β-catenin inhibition and sirtuin 1 (SIRT1) regulation following puerarin treatment. RESULTS Our study demonstrated that puerarin effectively inhibited cell growth in vitro and in vivo by increasing apoptosis in ovarian cancer cells. More importantly, puerarin sensitized cisplatin-resistant ovarian cancer cells to chemotherapy. Puerarin treatment decreased SIRT1 expression, which attenuated the nuclear accumulation of β-catenin to inhibit Wnt/β-catenin signaling. In addition, SIRT1 overexpression diminished the effects of puerarin treatment on cisplatin-resistant ovarian cancer cells. Further analysis supported SIRT1/β-catenin expression as a candidate biomarker for the disease progression of epithelial ovarian cancer. CONCLUSIONS Puerarin increased the apoptosis of platinum-resistant ovarian cancer cells. The mechanism is partly related to the downregulation of SIRT1 and subsequent inhibition of Wnt/β-catenin signaling.
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Affiliation(s)
- Jianxiu Duan
- Clinical Trial Research Ward, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China
| | - Mingyuan Yin
- Nursing Department, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China
| | - Yaqin Shao
- Agency for Clinical Trials of Drugs Office, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China
| | - Jiao Zheng
- Agency for Clinical Trials of Drugs Office, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China
| | - Shengdan Nie
- Agency for Clinical Trials of Drugs Office, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China
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