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She F, Zhang T, Lee TH. Multifaceted role of zipper-interacting protein kinase beyond cell death: Implication of ZIPK dysregulation in neuronal and vascular injuries. Pharmacol Res 2025; 216:107793. [PMID: 40409521 DOI: 10.1016/j.phrs.2025.107793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/15/2025] [Accepted: 05/20/2025] [Indexed: 05/25/2025]
Abstract
Zipper-interacting protein kinase (ZIPK) belongs to the death-associated protein kinase (DAPK) family and is a serine/threonine kinase. ZIPK is ubiquitously expressed in different types of tissues and cells. ZIPK is involved in many cellular functions, including cell death, smooth muscle contraction, transcriptional regulation, inflammatory signaling and the regulation of angiogenesis. The dysregulation of ZIPK has been shown to be involved in multiple diseases, including cancer, neurological diseases such as stroke, and cardiovascular diseases such as hypertension. The molecular mechanisms by which ZIPK inhibits the development of cancer have been well studied, but less is known about how ZIPK dysregulation is involved in vascular and neurological diseases. In this review, we summarize the current knowledge about the cellular processes in which ZIPK is involved and the pathological relevance of ZIPK dysregulation in diseases, with a focus on the role of ZIPK in vascular and neuronal functions. The molecular mechanisms by which ZIPK dysregulation contributes to cancer and vascular and neuronal diseases are discussed. We also review recent advances in the development of ZIPK modulators and their potential in treating vascular damage and neurological disorders. Multiple findings support that ZIPK has important functions in regulating vascular homeostasis and serves as a novel therapeutic target for alleviating neurological diseases.
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Affiliation(s)
- Fei She
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China
| | - Tao Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
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2
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Yang S, Yang Y, Xu L, Hao C, Chen J. DAPK3 is Essential for DBP-Induced Autophagy of Mouse Leydig Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413936. [PMID: 40047320 PMCID: PMC12061289 DOI: 10.1002/advs.202413936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/05/2025] [Indexed: 05/10/2025]
Abstract
Dibutyl phthalate (DBP) has been widely used in the manufacture of various daily and industrial products. As one of the most important endocrine disruptors, DBP has male reproductive toxicity and can lead to testicular dysfunction. In view of the fact that Leydig cells are important functional and structural units in the testis, their damage will affect testicular function. However, the underlying mechanism of DBP-caused damage to mouse Leydig cells remains elusive. In the study, it is confirmed that DBP can promote the expression of death-associated protein kinase 3 (DAPK3), thereby inducing autophagy of mouse Leydig cells by using in vivo and in vitro experiments. Also, bioinformatics analysis and molecular biology experimental techniques are utilized to further demonstrate that DBP-induced upregulation of DAPK3 results from both the activated transcription by specific protein 2 (Sp2) and the decreased ubiquitination and degradation by parkin RBR E3 ubiquitin-protein ligase (PRKN). Interestingly, melatonin can inhibit both Sp2/DAPK3 and PRKN/DAPK3 signaling pathways by inhibiting oxidative stress, thereby alleviating DBP-induced autophagy of mouse Leydig cells. Overall, the study unravels a novel regulatory mechanism of DBP-induced autophagy of mouse Leydig cells and identifies DAPK3 as a potential therapeutic target for DBP-caused damage to the male reproductive system.
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Affiliation(s)
- Si Yang
- Department of PhysiologySchool of Basic Medical SciencesJiangxi Medical CollegeNanchang UniversityNanchang330006P. R. China
| | - Ying Yang
- Huankui AcademyJiangxi Medical CollegeNanchang UniversityNanchang330006P. R. China
| | - Linlin Xu
- Department of PathologyThe First Affiliated HospitalJiangxi Medical CollegeNanchang UniversityNanchang330006P. R. China
| | - Chaoju Hao
- LibraryJiangxi Medical CollegeNanchang UniversityNanchang330006P. R. China
| | - Jiaxiang Chen
- Department of PhysiologySchool of Basic Medical SciencesJiangxi Medical CollegeNanchang UniversityNanchang330006P. R. China
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3
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Xiao X, Liu Y, Qu X, Liu L, Li GQ, Chen H, Zhou L, Liu Y. Aryl hydrocarbon receptor-regulated long non-coding RNAs: implications for glycolipid metabolism and prognosis in hepatocellular carcinoma. Front Oncol 2025; 15:1537481. [PMID: 40248203 PMCID: PMC12003141 DOI: 10.3389/fonc.2025.1537481] [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: 11/30/2024] [Accepted: 02/21/2025] [Indexed: 04/19/2025] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths with limited treatment options. Tumor metabolic disorder is elevated in HCC and activates the aryl hydrocarbon receptor (AHR), a transcription factor implicated in cancer progression. However, the role of AHR in regulating long non-coding RNAs (lncRNAs) and their impact on glycolipid metabolism remains underexplored. Materials and methods We investigated AHR's influence on several HCC cell lines treated with the AHR ligand. RNA sequencing was performed to identify the differentially expressed (DE) lncRNAs and mRNAs. We analyzed the differences and then conducted functional pathway enrichment of the identified DE lncRNAs and mRNAs. Furthermore, we constructed co-expression networks of lncRNAs and mRNAs and performed survival analysis using The Cancer Genome Atlas (TCGA) data. Results RNA sequencing identified a substantial number of lncRNAs and mRNAs. DEG analysis identified the significant differences between them related to cancer progression, with pathways such as PI3K-Akt, VEGF, and PPAR signaling highlighted. A co-expression network was utilized to elucidate the lncRNA-mRNA interactions and their regulation of glycolipid metabolism.Survival analysis identified the AHR-regulated lncRNAs associated with poor prognosis, like ASAP1-IT1 and RMDN2-AS1. Conclusion This study clarifies AHR's role in regulating gene expression and metabolism in HCC, revealing novel lncRNA biomarkers and potential therapeutic targets that could aid HCC. Further research is needed to explore AHR's effects on the regulation of glucose-lipid metabolism in HCC.
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Affiliation(s)
- Xiaoli Xiao
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yao Liu
- Department of Gastroenterology, the First Affiliated Hospital of Shaoyang University, Shaoyang, Hunan, China
| | - Xiaoyong Qu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, University of South China, Hengyang, Hunan, China
| | - Logen Liu
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Guo-Qing Li
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Honghui Chen
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Linlin Zhou
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yanping Liu
- Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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Luong TV, Cao MTT, Nguyen NVD, Dang HNN, Nguyen TT. Roles of autophagy and long non-coding RNAs in gastric cancer. World J Gastroenterol 2025; 31:101124. [PMID: 40124267 PMCID: PMC11924004 DOI: 10.3748/wjg.v31.i11.101124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 01/24/2025] [Accepted: 02/17/2025] [Indexed: 03/13/2025] Open
Abstract
Gastric cancer (GC) is one of the most aggressive malignancies worldwide and is characterized by its poor prognosis and resistance to conventional therapies. Autophagy and long non-coding RNAs (lncRNAs) play critical yet complex roles in GC, functioning as both tumor suppressors and promoters depending on the disease stage and context. Autophagy influences cellular homeostasis and metabolism, whereas lncRNAs regulate gene expression through epigenetic modifications, RNA sponging, and protein interactions. Notably, the interplay between lncRNAs and autophagy modulates tumor progression, metastasis, chemoresistance, and the tumor microenvironment. This study explored the intricate relationship between lncRNAs and autophagy in GC, highlighting their roles in pathogenesis and treatment resistance. By addressing current knowledge gaps and proposing innovative therapeutic strategies, we have emphasized the potential of targeting this dynamic interplay for improved diagnostic and therapeutic outcomes.
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Affiliation(s)
- Thang Viet Luong
- Department of Internal Medicine, University of Medicine and Pharmacy, Hue University, Hue 530000, Viet Nam
| | - Mai Thi Thu Cao
- Department of Biochemistry, University of Medicine and Pharmacy, Hue University, Hue 530000, Viet Nam
| | - Nam Van Duc Nguyen
- Department of Internal Medicine, University of Medicine and Pharmacy, Hue University, Hue 530000, Viet Nam
| | | | - Trung Tran Nguyen
- Department of Biotechnology, NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Viet Nam
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Mei Y, She F, Zhang L, Kim G, Li R, Zheng X, Wang Z, Chen R, Wang L, Chen D, Kim J, Zhang T, Lee TH. Zipper-interacting protein kinase mediates neuronal cell death and cognitive dysfunction in traumatic brain injury via regulating DEDD. Cell Death Dis 2025; 16:151. [PMID: 40032841 PMCID: PMC11876612 DOI: 10.1038/s41419-025-07474-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/07/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025]
Abstract
Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, the upstream trigger of TBI-induced neuronal loss and the underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated in Alzheimer's disease and ischemic stroke and to play a role in cellular apoptosis, while its pathological significance in TBI has not been reported. Herein, we discovered for the first time that ZIPK expression was markedly elevated in neurons after TBI and that ZIPK caused massive neuronal apoptosis in peri-contusional brain regions. Zipk haploinsufficiency antagonized neuronal cell death and reversed several typical neuropathological changes induced by TBI. Mechanistically, we found that ZIPK affected neuronal viability by modulating death effector domain-containing DNA binding protein (DEDD) and caspase-3 pathway. Specifically, ZIPK could bind to and phosphorylate DEDD at the S9 residue, thus enhancing the stability of DEDD, and leading to the activation of caspase-3-mediated apoptotic cascade in neurons. The rescue of neuronal loss by ZIPK downregulation effectively alleviated TBI-induced behavioral deficits by preserving motor and cognitive abilities in vivo, supporting the decisive role of ZIPK dysregulation in TBI-associated neuronal dysfunctions by modulating neuronal survival. Furthermore, pharmacological suppression of ZIPK activity by a specific inhibitor prior to TBI protected neurons from brain injury-induced cell death and neuronal degeneration in vitro and in vivo by preventing DEDD upregulation and caspase-3 activation. In conclusion, our data reveal the essential contribution of ZIPK to TBI-induced neuronal cell death through the DEDD/caspase-3 cascade, and suggest the potential of targeting ZIPK as an effective strategy for treating TBI-related neuropathologies.
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Affiliation(s)
- Yingxue Mei
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Fei She
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Ling Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Gamin Kim
- Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Korea
| | - Ruomeng Li
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Xiuzhi Zheng
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zonghai Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Renxuan Chen
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Long Wang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Dongmei Chen
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Jungho Kim
- Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Korea
| | - Tao Zhang
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
| | - Tae Ho Lee
- Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
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Duan Q, Wang W, Xiong H, Xiao J, Xiao H, Zhu F, Lu H. JAK2/ULK1 axis promotes cervical cancer progression by autophagy induction and SRPK1 phosphorylation. Oncogene 2025; 44:587-600. [PMID: 39633065 DOI: 10.1038/s41388-024-03246-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/19/2024] [Accepted: 11/29/2024] [Indexed: 12/07/2024]
Abstract
Cervical cancer is the most common gynecologic cancer. Autophagy is involved in the progression of CCa. ULK1 is a crucial kinase in autophagy initiation. However, few studies have investigated the role of ULK1 phosphorylation at tyrosine residues in the progression of CCa, and the underlying mechanism remains elusive. In this study, we demonstrated that JAK2 is a novel upstream kinase that phosphorylates ULK1 at the tyrosine site. JAK2 interacts with and phosphorylates ULK1 at Tyr1007. The phosphorylation of ULK1 at Y1007 increases its activity and stability, activates autophagy, and promotes the progression of CCa. We further showed that the phosphorylation of ULK1 at Y1007 is a predictive marker of CCa patient outcome. Furthermore, we identified SRPK1 as a potential downstream substrate of ULK1 to promote the progression of CCa. Our research sheds light on the molecular mechanism of CCa progression, through JAK2/ULK1 axis, and emphasizes the phosphorylation of ULK1 at Y1007 as a predictor of CCa.
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Affiliation(s)
- Qiuhong Duan
- Translational Medical Center, Huaihe Hospital, Henan University, Kaifeng, Henan, 475000, PR China.
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.
- Medical and industry crossover Research Institute of Medical college, Henan University, Kaifeng, Henan, 475000, PR China.
| | - Wei Wang
- Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430033, PR China
| | - Hua Xiong
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China
| | - Juanjuan Xiao
- Translational Medical Center, Huaihe Hospital, Henan University, Kaifeng, Henan, 475000, PR China
| | - Han Xiao
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430015, PR China.
| | - Feng Zhu
- Translational Medical Center, Huaihe Hospital, Henan University, Kaifeng, Henan, 475000, PR China.
- Medical and industry crossover Research Institute of Medical college, Henan University, Kaifeng, Henan, 475000, PR China.
| | - Hui Lu
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430015, PR China.
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7
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Sun Z, Zhang F, Liu X, Du X, Xiao Y, Sun K, Wang R. Dissecting the anti-pancreatic cancer mechanism of gold nanorods mediate photothermal therapy through quantitative proteomics analysis. Biochem Biophys Res Commun 2025; 747:151288. [PMID: 39798534 DOI: 10.1016/j.bbrc.2025.151288] [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: 12/17/2024] [Accepted: 01/02/2025] [Indexed: 01/15/2025]
Abstract
Gold nanorods (GNRs) mediated photothermal therapy (PTT) represents a promising technique for cancer treatment, utilizing GNRs in conjunction with near-infrared (NIR) laser irradiation to convert energy into heat. In the present study, we employed PTT to induce apoptosis in pancreatic cancer cells and investigated its underlying mechanisms through quantitative proteomics analysis. Initially, we established that temperatures ranging from 47 to 51°C significantly enhance cellular apoptosis without inducing necrosis. Furthermore, we identified key pathways involved in cell apoptosis, including apoptosis, oxidative stress, and proteasome pathways. Notably, thermal stimulation also resulted in the upregulation of proteins involved in autophagy, which intriguingly contribute to cellular apoptosis via autophagy regulation. Collectively, our findings demonstrate that GNRs-PTT is an effective therapeutic option for pancreatic cancer and provide a theoretical foundation for the clinical application of photothermal therapy. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD058930.
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Affiliation(s)
- Zhen Sun
- Department of Oncology, The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 110006, China
| | - Feng Zhang
- Department of Radiotherapy, The Second Affiliated Hospital of Dalian Medical University, No. 467 Zhongshan Road, Dalian, Liaoning, 110006, China
| | - Xixi Liu
- Department of Oncology, The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 110006, China
| | - Xiangning Du
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian, Liaoning, 116011, China
| | - Yan Xiao
- Department of Pathology, The Central Hospital of Jiangnan University, No. 68 Zhongshan Road, Wuxi, Jiangsu, 214000, China
| | - Kai Sun
- Department of Oncology, Ganzhou Cancer Hospital, No. 19 Shui donghuayuanqian, Ganzhou, Jiangxi, 314000, China.
| | - Ruoyu Wang
- Department of Oncology, The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, Liaoning, 110006, China.
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Likasitwatanakul P, Li Z, Doan P, Spisak S, Raghawan AK, Liu Q, Liow P, Lee S, Chen D, Bala P, Sahgal P, Aitymbayev D, Thalappillil JS, Papanastasiou M, Hawkins W, Carr SA, Park H, Cleary JM, Qi J, Sethi NS. Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.06.626451. [PMID: 39713466 PMCID: PMC11661112 DOI: 10.1101/2024.12.06.626451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.
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Affiliation(s)
- Pornlada Likasitwatanakul
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Paul Doan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Akhouri Kishore Raghawan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Qi Liu
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Priscilla Liow
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sunwoo Lee
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - David Chen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Pranshu Sahgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Jennifer S. Thalappillil
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Malvina Papanastasiou
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - William Hawkins
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Steven A. Carr
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
| | - Haeseong Park
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jun Qi
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nilay S. Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
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Lyu J, Zhang H, Wang C, Pan M. New insight in treating autoimmune diseases by targeting autophagy. Autoimmunity 2024; 57:2351872. [PMID: 38739691 DOI: 10.1080/08916934.2024.2351872] [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: 01/22/2024] [Accepted: 04/28/2024] [Indexed: 05/16/2024]
Abstract
Autophagy is a highly conserved biological process in eukaryotes, which degrades cellular misfolded proteins, damaged organelles and invasive pathogens in the lysosome-dependent manner. Autoimmune diseases caused by genetic elements, environments and aberrant immune responses severely impact patients' living quality and even threaten life. Recently, numerous studies have reported autophagy can regulate immune responses, and play an important role in autoimmune diseases. In this review, we summarised the features of autophagy and autophagy-related genes, enumerated some autophagy-related genes involved in autoimmune diseases, and further overviewed how to treat autoimmune diseases through targeting autophagy. Finally, we outlooked the prospect of relieving and curing autoimmune diseases by targeting autophagy pathway.
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Affiliation(s)
- Jiao Lyu
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Hongqian Zhang
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Chaoyang Wang
- The Key Medical Laboratory for Chemical Poison Detection of Henan Province, The Third People's Hospital of Henan Province, Zhengzhou, China
- Department of Biomedical Science, City University of Hong Kong, Hong Kong, China
| | - Mingyu Pan
- State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
- Department of Biomedical Science, City University of Hong Kong, Hong Kong, China
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10
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Wei Z, Hu X, Wu Y, Zhou L, Zhao M, Lin Q. Molecular Mechanisms Underlying Initiation and Activation of Autophagy. Biomolecules 2024; 14:1517. [PMID: 39766224 PMCID: PMC11673044 DOI: 10.3390/biom14121517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/15/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Autophagy is an important catabolic process to maintain cellular homeostasis and antagonize cellular stresses. The initiation and activation are two of the most important aspects of the autophagic process. This review focuses on mechanisms underlying autophagy initiation and activation and signaling pathways regulating the activation of autophagy found in recent years. These findings include autophagy initiation by liquid-liquid phase separation (LLPS), autophagy initiation in the endoplasmic reticulum (ER) and Golgi apparatus, and the signaling pathways mediated by the ULK1 complex, the mTOR complex, the AMPK complex, and the PI3KC3 complex. Through the review, we attempt to present current research progress in autophagy regulation and forward our understanding of the regulatory mechanisms and signaling pathways of autophagy initiation and activation.
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Affiliation(s)
| | | | | | | | | | - Qiong Lin
- School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China; (Z.W.); (X.H.); (Y.W.); (L.Z.); (M.Z.)
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11
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Feng Z, Ou Y, Deng X, Deng M, Yan X, Chen L, Zhou F, Hao L. Deubiquitinase USP10 promotes osteosarcoma autophagy and progression through regulating GSK3β-ULK1 axis. Cell Biosci 2024; 14:111. [PMID: 39218913 PMCID: PMC11367994 DOI: 10.1186/s13578-024-01291-9] [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: 04/10/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Deubiquitinating enzymes (DUBs) are pivotal in maintaining cell homeostasis by regulating substrate protein ubiquitination in both healthy and cancer cells. Ubiquitin-specific protease 10 (USP10) belongs to the DUB family. In this study, we investigated the clinical and pathological significance of USP10 and Unc-51-like autophagy activating kinase 1 (ULK1) in osteosarcoma (OS), as well as the mechanism of USP10 action in ULK1-mediated autophagy and disease progression. RESULTS The analysis of OS and adjacent normal tissues demonstrated that USP10 and ULK1 were significantly overexpressed in OS, and a positive association between their expression and malignant properties was observed. USP10 knockdown in OS cells reduced ULK1 mRNA and protein expression, whereas USP10 overexpression increased ULK1 mRNA and protein expression. In vitro experiments showed that USP10 induced autophagy, cell proliferation, and invasion by enhancing ULK1 expression in OS cell lines. Furthermore, we found that the regulation of ULK1-mediated autophagy, cell proliferation, and invasion in OS by USP10 was dependent on glycogen synthase kinase 3β (GSK3β) activity. Mechanistically, USP10 promoted ULK1 transcription by interacting with and stabilising GSK3β through deubiquitination, which, in turn, increased the activity of the ULK1 promoter, thereby accelerating OS progression. Using a xenograft mouse model, we showed that Spautin-1, a small-molecule inhibitor targeting USP10, significantly reduced OS development, with its anti-tumour activity significantly enhanced when combined with the chemotherapeutic agent cisplatin. CONCLUSION Collectively, we demonstrated that the USP10-GSK3β-ULK1 axis promoted autophagy, cell proliferation, and invasion in OS. The findings imply that targeting USP10 may offer a promising therapeutic avenue for treating OS.
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Affiliation(s)
- Zuxi Feng
- Departments of Orthopedics, the 2st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Yanghuan Ou
- Departments of Orthopedics, the 2st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Xueqiang Deng
- Departments of Orthopedics, the 2st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China
| | - Minghao Deng
- Nottingham Trent University, Clifton, Nottingham, NG11 8NS, UK
| | - Xiaohua Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang, 330031, China
| | - Leifeng Chen
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Medical Center for Cardiovascular Diseases, Neurological Diseases and Tumors of Jiangxi Province, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Fan Zhou
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, People's Republic of China.
| | - Liang Hao
- Departments of Orthopedics, the 2st Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330000, Jiangxi Province, China.
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Tian W, Zhu L, Luo Y, Tang Y, Tan Q, Zou Y, Chen K, Deng X, Tang H, Li H, Cai M, Xie X, Ye F. Autophagy Deficiency Induced by SAT1 Potentiates Tumor Progression in Triple-Negative Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2309903. [PMID: 39073262 PMCID: PMC11423137 DOI: 10.1002/advs.202309903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 06/18/2024] [Indexed: 07/30/2024]
Abstract
Aggressive triple-negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1-acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1-mediated methyl-5-cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.
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Affiliation(s)
- Wenwen Tian
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
- Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, P. R. China
| | - Lewei Zhu
- The First People's Hospital of Foshan, Foshan, 528000, P. R. China
| | - Yongzhou Luo
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Yuhui Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Qingjian Tan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Yutian Zou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Kun Chen
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P. R. China
| | - Xinpei Deng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Hailin Tang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Hongsheng Li
- Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, P. R. China
| | - Manbo Cai
- The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, P. R. China
| | - Xiaoming Xie
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Feng Ye
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
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Yu X, Feng M, Guo J, Wang H, Yu J, Zhang A, Wu J, Han Y, Sun Z, Liao Y, Zhao Q. MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy. Cell Death Differ 2024; 31:1085-1098. [PMID: 38783090 PMCID: PMC11303813 DOI: 10.1038/s41418-024-01314-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/07/2024] [Accepted: 05/08/2024] [Indexed: 05/25/2024] Open
Abstract
The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL plays a key role in liver disease. However, how MLKL contributes to hepatocarcinogenesis has not been fully elucidated. Herein, we report that MLKL is upregulated in a diethylnitrosamine (DEN)-induced murine HCC model and is associated with human hepatocellular carcinomas. Hepatocyte-specific MLKL knockout suppresses the progression of hepatocarcinogenesis. Conversely, MLKL overexpression aggravates the initiation and progression of DEN-induced HCC. Mechanistic study reveals that deletion of MLKL significantly increases the activation of autophagy, thereby protecting against hepatocarcinogenesis. MLKL directly interacts with AMPKα1 and inhibits its activity independent of its necroptotic function. Mechanistically, MLKL serves as a bridging molecule between AMPKα1 and protein phosphatase 1B (PPM1B), thus enhancing the dephosphorylation of AMPKα1. Consistently, MLKL expression correlates negatively with AMPKα1 phosphorylation in HCC patients. Taken together, our findings highlight MLKL as a novel AMPK gatekeeper that plays key roles in inhibiting autophagy and driving hepatocarcinogenesis, suggesting that the MLKL-AMPKα1 axis is a potential therapeutic target for HCC.
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Affiliation(s)
- Xianjun Yu
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Mengyuan Feng
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Jian Guo
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Haoyu Wang
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Jun Yu
- Department of Molecular and Cellular Biology, University of Geneva, Geneva, 1211, Switzerland
| | - Anjie Zhang
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Jingyi Wu
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
| | - Yamei Han
- Department of Biochemistry and Molecular Biology, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Zequn Sun
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
| | - Yingying Liao
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
| | - Qun Zhao
- Department of Gastroenterology, Renmin Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China.
- Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China.
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14
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Wen W, Ertas YN, Erdem A, Zhang Y. Dysregulation of autophagy in gastric carcinoma: Pathways to tumor progression and resistance to therapy. Cancer Lett 2024; 591:216857. [PMID: 38583648 DOI: 10.1016/j.canlet.2024.216857] [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: 02/06/2024] [Revised: 03/22/2024] [Accepted: 04/02/2024] [Indexed: 04/09/2024]
Abstract
The considerable death rates and lack of symptoms in early stages of gastric cancer (GC) make it a major health problem worldwide. One of the most prominent risk factors is infection with Helicobacter pylori. Many biological processes, including those linked with cell death, are disrupted in GC. The cellular "self-digestion" mechanism necessary for regular balance maintenance, autophagy, is at the center of this disturbance. Misregulation of autophagy, however, plays a role in the development of GC. In this review, we will examine how autophagy interacts with other cell death processes, such as apoptosis and ferroptosis, and how it affects the progression of GC. In addition to wonderful its role in the epithelial-mesenchymal transition, it is engaged in GC metastasis. The role of autophagy in GC in promoting drug resistance stands out. There is growing interest in modulating autophagy for GC treatment, with research focusing on natural compounds, small-molecule inhibitors, and nanoparticles. These approaches could lead to breakthroughs in GC therapy, offering new hope in the fight against this challenging disease.
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Affiliation(s)
- Wen Wen
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Turkey.
| | - Ahmet Erdem
- Institute for Quantitative Health Science and Engineering (IQ), Department of Biomedical Engineering, College of Engineering and Human Medicine, Michigan State University, East Lansing, MI, 48824, USA; Department of Biomedical Engineering, Kocaeli University, Umuttepe Campus, Kocaeli, 41001 Turkey.
| | - Yao Zhang
- Department of Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China.
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15
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Chen J, Li G, He X, Chen X, Chen Z, Liu D, Guo S, Huang T, Lin Y, Lan P, Lian L, He X. ELMO1 ameliorates intestinal epithelial cellular senescence via SIRT1/p65 signaling in inflammatory bowel disease-related fibrosis. Gastroenterol Rep (Oxf) 2024; 12:goae045. [PMID: 38756351 PMCID: PMC11096966 DOI: 10.1093/gastro/goae045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/01/2024] [Accepted: 04/10/2024] [Indexed: 05/18/2024] Open
Abstract
Background Intestinal fibrosis is a common complication in inflammatory bowel disease (IBD), which still lacks of reliable markers and therapeutic options. Cellular senescence has been considered an important mechanism of intestinal fibrosis, but the underlying molecular link remains elusive. Methods Tissues were stained using α-smooth muscle actin (α-SMA), fibronectin, and collagen I as markers of myofibroblastic differentiation. Cellular senescence was confirmed through Lamin B1 staining, senescence-associated β-galactosidase staining, and the expression of senescence-associated secretory phenotype (SASP) factors. We explored the relationship between senescence of intestinal epithelial cells (IECs) and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. The effects of irisin on cellular senescence and fibrosis were determined. Results Here, we identify engulfment and cell motility protein 1 (ELMO1) as a novel biomarker for intestinal cellular senescence and fibrosis. In fibrostrictured tissues from patients and murine models with IBD, significantly high levels of cellular senescence score and factors were noted, which positively correlated with the fibrotic regulator fibronectin. Senescent IECs, not fibroblast itself, released SASP factors to regulate fibroblast activation. Prolonging exposure to severe and persistent injurious stimuli decreased ELMO1 expression, which dampened SIRT1 deacetylase activity, enhanced NF-κB (p65) acetylation, and thereby accelerated cellular senescence. Deletion of ELMO1 led to senescent IECs accumulation and triggered premature fibrosis in murine colitis. Furthermore, irisin, inhibiting the degradation of ELMO1, could downregulate p65 acetylation, reduce IECs senescence, and prevent incipient intestinal fibrosis in murine colitis models. Conclusions This study reveals ELMO1 downregulation is an early symbol of intestinal senescence and fibrosis, and the altered ELMO1-SIRT1-p65 pathway plays an important role in intestinal cellular senescence and IBD-related fibrosis.
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Affiliation(s)
- Junguo Chen
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Thoracic Surgery, Thoracic Cancer Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Guanman Li
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- School of Medicine (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Xiaowen He
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xijie Chen
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Zexian Chen
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Danling Liu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shuang Guo
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Tianze Huang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yanyun Lin
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ping Lan
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Lei Lian
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiaosheng He
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital,Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Xu J, Wang Y, Li X, Zheng M, Li Y, Zhang W. Clinical value assessment for serum hsa_tsr013526 in the diagnosis of gastric carcinoma. ENVIRONMENTAL TOXICOLOGY 2024; 39:2753-2767. [PMID: 38251933 DOI: 10.1002/tox.24146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 12/29/2023] [Accepted: 01/06/2024] [Indexed: 01/23/2024]
Abstract
Gastric carcinoma (GC) is a malignant tumor that is detrimental to human health. Transfer RNA-derived small RNAs are a newly identified class of noncoding small RNAs with specific biological functions that are aberrantly expressed in cancer. The aim of this study was to investigate the potential of hsa_tsr013526 as a biomarker for GC. Quantitative real-time fluorescence polymerase chain reaction was used to detect the expression level of hsa_tsr013526. The molecular characteristics of hsa_tsr013526 were verified by agarose gel electrophoresis, Sanger sequencing, and separation of nuclear and cytoplasmic RNA fractions. By testing the receiver operating characteristic (ROC) curves, the diagnostic efficiency of GC using hsa_tsr013526 was determined. Finally, we predicted the downstream of hsa_tsr013526 using functional assays and bioinformatics analysis. Serum expression of hsa_tsr013526 was higher in GC patients than in healthy donors. Serum expression showed differential changes in GC patients, gastritis patients, and healthy donors. Chi-squared tests showed that high expression of hsa_tsr013526 was significantly correlated with T stage, lymphatic metastasis, and tumor node metastasis stage. ROC curve analysis indicated that GC patients could be discriminated from healthy donors or gastritis patients based on their serum levels of hsa_tsr013526. Furthermore, hsa_tsr013526 expression was significantly reduced in postoperative GC patients (p = .0016). High expression of hsa_tsr013526 promotes gastric cancer cell proliferation, invasion, and migration. Serum hsa_tsr013526 was stable and specific, and could be used for dynamic monitoring of GC patients. Therefore, hsa_tsr013526 may be a new biomarker for the diagnosis and postoperative monitoring of GC patients.
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Affiliation(s)
- Jing Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Medical School, Nantong University, Nantong, China
| | - Yue Wang
- Basic Medicine School, Xuzhou Medical University, Xuzhou, China
| | - Xian Li
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Yang Li
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Medical School, Nantong University, Nantong, China
| | - Weiwei Zhang
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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Xue VW, Liu S, Sun Q, Ning J, Li H, Wang W, Sayed S, Zhao X, Fu L, Lu D. CK1δ/ε inhibition induces ULK1-mediated autophagy in tumorigenesis. Transl Oncol 2024; 40:101863. [PMID: 38185060 PMCID: PMC10808987 DOI: 10.1016/j.tranon.2023.101863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
INTRODUCTION Autophagy is an important mechanism of cell homeostasis maintenance. As essential serine/threonine-protein kinases, casein kinase I family members affect tumorigenesis by regulating a variety of cellular progression. However, the mechanism by which they regulate autophagy remains unclear. MATERIALS AND METHODS We silenced CK1δ/ε in cancer cells and observed cell morphology, the expression of autophagy-related genes, and its impact on cancer cell growth and viability. By inhibiting CK1δ/ε-induced upregulation of autophagy genes, we profiled the regulatory mechanism of CK1δ/ε on autophagy and cancer cell growth. The impact of CK1δ/ε inhibition on tumor cell growth was also assessed in vivo. RESULTS Here, we found that CK1δ/ε played an important role in ULK1-mediated autophagy regulation in both lung cancer and melanoma cells. Mechanically, silencing CK1δ/ε increased ULK1 expression with enhanced autophagic flux and suppressed cancer cell proliferation, while ULK1 knockdown blocked the activation of autophagy caused by CK1δ/ε inhibition. By silencing CK1δ/ε in syngeneic mouse model bearing LLC1 murine lung cancer cells in vivo, we observed tumor growth suppression mediated by CK1δ/ε inhibition. CONCLUSION Our results provide evidence for the role of CK1δ/ε in the regulation of tumorigenesis via the ULK1-mediated autophagy, and also suggest the impact of CK1δ/ε inhibition on tumor growth and its significance as a potential therapeutic target.
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Affiliation(s)
- Vivian Weiwen Xue
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China; College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, China
| | - Shanshan Liu
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China
| | - Qi Sun
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China
| | - Jiong Ning
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China; Center for Molecular Biomedicine, Friedrich-Schiller-Universität Jena, Jena, Germany
| | - Huan Li
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China
| | - Weilan Wang
- Center for Healthy Longevity, National University of Singapore, Singapore
| | - Sapna Sayed
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China
| | - Xibao Zhao
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China
| | - Li Fu
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China.
| | - Desheng Lu
- Department of Pharmacology, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Marshall Laboratory of Biomedical Engineering, Shenzhen University Health Science Center, No. 1066 Xueyuan Avenue, Nanshan District, Shenzhen 518060, China.
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18
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Xiong D, Wei X, Huang W, Zheng J, Feng R. Prediction significance of autophagy-related genes in survival probability and drug resistance in diffuse large B-cell lymphoma. Aging (Albany NY) 2024; 16:1049-1076. [PMID: 38240686 PMCID: PMC10866451 DOI: 10.18632/aging.205282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 10/15/2023] [Indexed: 02/06/2024]
Abstract
BACKGROUND/AIMS Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has significant prognostic heterogeneity. This study aimed to generate a prognostic prediction model based on autophagy-related genes for DLBCL patients. METHODS Utilizing bioinformatics techniques, we analyzed the clinical information and transcriptome data of DLBCL patients from the Gene Expression Omnibus (GEO) database. Through unsupervised clustering, we identified new autophagy-related molecular subtypes and pinpointed differentially expressed genes (DEGs) between these subtypes. Based on these DEGs, a prognostic model was constructed using Cox and Lasso regression. The effectiveness, accuracy, and clinical utility of this prognostic model were assessed using numerous independent validation cohorts, survival analyses, receiver operating characteristic (ROC) curves, multivariate Cox regression analysis, nomograms, and calibration curves. Moreover, functional analysis, immune cell infiltration, and drug sensitivity analysis were performed. RESULTS DLBCL patients with different clinical characterizations (age, molecular subtypes, ECOG scores, and stages) showed different expression features of autophagy-related genes. The prediction model was constructed based on the eight autophagy-related genes (ADD3, IGFBP3, TPM1, LYZ, AFDN, DNAJC10, GLIS3, and CCDC102A). The prognostic nomogram for overall survival of DLBCL patients incorporated risk level, stage, ECOG scores, and molecular subtypes, showing excellent agreement between observed and predicted outcomes. Differences were noted in the proportions of immune cells (native B cells, Treg cells, CD8+ T cell, CD4+ memory activated T cells, gamma delta T cells, macrophages M1, and resting mast cells) between high-risk and low-risk groups. LYZ and ADD3 exhibited correlations with drug resistance to most chemotherapeutic drugs. CONCLUSIONS This study established a novel prognostic assessment model based on the expression profile of autophagy-related genes and clinical characteristics of DLBCL patients, explored immune infiltration and predicted drug resistance, which may guide precise and individualized immunochemotherapy regimens.
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Affiliation(s)
- Dan Xiong
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528308, Guangdong, China
| | - Xiaolei Wei
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Weiming Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jingxia Zheng
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ru Feng
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
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19
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Jian H, Chen Z, Du H, Liao T, Sun Y, Ke D, Yu Y. Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway. J Cell Mol Med 2024; 28:e17983. [PMID: 38070189 PMCID: PMC10805511 DOI: 10.1111/jcmm.17983] [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: 07/08/2023] [Revised: 09/14/2023] [Accepted: 09/26/2023] [Indexed: 01/25/2024] Open
Abstract
Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.
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Affiliation(s)
- Hui Jian
- Department of Gastrointestinal SurgeryAffiliated Hospital of Jianghan UniversityWuhanHubeiChina
| | - Zhi‐Qiang Chen
- Department of Gastrointestinal SurgeryAffiliated Hospital of Jianghan UniversityWuhanHubeiChina
| | - Heng Du
- Department of Gastrointestinal SurgeryHuanggang Central Hospital Affiliated to Yangtze UniversityHuanggangHubeiChina
| | - Ting Liao
- Department of GastroenterologyAffiliated Hospital of Jianghan UniversityWuhanHubeiChina
| | - Yi‐Chen Sun
- Department of OncologyAffiliated Hospital of Jianghan UniversityWuhanHubeiChina
| | - Dong Ke
- Department of Gastrointestinal SurgeryRenmin Hospital of Wuhan UniversityWuhanHubeiChina
| | - Yang Yu
- Department of Gastrointestinal SurgeryAffiliated Hospital of Jianghan UniversityWuhanHubeiChina
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20
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Sun J, Yu H, Wang Y, Li L, Zhu J, Ma P, Feng Z, Tu C. Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis. J Virol 2023; 97:e0098823. [PMID: 38038430 PMCID: PMC10734420 DOI: 10.1128/jvi.00988-23] [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: 08/12/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023] Open
Abstract
IMPORTANCE Autophagy is a conserved degradation process that maintains cellular homeostasis and regulates native and adaptive immunity. Viruses have evolved diverse strategies to inhibit or activate autophagy for their benefit. The paper reveals that CSFV NS5A mediates the dissociation of PP2A from Beclin 1 and the association of PP2A with DAPK3 by interaction with PPP2R1A and DAPK3, PP2A dephosphorylates DAPK3 to activate its protein kinase activity, and activated DAPK3 phosphorylates Beclin 1 to trigger autophagy, indicating that NS5A activates autophagy via the PP2A-DAPK3-Beclin 1 axis. These data highlight a novel mechanism by which CSFV activates autophagy to favor its replication, thereby contributing to the development of antiviral strategies.
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Affiliation(s)
- Jinfu Sun
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Haixiao Yu
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Yingnan Wang
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Liming Li
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Jinqi Zhu
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Ping Ma
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Zezhong Feng
- College of Life and Health Sciences, Northeastern University, Shenyang, China
- Key Laboratory of Bioresource Research and Development of Liaoning Province, Shenyang, China
| | - Changchun Tu
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, China
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21
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Bai X, Chen J, Zhang W, Zhou S, Dong L, Huang J, He X. YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation. Cancer Sci 2023; 114:4299-4313. [PMID: 37700438 PMCID: PMC10637062 DOI: 10.1111/cas.15953] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.
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Affiliation(s)
- Xuesong Bai
- Department of General SurgeryState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Jiemin Chen
- Department of GastroenterologyState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Wenqin Zhang
- Department of GastroenterologyState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Shengnan Zhou
- Department of General SurgeryState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Liangbo Dong
- Department of General SurgeryState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Jianhao Huang
- Department of General SurgeryState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
| | - Xiaodong He
- Department of General SurgeryState Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical SciencesBeijingChina
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22
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Clain JA, Boutrais S, Dewatines J, Racine G, Rabezanahary H, Droit A, Zghidi-Abouzid O, Estaquier J. Lipid metabolic reprogramming of hepatic CD4 + T cells during SIV infection. Microbiol Spectr 2023; 11:e0168723. [PMID: 37656815 PMCID: PMC10581067 DOI: 10.1128/spectrum.01687-23] [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: 04/24/2023] [Accepted: 06/24/2023] [Indexed: 09/03/2023] Open
Abstract
While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.
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Affiliation(s)
- Julien A. Clain
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Steven Boutrais
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Juliette Dewatines
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Gina Racine
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | | | - Arnaud Droit
- Proteomics Platform, CHU de Québec - Université Laval Research Center, Québec City, Québec, Canada
- Computational Biology Laboratory, CHU de Québec - Université Laval Research Center, Québec City, Québec, Canada
| | - Ouafa Zghidi-Abouzid
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
| | - Jérôme Estaquier
- Centre de Recherche du CHU de Québec, Université Laval, Québec City, Québec, Canada
- INSERM U1124, Université Paris, Paris, France
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23
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Wang Y, Que H, Li C, Wu Z, Jian F, Zhao Y, Tang H, Chen Y, Gao S, Wong CC, Li Y, Zhao C, Rong Y. ULK phosphorylation of STX17 controls autophagosome maturation via FLNA. J Cell Biol 2023; 222:e202211025. [PMID: 37389864 PMCID: PMC10316704 DOI: 10.1083/jcb.202211025] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/11/2023] [Accepted: 05/02/2023] [Indexed: 07/01/2023] Open
Abstract
Autophagy is a conserved and tightly regulated intracellular quality control pathway. ULK is a key kinase in autophagy initiation, but whether ULK kinase activity also participates in the late stages of autophagy remains unknown. Here, we found that the autophagosomal SNARE protein, STX17, is phosphorylated by ULK at residue S289, beyond which it localizes specifically to autophagosomes. Inhibition of STX17 phosphorylation prevents such autophagosome localization. FLNA was then identified as a linker between ATG8 family proteins (ATG8s) and STX17 with essential involvement in STX17 recruitment to autophagosomes. Phosphorylation of STX17 S289 promotes its interaction with FLNA, activating its recruitment to autophagosomes and facilitating autophagosome-lysosome fusion. Disease-causative mutations around the ATG8s- and STX17-binding regions of FLNA disrupt its interactions with ATG8s and STX17, inhibiting STX17 recruitment and autophagosome-lysosome fusion. Cumulatively, our study reveals an unexpected role of ULK in autophagosome maturation, uncovers its regulatory mechanism in STX17 recruitment, and highlights a potential association between autophagy and FLNA.
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Affiliation(s)
- Yufen Wang
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Huilin Que
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - ChuangPeng Li
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe Wu
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Fenglei Jian
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zhao
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
| | - Haohao Tang
- Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing, China
- School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China
| | - Yang Chen
- Center for Precision Medicine Multi-Omics Research, Peking University Health Science Center, Peking University, Beijing, China
- School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China
| | - Shuaixin Gao
- Human Nutrition Program and James Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
| | - Catherine C.L. Wong
- Clinical Research Institute, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Ying Li
- The State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Chongchong Zhao
- The HIT Center for Life Sciences, Harbin Institute of Technology, Harbin, China
| | - Yueguang Rong
- School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China
- Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, China
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24
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Zhong Q, Xiao X, Qiu Y, Xu Z, Chen C, Chong B, Zhao X, Hai S, Li S, An Z, Dai L. Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications. MedComm (Beijing) 2023; 4:e261. [PMID: 37143582 PMCID: PMC10152985 DOI: 10.1002/mco2.261] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 05/06/2023] Open
Abstract
Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain and long-chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.
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Affiliation(s)
- Qian Zhong
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Xina Xiao
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Yijie Qiu
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Zhiqiang Xu
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Chunyu Chen
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Baochen Chong
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Xinjun Zhao
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Shan Hai
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Shuangqing Li
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Zhenmei An
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
| | - Lunzhi Dai
- Department of Endocrinology and MetabolismGeneral Practice Ward/International Medical Center WardGeneral Practice Medical Center and National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China Hospital, Sichuan UniversityChengduChina
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25
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Yang P, Yang W, Wei Z, Li Y, Yang Y, Wang J. Novel targets for gastric cancer: The tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis and cuproptosis. Biomed Pharmacother 2023; 163:114883. [PMID: 37196545 DOI: 10.1016/j.biopha.2023.114883] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 05/19/2023] Open
Abstract
Gastric cancer (GC) is a fatal illness, and its mortality rate is very high all over the world. At present, it is a serious health problem for any country. It is a multifactorial disease due to the rising drug resistance and the increasing global cancer burden, the treatment of GC still faces many obstacles and problems. In recent years, research on GC is being carried out continuously, and we hope to address the new targets of GC treatment through this review. At the same time, we also hope to discover new ways to fight GC and create more gospel for clinical patients. First, we discuss the descriptive tumor microenvironment (TME), N6-methyladenosine (m6A), pyroptosis, autophagy, ferroptosis, and cuproptosis. Finally, we expounded on the new or potential targets of GC treatment.
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Affiliation(s)
- Peizheng Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Wanting Yang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Zhong Wei
- Gastrointestinal Surgery, Anhui Provincial Hospital, Hefei, China
| | - Yan Li
- Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), Department of Materials Sciences and Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Yinfeng Yang
- School of Medical Informatics Engineering, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
| | - Jinghui Wang
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
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26
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Shao D, Shen W, Miao Y, Gao Z, Pan M, Wei Q, Yan Z, Zhao X, Ma B. Sulforaphane prevents LPS-induced inflammation by regulating the Nrf2-mediated autophagy pathway in goat mammary epithelial cells and a mouse model of mastitis. J Anim Sci Biotechnol 2023; 14:61. [PMID: 37131202 PMCID: PMC10155371 DOI: 10.1186/s40104-023-00858-9] [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: 10/17/2022] [Accepted: 03/01/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Mastitis not only deteriorates the composition or quality of milk, but also damages the health and productivity of dairy goats. Sulforaphane (SFN) is a phytochemical isothiocyanate compound with various pharmacological effects such as anti-oxidant and anti-inflammatory. However, the effect of SFN on mastitis has yet to be elucidated. This study aimed to explore the anti-oxidant and anti-inflammatory effects and potential molecular mechanisms of SFN in lipopolysaccharide (LPS)-induced primary goat mammary epithelial cells (GMECs) and a mouse model of mastitis. RESULTS In vitro, SFN downregulated the mRNA expression of inflammatory factors (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6), inhibited the protein expression of inflammatory mediators (cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS)) while suppressing nuclear factor kappa-B (NF-κB) activation in LPS-induced GMECs. Additionally, SFN exhibited an antioxidant effect by increasing Nrf2 expression and nuclear translocation, up-regulating antioxidant enzymes expression, and decreasing LPS-induced reactive oxygen species (ROS) production in GMECs. Furthermore, SFN pretreatment promoted the autophagy pathway, which was dependent on the increased Nrf2 level, and contributed significantly to the improved LPS-induced oxidative stress and inflammatory response. In vivo, SFN effectively alleviated histopathological lesions, suppressed the expression of inflammatory factors, enhanced immunohistochemistry staining of Nrf2, and amplified of LC3 puncta LPS-induced mastitis in mice. Mechanically, the in vitro and in vivo study showed that the anti-inflammatory and anti-oxidative stress effects of SFN were mediated by the Nrf2-mediated autophagy pathway in GMECs and a mouse model of mastitis. CONCLUSIONS These results indicate that the natural compound SFN has a preventive effect on LPS-induced inflammation through by regulating the Nrf2-mediated autophagy pathway in primary goat mammary epithelial cells and a mouse model of mastitis, which may improve prevention strategies for mastitis in dairy goats.
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Affiliation(s)
- Dan Shao
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Wenxiang Shen
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Science, Lanzhou, 730050, China
| | - Yuyang Miao
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Zhen Gao
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Menghao Pan
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Qiang Wei
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
| | - Zuoting Yan
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Science, Lanzhou, 730050, China
| | - Xiaoe Zhao
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Baohua Ma
- Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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Lui WY, Bharti A, Wong NHM, Jangra S, Botelho MG, Yuen KS, Jin DY. Suppression of cGAS- and RIG-I-mediated innate immune signaling by Epstein-Barr virus deubiquitinase BPLF1. PLoS Pathog 2023; 19:e1011186. [PMID: 36802409 PMCID: PMC9983872 DOI: 10.1371/journal.ppat.1011186] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 03/03/2023] [Accepted: 02/06/2023] [Indexed: 02/23/2023] Open
Abstract
Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms of BPLF1 exerted potent suppressive effect on cGAS-STING-, RIG-I- and TBK1-induced IFN production. The observed suppression was reversed when DUB domain of BPLF1 was rendered catalytically inactive. The DUB activity of BPLF1 also facilitated EBV infection by counteracting cGAS-STING- and TBK1-mediated antiviral defense. BPLF1 associated with STING to act as an effective DUB targeting its K63-, K48- and K27-linked ubiquitin moieties. BPLF1 also catalyzed removal of K63- and K48-linked ubiquitin chains on TBK1 kinase. The DUB activity of BPLF1 was required for its suppression of TBK1-induced IRF3 dimerization. Importantly, in cells stably carrying EBV genome that encodes a catalytically inactive BPLF1, the virus failed to suppress type I IFN production upon activation of cGAS and STING. This study demonstrated IFN antagonism of BPLF1 mediated through DUB-dependent deubiquitination of STING and TBK1 leading to suppression of cGAS-STING and RIG-I-MAVS signaling.
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Affiliation(s)
- Wai-Yin Lui
- School of Biomedical Sciences, the University of Hong Kong, Pokfulam, Hong Kong
| | - Aradhana Bharti
- Faculty of Dentistry, the University of Hong Kong, Sai Yin Pun, Hong Kong
| | - Nok-Hei Mickey Wong
- School of Biomedical Sciences, the University of Hong Kong, Pokfulam, Hong Kong
| | - Sonia Jangra
- Faculty of Dentistry, the University of Hong Kong, Sai Yin Pun, Hong Kong
| | - Michael G. Botelho
- Faculty of Dentistry, the University of Hong Kong, Sai Yin Pun, Hong Kong
| | - Kit-San Yuen
- School of Biomedical Sciences, the University of Hong Kong, Pokfulam, Hong Kong
- School of Nursing, Tung Wah College, Kowloon, Hong Kong
- * E-mail: (K-SY); (D-YJ)
| | - Dong-Yan Jin
- School of Biomedical Sciences, the University of Hong Kong, Pokfulam, Hong Kong
- * E-mail: (K-SY); (D-YJ)
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Zhang L, Luo B, Lu Y, Chen Y. Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions. J Med Chem 2023; 66:1112-1136. [PMID: 36645394 DOI: 10.1021/acs.jmedchem.2c01606] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its role, as its name suggests, is mainly to regulate cell death. The DAPK family comprises five members, including DAPK1, DAPK2, DAPK3, DRAK1 and DRAK2, which show high homology in the common N-terminal kinase domain but differ in the extra-catalytic domain. Notably, previous research has suggested that the DAPK family plays an essential role in both the development and regulation of human diseases. However, only a few small-molecule inhibitors have been reported. In this Perspective, we mainly discuss the structure, biological function, and role of DAPKs in diseases and the currently discovered small-molecule inhibitors, providing valuable information for the development of the DAPK field.
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Affiliation(s)
- Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, China
| | - Boqin Luo
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, China
| | - Yingying Lu
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, China
| | - Yi Chen
- State Key Laboratory of Biotherapy and Cancer Center and Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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29
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Liang Z, Song J, Xu Y, Zhang X, Zhang Y, Qian H. Hesperidin Reversed Long-Term N-methyl- N-nitro- N-Nitroguanidine Exposure Induced EMT and Cell Proliferation by Activating Autophagy in Gastric Tissues of Rats. Nutrients 2022; 14:5281. [PMID: 36558440 PMCID: PMC9781858 DOI: 10.3390/nu14245281] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer is a common malignant tumor worldwide. N-methyl-N-nitro-N-nitroguanidine (MNNG) is one of the most important inducing factors of gastric cancer. Autophagy can affect the occurrence and development of gastric cancer, but the mechanism is not clear. Chemoprevention has been shown to be a rational and very promising approach to the prevention of gastric cancer. Hesperidin is a citrus flavone, an abundant polyphenol in citrus fruits and traditional Chinese medicine. It has an excellent phytochemistry that plays an intervention role in gastric cancer. However, it is unclear whether long-term exposure to MNNG will affect the occurrence of gastric cancer by regulating autophagy and whether hesperidin can play an intervention role in this process. In the present study, we demonstrated that long-term MNNG exposure inhibits autophagy in stomach tissues of rats, promotes the epithelial-mesenchymal transition (EMT) process and cell proliferation and suppresses the activity of the PI3K/AKT pathway. We further found that after rapamycin-activated autophagy, long-term MNNG exposure promoted cell proliferation and EMT were inhibited. In addition, hesperidin promotes autophagy and the activity of the PI3K/AKT pathway, as well as the suppression of proliferation and EMT in the stomach tissues of rats. Our findings indicate that hesperidin reverses MNNG-induced gastric cancer by activating autophagy and the PI3K/AKT pathway, which may provide a new basis for the early prevention and treatment of MNNG-induced gastric cancer.
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Affiliation(s)
- Zhaofeng Liang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated of Jiangsu University, Changzhou 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Jiajia Song
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Yumeng Xu
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Xinyi Zhang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Yue Zhang
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hui Qian
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated of Jiangsu University, Changzhou 213017, China
- Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, China
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Li G, Fu Q, Liu C, Peng Y, Gong J, Li S, Huang Y, Zhang H. The regulatory role of N6-methyladenosine RNA modification in gastric cancer: Molecular mechanisms and potential therapeutic targets. Front Oncol 2022; 12:1074307. [PMID: 36561529 PMCID: PMC9763625 DOI: 10.3389/fonc.2022.1074307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 11/16/2022] [Indexed: 12/12/2022] Open
Abstract
N6-methyladenosinen (m6A) methylation is a frequent RNA methylation modification that is regulated by three proteins: "writers", "erasers", and "readers". The m6A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Interestingly, recent research has linked m6A RNA modification to the occurrence and development of cancers, such as hepatocellular carcinoma and non-small cell lung cancer. This review summarizes the regulatory role of m6A RNA modification in gastric cancer (GC), including targets, the mechanisms of action, and the potential signaling pathways. Our present findings can facilitate our understanding of the significance of m6A RNA modification in GC.
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Affiliation(s)
- Gaofeng Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Qiru Fu
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Cong Liu
- Editorial Department of Journal of Hubei University of Science and Technology, Xianning, Hubei, China
| | - Yuxi Peng
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Jun Gong
- Department of Abdominal and Pelvic Medical Oncology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China
| | - Shilan Li
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Yan Huang
- Department of Clinical Laboratory, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, Hubei, China,*Correspondence: Haiyuan Zhang, ; Yan Huang,
| | - Haiyuan Zhang
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China,*Correspondence: Haiyuan Zhang, ; Yan Huang,
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Shen J, Liang C, Su X, Wang Q, Ke Y, Fang J, Zhang D, Duan S. Dysfunction and ceRNA network of the tumor suppressor miR-637 in cancer development and prognosis. Biomark Res 2022; 10:72. [PMID: 36175921 PMCID: PMC9524011 DOI: 10.1186/s40364-022-00419-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/13/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs ranging from 17 to 25 nt in length. miR-637 is down-regulated in most cancers and up-regulated only in clear cell renal cell carcinoma (ccRCC). miR-637 can target 21 protein-coding genes, which are involved in the regulation of cell growth, cell cycle, cell proliferation, epithelial-mesenchymal transition (EMT), cancer cell invasion and metastasis, etc. In glioma, the transcription factor ZEB2 can bind to the miR-637 promoter region and inhibit miR-637 expression. Besides, miR-637 could be negatively regulated by competing endogenous RNA (ceRNAs) comprising 13 circular RNA (circRNAs) and 9 long non-coding RNA (lncRNAs). miR-637 is involved in regulating five signaling pathways, including the Jak/STAT3, Wnt/β-catenin, PI3K/AKT, and ERK signaling pathways. Low miR-637 expression was significantly associated with larger tumors and later tumor node metastasis (TNM) staging in cancer patients. Low miR-637 expression was also associated with poorer overall survival (OS) in cancer patients such as glioblastoma and low-grade gliomas (GBM/LGG), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), and ovarian cancer (OV). Low expression of miR-637 increases the resistance of colorectal cancer (CRC) and human cholangiocarcinoma (CHOL) cancer cells to three anticancer chemotherapeutics (gemcitabine (dFdC), cisplatin (DDP), and oxaliplatin (OXA)). Our work summarizes the abnormal expression of miR-637 in various cancers, expounds on the ceRNA regulatory network and signaling pathway involved in miR-637, and summarizes the effect of its abnormal expression on the biological behavior of tumor cells. At the same time, the relationship between the expression levels of miR-637 and its related molecules and the prognosis and pathological characteristics of patients was further summarized. Finally, our work points out the insufficiency of miR-637 in current studies and is expected to provide potential clues for future miR-637-related studies.
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Affiliation(s)
- Jinze Shen
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Chenhao Liang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Xinming Su
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Qurui Wang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Yufei Ke
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Fang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China
| | - Dayong Zhang
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China.
| | - Shiwei Duan
- Department of Clinical Medicine, Zhejiang University City College School of Medicine, Hangzhou, Zhejiang, China.
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Shao BZ, Chai NL, Yao Y, Li JP, Law HKW, Linghu EQ. Autophagy in gastrointestinal cancers. Front Oncol 2022; 12:975758. [PMID: 36091106 PMCID: PMC9459114 DOI: 10.3389/fonc.2022.975758] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/11/2022] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal cancers are a group of cancers occurred in gastrointestinal tissues with high morbidity and mortality rate. Although numerous studies were conducted on the investigation of gastrointestinal cancers, the real mechanisms haven't been discovered, and no effective methods of prevention and treatment of gastrointestinal cancers have been developed. Autophagy, a vital catabolic process in organisms, have been proven to participate in various mechanisms and signaling pathways, thus producing a regulatory effect on various diseases. The role of autophagy in gastrointestinal cancers remains unclear due to its high complexity. In this review, firstly, the biological features of autophagy will be introduced. Secondly, the role of autophagy in three popular gastrointestinal cancers, namely esophageal cancer, gastric cancer, and colorectal cancer will be described and discussed by reviewing the related literature. We aimed to bring novel insights in exploring the real mechanisms for gastrointestinal cancers and developing effective and efficient therapeutic methods to treat gastrointestinal cancers.
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Affiliation(s)
- Bo-Zong Shao
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
- Department of Health Technology and Informatics, Faculty of Health and Social Science, The Hong Kong Polytechnic University, Hunghom, Hong Kong SAR, China
| | - Ning-Li Chai
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Yi Yao
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Jin-Ping Li
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - Helen Ka Wai Law
- Department of Health Technology and Informatics, Faculty of Health and Social Science, The Hong Kong Polytechnic University, Hunghom, Hong Kong SAR, China
| | - En-Qiang Linghu
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
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Assessment of the Effect of Overexpression of Death-Associated Protein Kinases 3 Using PEGFPN1 on Gastric Adenocarcinoma Cell Line (MKN45). INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2022. [DOI: 10.5812/ijcm-118185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Gastric cancer (GC) is one of the most common malignancies worldwide. An in-depth understanding of the molecular mechanisms that underlies tumor GC will lead to breakthroughs in the targeted treatment of GC. Based on multiple lines of evidence, death-associated protein kinase 3 (DAPK3) regulates both programmed cell death including apoptosis and autophagy. The widespread experimental evidence raises the possibility of using DAPK-based gene therapy strategies. Objectives: The aim of this study was to investigate the effect of overexpression of DAPK3 using the PEGFPN1 vector on the gastric adenocarcinoma cell line (MKN45). Methods: The MKN45 cell lines were cultured in a DMEM culture medium and, then, the recombinant vector PEGFPN1-DAPK3 was transfected into the cells by lipofectamine 2000. The effects of the overexpression of the DAPK3 gene on MKN45 cells were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), flow cytometry, and Real-time quantitative reverse transcription PCR (qRT-PCR) techniques. Results: Our findings indicated that overexpression of DAPK3 in MKN45 cells not only affects the expression of apoptosis-related genes but also changes the expression of autophagy-related genes. Additionally, overexpression of DAPK3 reduces the metabolic activity of cells. Conclusions: The overexpression of the DAPK3 gene can lead to cell death by both inducing apoptosis and autophagy pathways in the gastric adenocarcinoma cell line (MKN45). This anti-cancer activity may describe a hopeful strategy in the application of novel gene therapy for the treatment of gastric adenocarcinoma; however, further research is required to examine the clinical effectiveness of this strategy in GC treatment.
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Function and regulation of ULK1: From physiology to pathology. Gene 2022; 840:146772. [PMID: 35905845 DOI: 10.1016/j.gene.2022.146772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/03/2022] [Accepted: 07/24/2022] [Indexed: 11/21/2022]
Abstract
The expression of ULK1, a core protein of autophagy, is closely related to autophagic activity. Numerous studies have shown that pathological abnormal expression of ULK1 is associated with various human diseases such as neurological disorders, infections, cardiovascular diseases, liver diseases and cancers. In addition, new advances in the regulation of ULK1 have been identified. Furthermore, targeting ULK1 as a therapeutic strategy for diseases is gaining attention as new corresponding activators or inhibitors are being developed. In this review, we describe the structure and regulation of ULK1 as well as the current targeted activators and inhibitors. Moreover, we highlight the pathological disorders of ULK1 expression and its critical role in human diseases.
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Chen H, Zhang J, Sun X, Wang Y, Qian Y. Mitophagy-mediated molecular subtypes depict the hallmarks of the tumour metabolism and guide precision chemotherapy in pancreatic adenocarcinoma. Front Cell Dev Biol 2022; 10:901207. [PMID: 35938160 PMCID: PMC9353335 DOI: 10.3389/fcell.2022.901207] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/30/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Mitophagy is closely related to cancer initiation and progression. However, heterogeneity with reference to mitophagy remains unexplored in pancreatic adenocarcinoma (PAAD). Materials and methods: We used Reactome database to download the mitophagy-related, glycolysis-related and cholesterol biosynthesis-related signaling pathways. Unsupervised clustering using the “ConsensusClusterPlus” R package was performed to identify molecular subtypes related to mitophagy and metabolism. Prognosis-related mitophagy regulators were identified by univariate Cox regression analysis. Receiver operating characteristics (ROC) and Kaplan-Meier (K-M) survival analyses were used to assess the diagnostic and prognostic role of the hub genes and prognosis risk model. Weighted gene co-expression network analysis (WGCNA) was utilized for screening the mitophagy subtype-related hub genes. Metascape was utilized to carry out functional enrichment analysis. The “glmnet” R package was utilised for LASSO, and the “e1071” R package was utilised for SVM. Chemotherapeutic drug sensitivity was estimated using the R package “pRRophetic” and Genomics of Drug Sensitivity in Cancer (GDSC) database. The nomogram was established by the “rms” R package. Results: Three distinct mitophagy subtypes (low, high and intermediate) of PAAD were identified based on the landscape of mitophagy regulators. The high mitophagy subtype had the worst prognosis, highest mRNA expression-based stemness index scores and most hypoxic environment compared to the other subtypes. Additionally, glycolysis and cholesterol biosynthesis were significantly elevated. Three mitophagy subtype-specific gene signatures (CAST, CCDC6, and ERLIN1) were extracted using WGCNA and machine learning. Moreover, PAAD tumours were insensitive to Erlotinib, Sunitinib and Imatinib in the high mitophagy subtype and high CAST, CCDC6, and ERLIN1 expressed subtypes. Furthermore, CAST, CCDC6, and ERLIN1 affected immune cell infiltration (M1 and CD8Tcm), resulting in the altered prognosis of patients with PAAD. A nomogram was constructed to screen patients with the low mitophagy subtype, which showed a higher sensitivity to chemotherapeutic agents. Conclusion: Based on various bioinformatics tools and databases, the PAAD heterogeneity regarding mitophagy was systematically examined. Three different PAAD subtypes having different outcomes, metabolism patterns and chemosensitivity were observed. Moreover, three novel biomarkers that are closely associated with mitophagy and have the potential to guide individualised treatment regimens in PAAD were obtained.
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Affiliation(s)
- Hao Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jianlin Zhang
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xuehu Sun
- Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yao Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yeben Qian, ; Yao Wang,
| | - Yeben Qian
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Yeben Qian, ; Yao Wang,
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Lu L, Liang Q, Zhang X, Xu Y, Meng D, Liang Z. Autophagy Related Noncoding RNAs: Emerging Regulatory Factors of Gastric Cancer. Cancer Manag Res 2022; 14:2215-2224. [PMID: 35898946 PMCID: PMC9309173 DOI: 10.2147/cmar.s364761] [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: 03/02/2022] [Accepted: 07/12/2022] [Indexed: 11/29/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant cancers that seriously affect human health. Autophagy is a highly conserved self-defense mechanism found to plays an important role in the occurrence, progression, drug resistance, and prognosis of GC. Noncoding RNAs (ncRNAs) play a critical role in the occurrence and development of a variety of diseases including GC. In recent years, increasing attention has been given to research on autophagy-related ncRNAs, such as miRNA, lncRNA, and circRNA in GC. Herein, we briefly summarize the roles, functions, and the research progress of autophagy and autophagy-related ncRNAs in GC with a focus on the potential application in GC tumorigenesis, development, prognosis, and drug resistance. We also discussed prospects of clinical application, future research direction, and challenges in future research of autophagy-related ncRNAs.
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Affiliation(s)
- Ling Lu
- Child Healthcare Department, the Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China
| | - Qiaoyan Liang
- Health Care Department, People’s Liberation Army Navy No. 971 Hospital, Qingdao, People’s Republic of China
| | - Xinyi Zhang
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
| | - Yumeng Xu
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
| | - Dehua Meng
- Department of Allergy, Dongtai People’s Hospital, Yancheng, People’s Republic of China
| | - Zhaofeng Liang
- School of Medicine, Jiangsu University, Zhenjiang, People’s Republic of China
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Cytochrome B5 type A alleviates HCC metastasis via regulating STOML2 related autophagy and promoting sensitivity to ruxolitinib. Cell Death Dis 2022; 13:623. [PMID: 35851063 PMCID: PMC9293983 DOI: 10.1038/s41419-022-05053-8] [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: 10/27/2021] [Revised: 06/20/2022] [Accepted: 06/29/2022] [Indexed: 01/21/2023]
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing in the world. However, its role and underlying molecular mechanism in HCC progression remain unclear. We found that CYB5A plays a key role in HCC metastasis by inhibiting the JAK1/STAT3 pathway through binding to STOML2. CYB5A combined with STOML2 can predict the outcome of patients. To demonstrate the effect of CYB5A on JAK1 inhibitor function, we applied Ruxolitinib in metastatic tumors with high CYB5A expression and found that it slowed disease progression and prolonged survival in mice. To the best of our knowledge, this study is the first to report the Ruxolitinib effect on the metastatic ability of HCC cells in vivo and in vitro.
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38
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Chen HM, MacDonald JA. Death-associated protein kinases and intestinal epithelial homeostasis. Anat Rec (Hoboken) 2022; 306:1062-1087. [PMID: 35735750 DOI: 10.1002/ar.25022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/12/2022] [Accepted: 06/06/2022] [Indexed: 12/15/2022]
Abstract
The family of death-associated protein kinases (DAPKs) and DAPK-related apoptosis-inducing protein kinases (DRAKs) act as molecular switches for a multitude of cellular processes, including apoptotic and autophagic cell death events. This review summarizes the mechanisms for kinase activity regulation and discusses recent molecular investigations of DAPK and DRAK family members in the intestinal epithelium. In general, recent literature convincingly supports the importance of this family of protein kinases in the homeostatic processes that govern the proper function of the intestinal epithelium. Each of the DAPK family of proteins possesses distinct biochemical properties, and we compare similarities in the information available as well as those cases where functional distinctions are apparent. As the prototypical member of the family, DAPK1 is noteworthy for its tumor suppressor function and association with colorectal cancer. In the intestinal epithelium, DAPK2 is associated with programmed cell death, potential tumor-suppressive functions, and a unique influence on granulocyte biology. The impact of the DRAKs in the epithelium is understudied, but recent studies support a role for DRAK1 in inflammation-mediated tumor growth and metastasis. A commentary is provided on the potential importance of DAPK3 in facilitating epithelial restitution and wound healing during the resolution of colitis. An update on efforts to develop selective pharmacologic effectors of individual DAPK members is also supplied.
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Affiliation(s)
- Huey-Miin Chen
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Justin A MacDonald
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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39
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Ivey A, Pratt H, Boone BA. Molecular pathogenesis and emerging targets of gastric adenocarcinoma. J Surg Oncol 2022; 125:1079-1095. [PMID: 35481910 PMCID: PMC9069999 DOI: 10.1002/jso.26874] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 03/19/2022] [Indexed: 12/24/2022]
Abstract
Gastric adenocarcinoma (GC) is a devastating disease and is the third leading cause of cancer deaths worldwide. This heterogeneous disease has several different classification systems that consider histological appearance and genomic alterations. Understanding the etiology of GC, including infection, hereditary conditions, and environmental factors, is of particular importance and is discussed in this review. To improve survival in GC, we also must improve our therapeutic strategies. Here, we discuss new targets that warrant further exploration.
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Affiliation(s)
- Abby Ivey
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Hillary Pratt
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
| | - Brian A Boone
- Department of Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, Morgantown, West Virginia, USA
- Department of Surgery, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia, USA
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40
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Zou L, Liao M, Zhen Y, Zhu S, Chen X, Zhang J, Hao Y, Liu B. Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta Pharm Sin B 2022; 12:3743-3782. [PMID: 36213540 PMCID: PMC9532564 DOI: 10.1016/j.apsb.2022.06.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/27/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022] Open
Abstract
UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
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Affiliation(s)
- Ling Zou
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minru Liao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongqi Zhen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Yue Hao
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
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41
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Yu J, Qu L, Xia Y, Zhang X, Feng J, Duan M, Guo P, Lou Y, Lv P, Lu W, Chen Y. TMEM189 negatively regulates the stability of ULK1 protein and cell autophagy. Cell Death Dis 2022; 13:316. [PMID: 35393404 PMCID: PMC8991247 DOI: 10.1038/s41419-022-04722-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 02/22/2022] [Accepted: 03/11/2022] [Indexed: 12/27/2022]
Abstract
ULK1 is crucial for initiating autophagosome formation and its activity is tightly regulated by post-translational modifications and protein-protein interactions. In the present study, we demonstrate that TMEM189 (Transmembrane protein 189), also known as plasmanylethanolamine desaturase 1 (PEDS1), negatively regulates the proteostasis of ULK1 and autophagy activity. In TMEM189-overexpressed cells, the formation of autophagesome is impaired, while TMEM189 knockdown increases cell autophagy. Further investigation reveals that TMEM189 interacts with and increases the instability of ULK1, as well as decreases its kinase activities. The TMEM189 N-terminal domain is required for the interaction with ULK1. Additionally, TMEM189 overexpression can disrupt the interaction between ULK1 and TRAF6, profoundly impairs K63-linked polyubiquitination of ULK1 and self-association, leading to the decrease of ULK1 stability. Moreover, in vitro and in vivo experiments suggest that TMEM189 deficiency results in the inhibition of tumorigenicity of gastric cancer. Our findings provide a new insight into the molecular regulation of autophagy and laboratory evidence for investigating the physiological and pathological roles of TMEM189.
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Affiliation(s)
- Jiahong Yu
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Liujing Qu
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China.,Department of Clinical Laboratory, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai, Shandong Province, 264000, China
| | - Yan Xia
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Xuan Zhang
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Jinqiu Feng
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Mengyuan Duan
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Pengli Guo
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Yaxin Lou
- Medical and Healthy Analytical Center, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Ping Lv
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China
| | - Wenping Lu
- Department of Hepatobiliary Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China.
| | - Yingyu Chen
- Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, 38 Xueyuan Road, Beijing, 100191, China. .,Center for Human Disease Genomics, Peking University, Beijing, 38 Xueyuan Road, Beijing, 100191, China.
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42
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Paskeh MDA, Entezari M, Clark C, Zabolian A, Ranjbar E, Farahani MV, Saleki H, Sharifzadeh SO, Far FB, Ashrafizadeh M, Samarghandian S, Khan H, Ghavami S, Zarrabi A, Łos MJ. Targeted regulation of autophagy using nanoparticles: New insight into cancer therapy. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166326. [DOI: 10.1016/j.bbadis.2021.166326] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/31/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022]
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43
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Wang X, Lee J, Xie C. Autophagy Regulation on Cancer Stem Cell Maintenance, Metastasis, and Therapy Resistance. Cancers (Basel) 2022; 14:cancers14020381. [PMID: 35053542 PMCID: PMC8774167 DOI: 10.3390/cancers14020381] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/09/2022] [Accepted: 01/10/2022] [Indexed: 02/08/2023] Open
Abstract
Simple Summary Certain types of cancer have higher relapse rates compared to others, and cancer stem cells (CSCs) have been shown as the main drivers of cancer relapse and cancer severity. This subpopulation of cells displays stem-like characteristics which bolster tumorigenesis along with metastasis and lead to poorer prognoses. Autophagy has been studied as a mechanism by which CSCs maintain stemness and acquire resistance to chemotherapy and radiation. The aim of this review is to condense and organize what has been recently published on the connection between cancer stem cells (CSCs) and autophagy. Multiple studies on autophagy have suggested that the pathway is a double-edged sword, which can either undermine or enhance CSC characteristics depending on interactions with different pathways. Thus, future research should investigate regulation of autophagy in combination with traditional cancer therapies as a possible method to effectively eliminate CSCs and minimize cancer relapse. Abstract Cancer stem cells (CSCs) are a subset of the tumor population that play critical roles in tumorigenicity, metastasis, and relapse. A key feature of CSCs is their resistance to numerous therapeutic strategies which include chemotherapy, radiation, and immune checkpoint inhibitors. In recent years, there is a growing body of literature that suggests a link between CSC maintenance and autophagy, a mechanism to recycle intracellular components during moments of environmental stress, especially since CSCs thrive in a tumor microenvironment that is plagued with hypoxia, acidosis, and lack of nutrients. Autophagy activation has been shown to aid in the upkeep of a stemness state along with bolstering resistance to cancer treatment. However, recent studies have also suggested that autophagy is a double-edged sword with anti-tumorigenic properties under certain circumstances. This review summarizes and integrates what has been published in the literature in terms of what role autophagy plays in stemness maintenance of CSCs and suggests that there is a more complex interplay between autophagy and apoptosis which involves multiple pathways of regulation. Future cancer therapy strategies are needed to eradicate this resistant subset of the cell population through autophagy regulation.
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44
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Xu Y, Chen Y, Yao Y, Xie H, Lu G, Du C, Cheng J, Zhou J. VIRMA contributes to non-small cell lung cancer progression via N 6-methyladenosine-dependent DAPK3 post-transcriptional modification. Cancer Lett 2021; 522:142-154. [PMID: 34520821 DOI: 10.1016/j.canlet.2021.08.027] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/31/2021] [Accepted: 08/21/2021] [Indexed: 01/08/2023]
Abstract
N6-methyladenosine (m6A) has been reported to be abnormally expressed in non-small cell lung cancer (NSCLC), and plays a vital role in regulation of cell proliferation, invasion and metastasis. Vir-Like m6A methyltransferase associated (VIRMA, also called KIAA1429) has not been well studied in NSCLC. Thus, in this study, we investigated the biological impact and underlying mechanism of VIRMA in NSCLC. High expression of VIRMA was testified in patients with NSCLC and predicted worse prognosis in patients. VIRMA facilitated cell proliferation and tumor growth both in vitro and in vivo. Furthermore, VIRMA-regulated m6A modifications led to post-transcriptional suppression of death-associated protein kinase 3 (DAPK3, also called ZIP or ZIPK) through the YT521-B homology domain-containing family proteins 2/3(YTHDF2/3). Inhibition of DAPK3 rescued the tumor-suppressive phenotypes induced by VIRMA deficiency. In conclusion, VIRMA-guided m6A modifications promoted NSCLC progression via m6A-dependent degradation of DAPK3 mRNA. Therefore, VIRMA may be a novel therapeutic target in NSCLC.
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Affiliation(s)
- Yongfang Xu
- Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Yunhao Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Yinan Yao
- Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Guohua Lu
- Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Chengli Du
- Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Jun Cheng
- Department of Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China
| | - Jianying Zhou
- Department of Respiratory Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, PR China.
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45
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Bu F, Zhang J, Shuai W, Liu J, Sun Q, Ouyang L. Repurposing drugs in autophagy for the treatment of cancer: From bench to bedside. Drug Discov Today 2021; 27:1815-1831. [PMID: 34808390 DOI: 10.1016/j.drudis.2021.11.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/14/2021] [Accepted: 11/12/2021] [Indexed: 02/06/2023]
Abstract
Autophagy is a multistep degradation pathway involving the lysosome, which supports nutrient reuse and metabolic balance, and has been implicated as a process that regulates cancer genesis and development. Targeting tumors by regulating autophagy has become a therapeutic strategy of interest. Drugs with other indications can have antitumor activity by modulating autophagy, providing a shortcut to developing novel antitumor drugs (i.e., drug repurposing/repositioning), as successfully performed for chloroquine (CQ); an increasing number of repurposed drugs have since advanced into clinical trials. In this review, we describe the application of different drug-repurposing approaches in autophagy for the treatment of cancer and focus on repurposing drugs that target autophagy to treat malignant neoplasms.
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Affiliation(s)
- Faqian Bu
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Jifa Zhang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Wen Shuai
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Jie Liu
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Qiu Sun
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
| | - Liang Ouyang
- State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
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46
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Yang R, Ma M, Yu S, Li X, Zhang J, Wu S. High Expression of PAMR1 Predicts Favorable Prognosis and Inhibits Proliferation, Invasion, and Migration in Cervical Cancer. Front Oncol 2021; 11:742017. [PMID: 34671559 PMCID: PMC8521121 DOI: 10.3389/fonc.2021.742017] [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: 07/15/2021] [Accepted: 09/13/2021] [Indexed: 12/24/2022] Open
Abstract
Peptidase domain containing associated with muscle regeneration 1 (PAMR1) is frequently lost in breast cancer samples and is considered as a tumor suppressor. The roles and mechanisms of PAMR1 in other types of cancers are still unclear. In our present study, we identified PAMR1 as an invasion-related regulator in cervical cancer. Public database and immunohistochemical (IHC) analysis showed that the expression level of PAMR1 in cervical cancer tissues was lower than that in normal cervix tissues and was negatively related to clinicopathologic features. The high expression of PAMR1 also predicted a better prognosis of cervical cancer patients. CCK8, Transwell, and wound-healing assays demonstrated that knockdown of PAMR1 facilitated the proliferation, migration, and invasion of cervical cancer cells. Additionally, gene set enrichment analysis (GSEA) showed a variety of cancer-related pathways potentially activated or suppressed by PAMR1. Moreover, we verified that PAMR1 inhibited MYC target and mTORC1 signaling pathways. In conclusion, our study revealed the suppressor role of PAMR1 in cervical cancer, providing a new insight into the molecular mechanism of cervical cancer progression.
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Affiliation(s)
- Rui Yang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingjun Ma
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sihui Yu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xi Li
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiawen Zhang
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sufang Wu
- Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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47
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Papaefthymiou A, Christodoulidis G, Koffas A, Doulberis M, Polyzos SA, Manolakis A, Potamianos S, Kapsoritakis A, Kountouras J. Role of autophagy in gastric carcinogenesis. World J Gastrointest Oncol 2021; 13:1244-1262. [PMID: 34721765 PMCID: PMC8529927 DOI: 10.4251/wjgo.v13.i10.1244] [Citation(s) in RCA: 4] [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: 02/16/2021] [Revised: 04/06/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.
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Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
| | | | - Apostolos Koffas
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Michael Doulberis
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
- Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Aarau 5001, Switzerland
| | - Stergios A Polyzos
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
| | - Anastasios Manolakis
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Spyros Potamianos
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Andreas Kapsoritakis
- Department of Gastroenterology, University Hospital of Larissa, Larissa 41110, Thessaly, Greece
| | - Jannis Kountouras
- Department of Medicine, Second Medical Clinic, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki 54642, Macedonia, Greece
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48
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The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer. Int J Mol Sci 2021; 22:ijms222010964. [PMID: 34681622 PMCID: PMC8535862 DOI: 10.3390/ijms222010964] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/02/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases.
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49
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Fan H, Ou Q, Su Q, Li G, Deng Z, Huang X, Bi J. ZIPK activates the IL-6/STAT3 signaling pathway and promotes cisplatin resistance in gastric cancer cells. FEBS Open Bio 2021; 11:2655-2667. [PMID: 34375503 PMCID: PMC8409285 DOI: 10.1002/2211-5463.13270] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 05/06/2021] [Accepted: 08/09/2021] [Indexed: 11/24/2022] Open
Abstract
Gastric cancer is one of the most common malignant cancers globally. Chemotherapy resistance remains a major obstacle in the treatment of gastric cancer, and the molecular mechanisms underlying drug resistance are still not well understood. We previously reported that Zipper interacting protein kinase (ZIPK), also known as death‐associated protein kinase3, exerts an oncogenic effect on gastric cancer via activation of Akt/NF‐κB signaling and promotion of stemness. Here, we explored the roles of ZIPK in cisplatin resistance. We report that ZIPK enhances cell proliferation and invasion and reduces the antitumor activity of cisplatin in gastric cancer. In addition, our western blot data suggest that ZIPK activated the IL‐6/STAT3 signaling pathway. Furthermore, ZIPK increased the expression of IL‐6 and multidrug‐resistance genes. Using the STAT3 inhibitor stattic to block the IL‐6/STAT3 signaling pathway strongly increased the sensitivity of ZIPK‐expressed cells to cisplatin. In conclusion, ZIPK may play a role in cisplatin resistance through activation of the IL‐6/ STAT3 signaling pathway. Inhibition of STAT3 in gastric cancer overexpressing ZIPK might have potential to improve the efficacy of cisplatin.
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Affiliation(s)
- Haonan Fan
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qifeng Ou
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiao Su
- Laboratory Animal Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guanman Li
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,School of Medicine (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Zhijuan Deng
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Ultrasound Medical Center, the First people's Hospital of Chenzhou, Chenzhou, China
| | - Xiaohui Huang
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiong Bi
- Laboratory of General Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Chen HM, MacDonald JA. Network analysis identifies DAPK3 as a potential biomarker for lymphatic invasion and colon adenocarcinoma prognosis. iScience 2021; 24:102831. [PMID: 34368650 PMCID: PMC8326195 DOI: 10.1016/j.isci.2021.102831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022] Open
Abstract
Colon adenocarcinoma is a prevalent malignancy with significant mortality. Hence, the identification of molecular biomarkers with prognostic significance is important for improved treatment and patient outcomes. Clinical traits and RNA-Seq of 551 patient samples in the UCSC Toil Recompute Compendium of The Cancer Genome Atlas TARGET and Genotype Tissue Expression project datasets (primary_site = colon) were used for weighted gene co-expression network analysis to reveal the association between gene networks and cancer cell invasion. One module, containing 151 genes, was significantly correlated with lymphatic invasion, a histopathological feature of higher risk colon cancer. DAPK3 (death-associated protein kinase 3) was identified as the pseudohub of the module. Gene ontology identified gene enrichment related to cytoskeletal organization and apoptotic signaling processes, suggesting modular involvement in tumor cell survival, migration, and epithelial-mesenchymal transformation. Although DAPK3 expression was reduced in patients with colon cancer, high expression of DAPK3 was significantly correlated with greater lymphatic invasion and poor overall survival.
WCGNA reveals a gene module linked to lymphatic invasion in colon adenocarcinoma DAPK3 is a pseudohub gene with differential expression in colon cancer Gene ontology identified relationships to cytoskeletal organization and apoptosis DAPK3 was correlated with lymphatic invasion and poor overall survival
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Affiliation(s)
- Huey-Miin Chen
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada
| | - Justin A MacDonald
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada
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