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Xu Z, Lei Z, Peng S, Fu X, Xu Y, Pan G. Dysregulation of deubiquitinases in gastric cancer progression. Front Oncol 2024; 14:1456710. [PMID: 39605891 PMCID: PMC11598704 DOI: 10.3389/fonc.2024.1456710] [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: 06/29/2024] [Accepted: 10/24/2024] [Indexed: 11/29/2024] Open
Abstract
Gastric cancer (GC), characterized by a high incidence rate, poses significant clinical challenges owing to its poor prognosis despite advancements in diagnostic and therapeutic approaches. Therefore, a comprehensive understanding of the molecular mechanisms driving GC progression is crucial for identifying predictive markers and defining treatment targets. Deubiquitinating enzymes (DUBs), also called deubiquitinases, function as reverse transcriptases within the ubiquitin-proteasome system to counteract protein degradation. Recent findings suggest that DUB dysregulation could be a crucial factor in GC pathogenesis. In this review, we examined recent research findings on DUBs in the context of GC, elucidating their molecular characteristics, categorizations, and roles while also exploring the potential mechanisms underlying their dysregulation in GC. Furthermore, we assessed the therapeutic efficacy of DUB inhibitors in treating malignancies and evaluated the prevalence of aberrant DUB expression in GC.
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Affiliation(s)
| | | | | | | | | | - Guoqing Pan
- First Affiliated Hospital of Kunming Medical University, Department of Pathology, Kunming, China
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Li Y, Liu J, Wu S, Xiao J, Zhang Z. Ferroptosis: opening up potential targets for gastric cancer treatment. Mol Cell Biochem 2024; 479:2863-2874. [PMID: 38082184 DOI: 10.1007/s11010-023-04886-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/24/2023] [Indexed: 10/15/2024]
Abstract
The fifth most frequent cancer in the world is gastric cancer. It ranks as the fourth most common reason for cancer-related deaths. Even though surgery is the only curative treatment for stomach cancer, adding adjuvant radiotherapy and chemotherapy is preferable than only surgery. The majority of patients, however, are discovered to be extremely tardy the first time and have a terrible prognosis. Therefore, it is necessary to create more viable therapy modalities. A growing number of studies in recent years have shown that ferroptosis and many cancer types are related. This gives our treatment a fresh viewpoint. We investigated the relationship between different signal pathways and non-coding RNA on ferroptosis in gastric cancer cells. Also discussed the targets cause ferroptosis resistance increased or reduced to the influence of the chemoresistance,proliferation and metastasis.
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Affiliation(s)
- Yuwei Li
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China
| | - Jiangrong Liu
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China
| | - Shihua Wu
- Department of Pathology, The Second Affiliated Hospital, Shaoyang University, Shaoyang, 422000, Hunan, China
| | - Juan Xiao
- Department of Head and Neck Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Zhiwei Zhang
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, 28 Changsheng Road, Hengyang, 421001, Hunan, China.
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Liu K, Gao Q, Jia Y, Wei J, Chaudhuri SM, Wang S, Tang A, Mani NL, Iyer R, Cheng Y, Gao B, Lu W, Sun Z, Zhang B, Liu H, Fang D. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis. iScience 2024; 27:110592. [PMID: 39246448 PMCID: PMC11378969 DOI: 10.1016/j.isci.2024.110592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/28/2024] [Accepted: 07/24/2024] [Indexed: 09/10/2024] Open
Abstract
Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.
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Affiliation(s)
- Kun Liu
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Qiong Gao
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China
| | - Yuzhi Jia
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Juncheng Wei
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shuvam Mohan Chaudhuri
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Shengnan Wang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Amy Tang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Nikita Lavanya Mani
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Radhika Iyer
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Yang Cheng
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Beixue Gao
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Weiyuan Lu
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Zhaolin Sun
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China
| | - Bin Zhang
- Department of Medicine, Hematology/Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Huiping Liu
- Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Deyu Fang
- Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
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Rizk NI, Kassem DH, Abulsoud AI, AbdelHalim S, Yasser MB, Kamal MM, Hamdy NM. Revealing the role of serum exosomal novel long non-coding RNA NAMPT-AS as a promising diagnostic/prognostic biomarker in colorectal cancer patients. Life Sci 2024; 352:122850. [PMID: 38901687 DOI: 10.1016/j.lfs.2024.122850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/08/2024] [Accepted: 06/14/2024] [Indexed: 06/22/2024]
Abstract
AIMS Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Nicotinamide phosphoribosyl-transferase (NAMPT) was found to be over-expressed in several cancers including CRC. NAMPT-Antisense (NAMPT-AS) is a novel long non-coding RNA (lncRNA) recently reported to be associated with triple negative breast cancer. However, its role in CRC has not been investigated. This study was designed to explore the role of lncRNA NAMPT-AS in CRC, and to investigate its circulating serum exosomal levels in subjects with/without CRC. MAIN METHODS We analyzed CRC patients' data in The Cancer Genome Atlas (TCGA). LncRNA NAMPT-AS and NAMPT mRNA levels were measured in serum exosomes isolated from CRC patients and healthy control subjects and were also measured in CRC-tissues using qRT-PCR. Serum NAMPT protein levels were measured by ELISA, and immunohistochemical analyses were done for NAMPT and Ki67 in CRC tissues. KEY FINDINGS Serum exosomal NAMPT-AS levels were found to be significantly higher in CRC patients compared to control subjects and significantly positively correlated with serum exosomal NAMPT mRNA and circulating NAMPT protein. Tissue NAMPT-AS was found to be significantly positively associated with tissue and serum exosomal NAMPT levels. Higher serum exosomal NAMPT-AS levels were found to be associated with higher susceptibility for CRC. Gene-ontology results and survival analysis of TCGA-data showed a potential classification of CRC samples based on NAMPT-AS levels and association of NAMPT-AS upregulation with poor CRC prognosis and survival. SIGNIFICANCE These results portray NAMPT-AS as a novel potential diagnostic/prognostic biomarker and key molecular mediator in CRC.
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Affiliation(s)
- Nehal I Rizk
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt
| | - Dina H Kassem
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt; Department of Biochemistry, Faculty of Pharmacy (Boys Branch), Al-Azhar University, Nasr City, Cairo, Egypt
| | - Sherif AbdelHalim
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Montaser Bellah Yasser
- Bioinformatics Group, Center for Informatics Sciences (CIS), School of Information Technology and Computer Science (ITCS), Nile University, Giza, Egypt
| | - Mohamed M Kamal
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Health Research Centre of Excellence, Drug Research and Development Group, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt.
| | - Nadia M Hamdy
- Biochemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Zhou Y, Chu P, Wang Y, Li N, Gao Q, Wang S, Wei J, Xue G, Zhao Y, Jia H, Song J, Zhang Y, Pang Y, Zhu H, Sun J, Ma S, Su C, Hu B, Zhao Z, Zhang H, Lu J, Wang J, Wang H, Sun Z, Fang D. Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22-mediated lipolysis circuit. SCIENCE ADVANCES 2024; 10:eado1533. [PMID: 39151008 PMCID: PMC11328899 DOI: 10.1126/sciadv.ado1533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/10/2024] [Indexed: 08/18/2024]
Abstract
Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the Atgl gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.
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Affiliation(s)
- Yuanzhang Zhou
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Peng Chu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
- Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Ya Wang
- Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116044, China
| | - Na Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Qiong Gao
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
- Department of Pathology & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Shengnan Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
- Department of Pathology & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Juncheng Wei
- Department of Pathology & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Guoqing Xue
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Yue Zhao
- Department of Clinical Laboratory, Dalian Municipal Central Hospital, Dalian 116000, China
| | - Huijun Jia
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Jiankun Song
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Yue Zhang
- Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116044, China
| | - Yujie Pang
- Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116044, China
| | - Houyu Zhu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Jia Sun
- Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Suxian Ma
- Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Chen Su
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Bingjin Hu
- Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Zhuoyue Zhao
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
| | - Hui Zhang
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Janice Lu
- Department of Medicine & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jian Wang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
| | - Hongjiang Wang
- Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116044, China
| | - Zhaolin Sun
- Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China
- Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China
| | - Deyu Fang
- Department of Pathology & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Lu W, Chu P, Tang A, Si L, Fang D. The secoiridoid glycoside Gentiopicroside is a USP22 inhibitor with potent antitumor immunotherapeutic activity. Biomed Pharmacother 2024; 177:116974. [PMID: 38968798 DOI: 10.1016/j.biopha.2024.116974] [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: 03/29/2024] [Revised: 05/28/2024] [Accepted: 06/15/2024] [Indexed: 07/07/2024] Open
Abstract
Over the past decade, immunotherapies have brought about significant changes in how we approach the treatment of various solid tumors and blood-related cancers. However, the effectiveness of checkpoint blockade therapy has been constrained to a rate of under 30 %. A significant challenge in the realm of tumor immunotherapy revolves around comprehending the mechanisms through which regulatory T (Treg) cells induce immunosuppression. We have recently discovered that USP22 (ubiquitin-specific peptidase 22) a deubiquitinating enzyme that is increased in various tumors, is an oncogene and controls Treg immune suppressive activity for tumor evasion, providing a rationale for USP22 targeting to achieve both onco- and immuno-therapeutic efficacies. Herein, we identified the traditional Chinese secoiridoid compound gentiopicroside as a USP22 inhibitor. Gentiopicroside treatment decreased the forkhead box P3 (Foxp3) expression, which subsequently reduced Treg immune suppressive activity. Treatment of cancer cells by gentiopicroside resulted in an increase in histone 2B monoubiquitination (H2Bub) in a USP22-dependent manner and a decrease in programmed cell death ligand 1 (PD-L1) expression, both of which are known as USP22-specific substrates. Docking and molecular dynamic simulation revealed that gentiopicroside stably binds to USP22 catalytic pocket, supporting that gentiopicroside is a USP22 inhibitor. Importantly, administration of gentiopicroside to mice significantly inhibited the growth of syngenetic lung adenocarcinoma. Further analysis of intratumoral immune cells revealed a dramatic increase CD8+ T cell production of IFN-γ and granzyme B (GZMB), confirming that gentiopicroside enhances antitumor immunity. Our study revealed that gentiopicroside is a USP22-specific inhibitor with potent antitumor therapeutic potentials.
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Affiliation(s)
- Weiyuan Lu
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA; Department of Pediatrics, The Sixth Affiliated Hospital of Harbin Medical University, Heilongjiang 150028, China
| | - Peng Chu
- College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Amy Tang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Ligang Si
- Department of Pediatrics, The Sixth Affiliated Hospital of Harbin Medical University, Heilongjiang 150028, China
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
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Liu S, Lv Q, Mao X, Dong H, Xu W, Du X, Jia W, Feng K, Zhang J, Zhang Y. O-GlcNAcylated RALY Contributes to Hepatocellular Carcinoma Cells Proliferation by Regulating USP22 mRNA Nuclear Export. Int J Biol Sci 2024; 20:3675-3690. [PMID: 38993567 PMCID: PMC11234212 DOI: 10.7150/ijbs.97397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/06/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly tumors; however, its pathogenic mechanism remains largely elusive. In-depth researches are needed to reveal the expression regulatory mechanisms and functions of the RNA-binding protein RALY in HCC. Here, we identify RALY as a highly expressed oncogenic factor that affects HCC cells proliferation both in vitro and in vivo. O-GlcNAcylation of RALY at Ser176 enhances its stability by protecting RALY from TRIM27-mediated ubiquitination, thus maintaining hyper-expression of the RALY protein. Mechanistically, RALY interacts with USP22 messenger RNA, as revealed by RNA immunoprecipitation, to increase their cytoplasmic localization and protein expression, thereby promoting the proliferation of HCC cells. Furthermore, we develop a novel RALY protein degrader based on peptide proteolysis-targeting chimeras, named RALY-PROTAC, which we chemically synthesize by linking a RALY-targeting peptide with the E3 ubiquitin ligase recruitment ligand pomalidomide. In conclusion, our findings demonstrate a novel mechanism by which O-GlcNAcylation/RALY/USP22 mRNA axis aggravates HCC cells proliferation. RALY-PROTACs as degraders of the RALY protein exhibit potential as therapeutic drugs for RALY-overexpressing HCC.
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Affiliation(s)
- Shiwei Liu
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Qingpeng Lv
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Xinyu Mao
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Hui Dong
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Wenjing Xu
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Xuanlong Du
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Weilu Jia
- School of Medicine, Southeast University, Nanjing 210009, China
| | - Kun Feng
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Jiaqi Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
- School of Medicine, Southeast University, Nanjing 210009, China
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Alhasan BA, Morozov AV, Guzhova IV, Margulis BA. The ubiquitin-proteasome system in the regulation of tumor dormancy and recurrence. Biochim Biophys Acta Rev Cancer 2024; 1879:189119. [PMID: 38761982 DOI: 10.1016/j.bbcan.2024.189119] [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: 01/01/2024] [Revised: 05/12/2024] [Accepted: 05/15/2024] [Indexed: 05/20/2024]
Abstract
Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.
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Affiliation(s)
- Bashar A Alhasan
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.
| | - Alexey V Morozov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia.
| | - Irina V Guzhova
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.
| | - Boris A Margulis
- Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia.
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9
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Yin Z, Zhang X, Sun X, Huo Y, Ji N, Chen K. Mogrol-mediated enhancement of radiotherapy sensitivity in non-small cell lung cancer: a mechanistic study. Am J Physiol Cell Physiol 2024; 326:C1753-C1768. [PMID: 38682239 DOI: 10.1152/ajpcell.00684.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 04/12/2024] [Accepted: 04/12/2024] [Indexed: 05/01/2024]
Abstract
This study investigated mogrol's impact on non-small cell lung cancer (NSCLC) radiosensitivity and underlying mechanisms, using various methods including assays, bioinformatics, and xenograft models. CCK-8, clonogenic, flow cytometry, TUNEL, and Western blot assays evaluated mogrol and radiation effects on NSCLC viability and apoptosis. Ubiquitin-specific protease 22 (USP22) expression in NSCLC patient tissues was determined by RT-qPCR and Western blot. A xenograft model validated mogrol's effects on tumor growth. Bioinformatics identified four ubiquitin-specific proteases, including USP22, in NSCLC. Kaplan-Meier analysis confirmed USP22's value in lung cancer survival. Human Protein Atlas (HPA) database analysis indicated higher USP22 expression in lung cancer tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis implicated ERK1/2 in NSCLC progression, and molecular docking showed stability between mogrol and ERK1/2. Further in vivo and in vitro experiments have demonstrated that mogrol enhances the inhibitory effect of radiation on NSCLC cell viability and clonogenic capacity. Cell viability and clonogenic capacity are reduced by >50%, and an increase in cellular apoptosis is observed, with apoptotic levels reaching 10%. USP22 expression was significantly elevated in NSCLC tissues, particularly in radiotherapy-resistant patients. Mogrol downregulated USP22 expression by inhibiting the ERK/CREB pathway, lowering COX2 expression. Mogrol also enhanced radiation's inhibition of tumor growth in mice. Mogrol enhances NSCLC radiosensitivity by downregulating USP22 via the ERK/CREB pathway, leading to reduced COX2 expression.NEW & NOTEWORTHY Mogrol enhances non-small cell lung cancer (NSCLC) cell sensitivity to radiotherapy by downregulating USP22 through the ERK/CREB pathway, reducing COX2 expression. These findings highlight mogrol's potential as an adjunct to improve NSCLC radiotherapy and open avenues for further research and clinical applications.
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Affiliation(s)
- Zhongbo Yin
- Department of Pathology, Baoan Central Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Xuedong Zhang
- Department of Pathology, Baoan Central Hospital of Shenzhen, Shenzhen, Guangdong, China
| | - Xiao Sun
- Master Degree Candidate, Affiliated Central Hospital of Shenyang Medical College, Shenyang, Liaoning, China
| | - Yunlong Huo
- Department of Pathology, Shengjing Hospital affiliated to China Medical University, Shenyang, Liaoning, China
| | - Nan Ji
- Department of Docimasiology, Baoan Central Hospital of Shenzhen, China, Shenzhen, Guangdong, China
| | - Keyan Chen
- Department of Laboratory Animal Science, China Medical University, Shenyang, Liaoning, China
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10
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Zhang Q, Zhu J, Xie J, Gu Y, Chen L. USP22 as a key regulator of glycolysis pathway in osteosarcoma: insights from bioinformatics and experimental approaches. PeerJ 2024; 12:e17397. [PMID: 38784391 PMCID: PMC11114114 DOI: 10.7717/peerj.17397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
Background Osteosarcoma is the most common primary malignant bone tumor, but its pathogenesis remains unclear. Ubiquitin-specific processing peptidase 22 (USP22) is reported to be highly expressed and associated with tumor malignancy and prognosis in cancers. However, the role and mechanism of USP22 in osteosarcoma is not fully understood. This study aims to investigate the function and potential mechanism of USP22 in osteosarcoma using bioinformatics analysis combined with experimental validation. Methods We first integrated transcriptomic datasets and clinical information of osteosarcoma from GEO and TCGA databases to assess the expression and prognostic value of USP22 in osteosarcoma. Then, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify USP22-related co-expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the biological functions and signaling pathways of USP22 co-expressed genes. To validate the accuracy of bioinformatics analyses, we downregulated USP22 expression in osteosarcoma cell line Sao-2 using siRNA and assessed its effect on cell proliferation, migration, invasion, apoptosis, and regulation of key signaling pathways. Results We found that USP22 was highly expressed in osteosarcoma tissues and correlated with poor prognosis in osteosarcoma patients. USP22 also showed potential as a diagnostic marker for osteosarcoma. In addition, 344 USP22-related co-expressed genes were identified, mainly involved in signaling pathways such as glycolysis, oxidative phosphorylation, spliceosome, thermogenesis, and cell cycle. The in vitro experiments confirmed the accuracy and reliability of bioinformatics analyses. We found that downregulation of USP22 could inhibit Sao-2 cell proliferation, migration, invasion, and induce apoptosis. Furthermore, downregulation of USP22 significantly reduced aerobic glycolysis levels in Sao-2 cells and inhibited the expression of key enzymes and transporters in aerobic glycolysis pathways such as HK2, PKM2, and GLUT1. Conclusions USP22 plays a critical role in the occurrence, development, and prognosis of osteosarcoma. USP22 could influence Sao-2 cell proliferation, apoptosis, migration, and invasion by regulating the glycolysis pathway, thereby promoting osteosarcoma progression. Therefore, USP22 may be a potential therapeutic target for the treatment of osteosarcoma.
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Affiliation(s)
- Qiao Zhang
- Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jinwei Zhu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jian Xie
- Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yurong Gu
- Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lu Chen
- Department of Orthopaedics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
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11
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Chen KC, Dhar T, Chen CR, Chen ECY, Peng CC. Nicotinamide phosphoribosyltransferase modulates PD-L1 in bladder cancer and enhances immunotherapeutic sensitivity. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167106. [PMID: 38428685 DOI: 10.1016/j.bbadis.2024.167106] [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: 10/31/2023] [Revised: 02/11/2024] [Accepted: 02/25/2024] [Indexed: 03/03/2024]
Abstract
Bladder cancer (BLCA) is one of the most prevalent malignancies worldwide with a high mortality rate and poor response to immunotherapy in patients expressing lower programmed death ligand 1 (PD-L1) levels. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme responsible for the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from nicotinamide was reported to be overexpressed in various cancers; however, the role of NAMPT in BLCA is obscure. Immunohistochemistry of tissue microarrays, a real-time polymerase chain reaction, Western blotting, proliferation assay, NAD+ quantification, transwell-migration assay, and colony-formation assay were performed to measure NAMPT and PD-L1 expression levels in patients and the effect of NAMPT inhibition on T24 cells. Our study revealed that NAMPT expression was upregulated in BLCA patients with different grades and associated with poor T-cell infiltration. Notably, FK866-mediated NAMPT inhibition decreased cell viability by depleting NAD+, and reducing the migration ability and colony-formation ability of T24 cells. Interestingly, NAMPT negatively regulated PD-L1 under an interferon (IFN)-γ-mediated microenvironment. However, exogenous NAMPT activator has no effect on PD-L1. NAD+ supplementation also only increased PD-L1 in the absence of IFN-γ. Conclusively, NAMPT is crucial for BLCA tumorigenic properties, and it regulates expression of the PD-L1 immune checkpoint protein. NAMPT could be considered a target for modulating sensitivity to immunotherapy.
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Affiliation(s)
- Kuan-Chou Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Urology, Taipei Medical University Shuang-Ho Hospital, Zhong-He District, New Taipei City 23561, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei, 11031, Taiwan
| | - Trayee Dhar
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chang-Rong Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Eugene Chang-Yu Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chiung-Chi Peng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
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12
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Li KQ, Bai X, Ke AT, Ding SQ, Zhang CD, Dai DQ. Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer. Biomed Pharmacother 2024; 173:116323. [PMID: 38401523 DOI: 10.1016/j.biopha.2024.116323] [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: 12/04/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 02/26/2024] Open
Abstract
Deubiquitination, a post-translational modification regulated by deubiquitinases, is essential for cancer initiation and progression. Ubiquitin-specific proteases (USPs) are essential elements of the deubiquitinase family, and are overexpressed in gastric cancer (GC). Through the regulation of several signaling pathways, such as Wnt/β-Catenin and nuclear factor-κB signaling, and the promotion of the expression of deubiquitination- and stabilization-associated proteins, USPs promote the proliferation, metastasis, invasion, and epithelial-mesenchymal transition of GC. In addition, the expression of USPs is closely related to clinicopathological features, patient prognosis, and chemotherapy resistance. USPs therefore could be used as prognostic biomarkers. USP targeting small molecule inhibitors have demonstrated strong anticancer activity. However, they have not yet been tested in the clinic. This article provides an overview of the latest fundamental research on USPs in GC, aiming to enhance the understanding of how USPs contribute to GC progression, and identifying possible targets for GC treatment to improve patient survival.
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Affiliation(s)
- Kai-Qiang Li
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Xiao Bai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Ang-Ting Ke
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Si-Qi Ding
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Chun-Dong Zhang
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China
| | - Dong-Qiu Dai
- Department of Surgical Oncology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China; Cancer Center, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China.
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Seo JH, Ryu S, Cheon SY, Lee SJ, Won SJ, Yim CD, Lee HJ, Hah YS, Park JJ. Sirt6-Mediated Cell Death Associated with Sirt1 Suppression in Gastric Cancer. Cancers (Basel) 2024; 16:387. [PMID: 38254877 PMCID: PMC10814469 DOI: 10.3390/cancers16020387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/04/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Gastric cancer, one of the leading causes of cancer-related death, is strongly associated with H. pylori infection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects. METHODS After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis. RESULTS Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis. CONCLUSION We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.
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Affiliation(s)
- Ji Hyun Seo
- Department of Pediatrics, Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju 52725, Republic of Korea;
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
| | - Somi Ryu
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - So Young Cheon
- Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea;
| | - Seong-Jun Lee
- Department of Convergence of Medical Sciences, Gyeongsang National University, Jinju 52725, Republic of Korea
| | - Seong-Jun Won
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Chae Dong Yim
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Hyun-Jin Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Chung-Ang University, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong 06973, Republic of Korea
| | - Young-Sool Hah
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
- Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea;
| | - Jung Je Park
- Institute of Medical Science, Gyeongsang National University, Jinju 52725, Republic of Korea; (S.R.); (C.D.Y.)
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Gyeongsang National University, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
- Biomedical Research Institute, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea;
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Yong J, Cai S, Zeng Z. Targeting NAD + metabolism: dual roles in cancer treatment. Front Immunol 2023; 14:1269896. [PMID: 38116009 PMCID: PMC10728650 DOI: 10.3389/fimmu.2023.1269896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is indispensable for various oxidation-reduction reactions in mammalian cells, particularly during energy production. Malignant cells increase the expression levels of NAD+ biosynthesis enzymes for rapid proliferation and biomass production. Furthermore, mounting proof has indicated that NAD-degrading enzymes (NADases) play a role in creating the immunosuppressive tumor microenvironment (TME). Interestingly, both inhibiting NAD+ synthesis and targeting NADase have positive implications for cancer treatment. Here we summarize the detrimental outcomes of increased NAD+ production, the functions of NAD+ metabolic enzymes in creating an immunosuppressive TME, and discuss the progress and clinical translational potential of inhibitors for NAD+ synthesis and therapies targeting NADase.
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Affiliation(s)
- Jiaxin Yong
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Songqing Cai
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
| | - Zhaolei Zeng
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China
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Han X, Yin M, Gong C, Zhang C, Zhu G, Hu M, Tan K, Jiang L, Wang G, Li L. A1BG-AS1 promotes the biological functions of osteosarcoma cells via regulating the microRNA-148a-3p/USP22 axis and stabilizing the expression of SIRT1 through deubiquitinase function. Expert Opin Ther Targets 2023; 27:1017-1029. [PMID: 37747800 DOI: 10.1080/14728222.2023.2263908] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 09/24/2023] [Indexed: 09/27/2023]
Abstract
BACKGROUND The study aims to explore the role of A1BG antisense RNA 1 (A1BG-AS1), microRNA (miR)-148a-3p and ubiquitin-specific protease 22 (USP22) on osteosarcoma (OS) cell growth. RESEARCH DESIGN & METHODS A1BG-AS1, miR-148a-3p, USP22, and silent information regulator 2 homolog 1 (SIRT1) levels in OS tissues and cells were determined. The effects of A1BG-AS1, miR-148a-3p, and USP22 on the biological functions of OS cells were examined by functional assays. In vivo assay was conducted to observe the effect of A1BG-AS1 on OS growth in vitro. The relationship of A1BG-AS1, miR-148a-3p, and USP22 was analyzed by bioinformatics analysis, RNA-fluorescence in situ hybridization, luciferase activity, and RNA binding protein immunoprecipitation assays. The relation between USP22 and SIRT1 was evaluated by immunoprecipitation. RESULTS A1BG-AS1 and USP22 were highly expressed, and miR-148a-3p was lowly expressed in OS tissues and cells. Down-regulation of A1BG-AS1 and USP22 or up-regulation of miR-148a-3p impaired the malignant behaviors of OS cells. A1BG-AS1 sponged miR-148a-3p, and miR-148a-3p targeted USP22, thereby inhibiting USP22 expression. Up-regulating USP22 reversed the A1BG-AS1 suppression-induced phenotypic inhibition of OS cells. USP22 affected the biological functions of OS cells by deubiquitinating SIRT1. CONCLUSION A1BG-AS1 facilitates the biological functions of OS cells via mediating the miR-148a-3p/USP22 axis.
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Affiliation(s)
- Xiuxin Han
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin, China
| | - Mengfan Yin
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin, China
- Department of Orthopedic Surgery, Tianjin Fifth Central Hospital, Tianjin, China
| | - Chen Gong
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
| | - Chao Zhang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin, China
| | - Genbao Zhu
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
| | - Mengxue Hu
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
| | - Kemeng Tan
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
| | - La Jiang
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
| | - Guowen Wang
- Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center of Cancer, Tianjin, China
| | - Lili Li
- General Clinical Research Center, Anhui Wanbei Coal-Electricity Group General Hospital, Suzhou, Anhui, China
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Liu K, Gao Q, Jia Y, Wei J, Chaudhuri S, Wang S, Tang A, Mani N, Iyer R, Cheng Y, Gao B, Lu W, Sun Z, Liu H, Fang D. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis. RESEARCH SQUARE 2023:rs.3.rs-2922367. [PMID: 37398311 PMCID: PMC10312927 DOI: 10.21203/rs.3.rs-2922367/v1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in cancer stemness and metastasis. However, the molecular mechanisms underlying how integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from cancer signature gene USP22 is essential to maintain the stemness of breast cancer cells through promoting the transcription of a group of integrin family members in particular integrin β1 (ITGB1). Both genetic and pharmacological USP22 inhibition largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Integrin β1 reconstitution partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly unbiased analysis of the TCGA database revealed a strong positive correlation between the death from cancer signature gene ubiquitin-specific peptidase 22 (USP22) and ITGB1, both of which are critical for cancer stemness, in more than 90% of human cancer types, implying that USP22 functions as a key factor to maintain stemness for a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis critical for cancer stemness and offers a potential target for antitumor therapy.
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Guan J, Zhang ZY, Sun JH, Wang XP, Zhou ZQ, Qin L. LITAF inhibits colorectal cancer stemness and metastatic behavior by regulating FOXO1-mediated SIRT1 expression. Clin Exp Metastasis 2023:10.1007/s10585-023-10213-x. [PMID: 37266842 DOI: 10.1007/s10585-023-10213-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 05/20/2023] [Indexed: 06/03/2023]
Abstract
Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) is a transcription factor that activates the transcription of TNF-α and regulates the inflammatory response. LITAF has been found to have potential anti-cancer effects of in several tumors. However, the role of LITAF in colorectal cancer (CRC) remains unclear. Through a comprehensive pan-cancer analysis of the Cancer Genome Atlas (TCGA), LITAF was identified as a differentially downregulated gene in CRC. We hypothesized that LITAF may participate in the modulation of CRC progression. The present study was aimed to investigate the expression profile of LITAF in CRC and its effect on metastatic behavior and stemness as well as the underlying molecular mechanism. The expression profile of LITAF in CRC, and its relationship with the prognosis of CRC were explored using public databases. LITAF expression was detected by quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry. Furthermore, the effects of overexpression or knockdown of LITAF on cell proliferation, apoptosis, migration, invasion, and stemness of CRC cells were investigated in vitro. The regulatory effect of LITAF on forkhead Box O 1 (FOXO1)-sirtuin 1 (SIRT1) signaling axis was also explored. In addition, a xenograft mouse model was used to investigate the in-vivo role of LITAF. LITAF was downregulated in tumor tissues and its expression was associated with the prognosis, pathological stage and liver metastasis. In-vitro experiments confirmed that LITAF inhibited tumor cell proliferation, migration, invasion and stemness, and induced cell apoptosis. In vivo experiments demonstrated that LITAF inhibited the tumorigenicity and liver metastasis in tumor-bearing mice. Additionally, LITAF promoted FOXO1-mediated SIRT1 inhibition, thus regulating cancer stemness and malignant phenotypes. LITAF was silenced in CRC and it participated in the progression of CRC by inhibiting CRC cell stemness, and malignant phenotypes. Therefore, LITAF may serve as a novel biomarker of CRC prognosis.
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Affiliation(s)
- Jiao Guan
- Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zheng-Yun Zhang
- Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Jian-Hua Sun
- Department of Emergency, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xin-Ping Wang
- Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zun-Qiang Zhou
- Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Lei Qin
- Department of Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
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Deng T, Zhong P, Lou R, Yang X. RNF220 promotes gastric cancer growth and stemness via modulating the USP22/wnt/β-catenin pathway. Tissue Cell 2023; 83:102123. [PMID: 37295272 DOI: 10.1016/j.tice.2023.102123] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 05/15/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023]
Abstract
Gastric cancer (GC) is a prevalent malignancy that seriously threatens the health and life of patients. Although Ring finger 220 (RNF220) has been demonstrated to participate in the development of various cancers, its role and mechanism in GC remain undiscovered. The expression of RNF220 was determined by The Cancer Genome Atlas (TCGA) database and Western blot. Additionally, the overall survival (OS) and post-progression survival (PPS) were analyzed based on the levels of RNF220 in the TCGA database. The role and mechanism of RNF220 in growth and stemness were investigated using cell counting kit-8, colony formation, sphere-formation, co-immunoprecipitation, and Western blot experiments. Furthermore, the role of RNF220 was investigated in a xenografted mouse model. The expression of RNF220 was found to be upregulated in GC, which predicted unfavorable OS and PPS in patients with GC. Knockdown of RNF220 reduced cell viability, colony numbers, numbers of spheres formation, and the relative protein levels of Nanog, Sox2, and Oct4 in both AGS and MKN-45 cells. Moreover, overexpression of RNF220 increased cell viability and the numbers of spheres formation in MKN-45 cells. Mechanistically, RNF220 bound to USP22, and interference of RNF220 downregulated the Wnt/β-catenin axis via USP22, which was confirmed by the overexpression of USP22 in both cell lines. Furthermore, silencing of RNF220 significantly decreased tumor volume and weight, the level of Ki-67, and the relative protein levels of USP22, β-catenin, c-myc, Nanog, Sox2, and Oct4. Taken together, downregulation of RNF220 suppressed GC cell growth and stemness by downregulating the USP22/Wnt/β-catenin axis.
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Affiliation(s)
- Taozhi Deng
- Department of Gastroenterology, Hainan Cancer Hospital, Haikou, Hainan 570000, China
| | - Ping Zhong
- Department of Gastroenterology, Hainan Cancer Hospital, Haikou, Hainan 570000, China
| | - Runlong Lou
- Department of Gastroenterology, Hainan Cancer Hospital, Haikou, Hainan 570000, China
| | - Xiaojun Yang
- Department of Gastroenterology, Suzhou BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Suzhou, Jiangsu 215010, China.
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Yin JY, Lu XT, Hou ML, Cao T, Tian Z. Sirtuin1-p53: a potential axis for cancer therapy. Biochem Pharmacol 2023; 212:115543. [PMID: 37037265 DOI: 10.1016/j.bcp.2023.115543] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 03/31/2023] [Accepted: 04/03/2023] [Indexed: 04/12/2023]
Abstract
Sirtuin1 (SIRT1) is a conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that plays key roles in a range of cellular events, including the maintenance of genome stability, gene regulation, cell proliferation, and apoptosis. P53 is one of the most studied tumor suppressors and the first identified non-histone target of SIRT1. SIRT1 deacetylates p53 in a NAD+-dependent manner and inhibits its transcriptional activity, thus exerting action on a series of pathways related to tissue homeostasis and various pathological states. The SIRT1-p53 axis is thought to play a central role in tumorigenesis. Although SIRT1 was initially identified as a tumor promoter, evidence now indicates that SIRT1 may also act as a tumor suppressor. This seemingly contradictory evidence indicates that the functionality of SIRT1 may be dictated by different cell types and intracellular localization patterns. In this review, we summarize recent evidence relating to the interactions between SIRT1 and p53 and discuss the relative roles of these two molecules with regards to cancer-associated cellular events. We also provide an overview of current knowledge of SIRT1-p53 signaling in tumorigenesis. Given the vital role of the SIRT1-p53 pathway, targeting this axis may provide promising strategies for the treatment of cancer.
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Affiliation(s)
- Jia-Yi Yin
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Xin-Tong Lu
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Meng-Ling Hou
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Ting Cao
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China
| | - Zhen Tian
- College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
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Cao Z, An L, Han Y, Jiao S, Zhou Z. The Hippo signaling pathway in gastric cancer. Acta Biochim Biophys Sin (Shanghai) 2023. [PMID: 36924251 DOI: 10.3724/abbs.2023038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control and tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks of cancer. The last decade witnessed a burst of investigations dissecting how Hippo dysregulation contributes to tumorigenesis, highlighting the therapeutic potential of targeting this pathway for tumor intervention. In this review, we systemically document studies on the Hippo pathway in the contexts of gastric tumor initiation, progression, metastasis, acquired drug resistance, and the emerging development of Hippo-targeting strategies. By summarizing major open questions in this field, we aim to inspire further in-depth understanding of Hippo signaling in GC development, as well as the translational implications of targeting Hippo for GC treatment.
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Affiliation(s)
- Zhifa Cao
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China.,CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Liwei An
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Yi Han
- Department of Stomatology, Shanghai Tenth People's Hospital, Department of Biochemistry and Molecular Biology, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.,Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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21
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Zhao H, Ding Y, Zhang L. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis. Open Med (Wars) 2023; 18:20220620. [PMID: 36820068 PMCID: PMC9938643 DOI: 10.1515/med-2022-0620] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 02/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with high mortality. Sirtuin 1 (SIRT1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) are abnormally expressed in GC cells and related to p53, which is involved in ferroptosis. Thus, we explore the mechanism via which SIRT1, APE1, and p53 impact ferroptosis in GC cells. Specifically, GC cells were transfected with small-interfering RNA for SIRT1 (SiSIRT1) or small-interfering RNA for APE1 (SiAPE1) or with short-hairpin RNA for p53, and the cell viability, Fe2+, malondialdehyde (MDA), and glutathione (GSH) contents were detected by cell counting kit-8 assay and enzyme-linked immunosorbent assay. Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were conducted to quantify SIRT1, APE1, p53, solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) levels in GC cells. Silencing of SIRT1 decreased viability, GSH content, and expressions of GPX4 and SLC7A11, while increased Fe2+, MDA content, and p53 expression in GC cells. Such aforementioned effects were reversed by APE1 overexpression. Also, SiAPE1 generated the same effects as SiSIRT1 on the above aspects, which was offset by p53 silencing. In short, SIRT1/APE1 promotes the growth of GC cells by targeting p53 to inhibit ferroptosis.
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Affiliation(s)
- Huijin Zhao
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Yuanyi Ding
- Department of No. 2 General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
| | - Lan Zhang
- Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050000, China
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22
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Jin S, Kudo Y, Horiguchi T. The Role of Deubiquitinating Enzyme in Head and Neck Squamous Cell Carcinoma. Int J Mol Sci 2022; 24:ijms24010552. [PMID: 36613989 PMCID: PMC9820089 DOI: 10.3390/ijms24010552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/20/2022] [Accepted: 12/24/2022] [Indexed: 12/30/2022] Open
Abstract
Ubiquitination and deubiquitination are two popular ways for the post-translational modification of proteins. These two modifications affect intracellular localization, stability, and function of target proteins. The process of deubiquitination is involved in histone modification, cell cycle regulation, cell differentiation, apoptosis, endocytosis, autophagy, and DNA repair after damage. Moreover, it is involved in the processes of carcinogenesis and cancer development. In this review, we discuss these issues in understanding deubiquitinating enzyme (DUB) function in head and neck squamous cell carcinoma (HNSCC), and their potential therapeutic strategies for HNSCC patients are also discussed.
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23
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Poniewierska-Baran A, Warias P, Zgutka K. Sirtuins (SIRTs) As a Novel Target in Gastric Cancer. Int J Mol Sci 2022; 23:ijms232315119. [PMID: 36499440 PMCID: PMC9737976 DOI: 10.3390/ijms232315119] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022] Open
Abstract
Gastric cancer is a major health burden worldwide. Among all neoplasms, gastric cancer is the fifth most common and the third most deadly type of cancer. It is known that sirtuins (SIRTs), are NAD+-dependent histone deacetylases regulating important metabolic pathways. High expression of SIRTs in the human body can regulate metabolic processes; they prevent inflammation but also resist cell death and aging processes. The seven members of this family enzymes can also play a fundamental role in process of carcinogenesis by influencing cell viability, apoptosis and metastasis. This review collects and discusses the role of all seven sirtuins (SIRT1-SIRT7) in the pathogenesis of gastric cancer (GC).
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Affiliation(s)
- Agata Poniewierska-Baran
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland
- Correspondence:
| | - Paulina Warias
- Department of Physiology, Pomeranian Medical University in Szczecin, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
| | - Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University, Szczecin, Żołnierska 54, 70-210 Szczecin, Poland
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24
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An T, Lu Y, Gong Z, Wang Y, Su C, Tang G, Hou J. Research Progress for Targeting Deubiquitinases in Gastric Cancers. Cancers (Basel) 2022; 14:cancers14235831. [PMID: 36497313 PMCID: PMC9735992 DOI: 10.3390/cancers14235831] [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: 10/24/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Gastric cancers (GCs) are malignant tumors with a high incidence that threaten global public health. Despite advances in GC diagnosis and treatment, the prognosis remains poor. Therefore, the mechanisms underlying GC progression need to be identified to develop prognostic biomarkers and therapeutic targets. Ubiquitination, a post-translational modification that regulates the stability, activity, localization, and interactions of target proteins, can be reversed by deubiquitinases (DUBs), which can remove ubiquitin monomers or polymers from modified proteins. The dysfunction of DUBs has been closely linked to tumorigenesis in various cancer types, and targeting certain DUBs may provide a potential option for cancer therapy. Multiple DUBs have been demonstrated to function as oncogenes or tumor suppressors in GC. In this review, we summarize the DUBs involved in GC and their associated upstream regulation and downstream mechanisms and present the benefits of targeting DUBs for GC treatment, which could provide new insights for GC diagnosis and therapy.
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Affiliation(s)
- Tao An
- School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yanting Lu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250353, China
| | - Zhaoqi Gong
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Yongtao Wang
- School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Chen Su
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen 361005, China
| | - Guimei Tang
- School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
- Correspondence: (G.T.); (J.H.)
| | - Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China
- Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen 361005, China
- Correspondence: (G.T.); (J.H.)
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STIL Promotes Tumorigenesis of Bladder Cancer by Activating PI3K/AKT/mTOR Signaling Pathway and Targeting C-Myc. Cancers (Basel) 2022; 14:cancers14235777. [PMID: 36497260 PMCID: PMC9739707 DOI: 10.3390/cancers14235777] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/19/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
SCL/TAL1 interrupting locus (STIL) regulates centriole replication and causes chromosome instability, which is closely related to malignant tumors. The purpose of our study was to investigate the role of STIL in bladder cancer (BC) tumorigenesis for the first time. The public database indicated that STIL is highly expressed and correlated with the cell cycle in BC. Immunohistochemistry staining showed that STIL expression is significantly elevated in BC tissues compared with paracancer tissues. CRISPR-Cas9 gene editing technology was used to induce BC cells to express STIL-specific sgRNA, revealing a significantly delayed growth rate in STIL knockout BC cells. Moreover, cell cycle arrest in the G0/G1 phase was triggered by decreasing STIL, which led to delayed BC cell growth in vitro and in vivo. Mechanically, STIL knockout inhibited the PI3K/AKT/mTOR pathway and down-regulated the expression of c-myc. Furthermore, SC79 (AKT activating agent) partially reversed the inhibitory effects of STIL knockout on the proliferation and migration of BC cells. In conclusion, STIL enhanced the PI3K/AKT/mTOR pathway, resulting in increased expression of c-myc, ultimately promoting BC occurrence and progression. These results indicate that STIL might be a potential target for BC patients.
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26
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Guo J, Zhao J, Fu W, Xu Q, Huang D. Immune Evasion and Drug Resistance Mediated by USP22 in Cancer: Novel Targets and Mechanisms. Front Immunol 2022; 13:918314. [PMID: 35935969 PMCID: PMC9347222 DOI: 10.3389/fimmu.2022.918314] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.
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Affiliation(s)
- Jinhui Guo
- Qingdao Medical College, Qingdao University, Qingdao, China
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jie Zhao
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Wen Fu
- Qingdao Medical College, Qingdao University, Qingdao, China
| | - Qiuran Xu
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Dongsheng Huang
- Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
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27
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Wang Y, Jia Z, Gao J, Zhou T, Zhang X, Zu G. Clinicopathological and Prognostic Value of USP22 Expression in Gastric Cancer: A Systematic Review and Meta-Analysis and Database Validation. Front Surg 2022; 9:920595. [PMID: 35784926 PMCID: PMC9243499 DOI: 10.3389/fsurg.2022.920595] [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: 04/14/2022] [Accepted: 05/26/2022] [Indexed: 01/02/2023] Open
Abstract
Background It has been reported that there is a correlation between the level of ubiquitin-specific protease 22 (USP22) and the clinicopathological parameters and prognosis of gastric cancer (GC) patients, but the conclusions are inconsistent. Hence, a meta-analysis must be conducted to clarify the relationship between USP22 expression and clinicopathological and prognostic value of GC patients to provide more accurate evidence. Methods According to the predetermined selection criteria, systematic file retrieval was performed. The hazard ratio (HR) or odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the relationship between USP22 expression and clinicopathological and prognostic value of GC patients. Results In a total of 802 patients, those with GC were finally included in 6 studies. The pooled results demonstrated that the expression of USP22 was significantly increased in GC tissues compared with control tissues (OR = 9.947, 95% CI, 6.074–16.291, P = 0.000), and USP22 expression was related to lymph node metastasis (OR = 2.415, 95% CI, 1.082, P = 0.031), distant metastasis (OR = 3.956, 95% CI, 1.365–11.464, P = 0.011) and TNM stage (OR = 2.973, 95% CI, 1.153–7.666, P = 0.024). Nevertheless, the expression of USP22 was not correlated with gender (OR = 1.202, 95% CI, 0.877–1.648, P = 0.253), age (OR = 1.090, 95% CI, 0.811–1.466, P = 0.568), tumor size (OR = 0.693,95% CI, 0.348–1.380, P = 0.297), tumor differentiation (OR = 1.830, 95%CI, 0.948–3.531, P = 0.072) and depth of invasion (OR = 2.320, 95% CI, 0.684–7.871, P = 0.177). Moreover, a high expression of USP22 predicted a poor overall survival (OS) in GC patients (HR = 2.012, 95% CI, 1.522–2.658, P = 0.000). The database of Kaplan–Meier plotter confirmed that a high expression of USP22 was correlated with poor prognostics in GC patients (HR = 1.41, 95% CI, 1.18–1.68, P < 0.01). Conclusion USP22 overexpression in GC tissues is positively related to lymph node metastasis, distant metastasis and TNM stage and indicates a poor clinical outcome of GC patients, but it is not associated with age, gender, depth of invasion, tumor differentiation and tumor size of GC patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: 338361.
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Affiliation(s)
- Yuhang Wang
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
- Department of Graduate School, Dalian Medical University, Dalian, China
| | - Zirui Jia
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
- Department of Graduate School, Dalian Medical University, Dalian, China
| | - Jiacheng Gao
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
- Department of Graduate School, Dalian Medical University, Dalian, China
| | - Tingting Zhou
- Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiangwen Zhang
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
- Correspondence: Guo Zu Xiangwen Zhang
| | - Guo Zu
- Department of General Surgery, The Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China
- Correspondence: Guo Zu Xiangwen Zhang
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28
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Zheng Z, Shang Y, Xu R, Yan X, Wang X, Cai J, Bai Z, Liu X, Yin J, Zhang J, Zhang Z. Ubiquitin specific peptidase 38 promotes the progression of gastric cancer through upregulation of fatty acid synthase. Am J Cancer Res 2022; 12:2686-2696. [PMID: 35812059 PMCID: PMC9251701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/09/2022] [Indexed: 06/15/2023] Open
Abstract
Gastric cancer (GC) is a malignant tumor with an adverse health effect worldwide, whereas the underlying mechanism of GC development remains controversial. Identification of biomarkers is critical for the treatment of GC. Increasing evidence demonstrates that protein modification plays a pivotal role in carcinogenesis. USP38 is a member of the ubiquitin-specific protease (USP) family, which promotes protein stability by deubiquitinating the target proteins. In this study, we focused on the effect of USP38 on the GC and explored its underlying mechanism. The Cancer Genome Atlas (TCGA) database was used to evaluate the expression of USP38. AGS and HGC27 cells were treated with siRNA targeting USP38 or plasmids overexpressing USP38 to disturb levels of USP38. Immumohistochemical staining was performed to detect the level of USP38 and FASN. RT-qPCR and Western blotting (WB) were used to analyze the expression of mRNA and protein respectively. CCK8 assay, colony formation, cell migration assay, and cell apoptosis and cell cycle were performed to assess cell proliferation and migration ability. A subcutaneous tumor mice model was carried to verify the effect of USP38 on the GC in vivo. In this research, we found that USP38 was overexpressed in GC tissues, and USP38 contributed to GC cell proliferation, migration and tumorigenesis. Cell cycle and apoptosis were also regulated by USP38. Mechanistically, USP38 interacted with FASN, which resulted in enhanced protein stability of FASN and increased triglyceride production. Furthermore, FASN was critical for GC cell growth, migration and tumor development triggered by USP38 overexpression because its inhibitor orilistat reversed phenotypes in USP38 overexpressed GC cells. Collectively, USP38 overexpression is critical for GC cell growth, migration and tumorigenesis. Targeting FASN with inhibitors could be used as a potential treatment for GC patients with highly expressed USP38.
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Affiliation(s)
- Zhi Zheng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Yuxi Shang
- Department of Hematology, Fuxing Hospital, Eighth Clinical Medical College, Capital Medical UniversityBeijing, China
| | - Rui Xu
- Department of Pathology, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
| | - Xiaosheng Yan
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Xi Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Jun Cai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Zhigang Bai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Xiaoye Liu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Jie Yin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Jun Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis ResearchBeijing, China
- National Clinical Research Center for Digestive DiseasesBeijing, China
- Beijing Institute of Clinical MedicineBeijing, China
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29
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Gasparrini M, Audrito V. NAMPT: A critical driver and therapeutic target for cancer. Int J Biochem Cell Biol 2022; 145:106189. [PMID: 35219878 DOI: 10.1016/j.biocel.2022.106189] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 02/08/2023]
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) possesses a vital role in mammalian cells due to its activity as a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide (NAD) from nicotinamide. NAD is an essential redox cofactor, but it also functions as a substrate for NAD-consuming enzymes, regulating multiple cellular processes such as DNA repair and gene expression, fundamental to sustain tumor growth and survival and energetic needs. A common strategy that several tumor types adopt to sustain NAD synthesis is to over-express NAMPT. However, beside its intracellular functions, this enzyme has a second life outside of cells exerting cytokine-like functions and mediating pro-inflammatory conditions activating signaling pathways. While the effects of NAMPT/NAD axis on energetic metabolism in tumors has been well-established, increasing evidence demonstrated the impact of NAMPT over-expression (intra-/extra-cellular) on several tumor cellular processes, including DNA repair, gene expression, signaling pathways, proliferation, invasion, stemness, phenotype plasticity, metastatization, angiogenesis, immune regulation, and drug resistance. For all these reasons, NAMPT targeting has emerged as promising anti-cancer strategy to deplete NAD and impair cellular metabolism, but also to counteract the other NAMPT-related functions. In this review, we summarize the key role of NAMPT in multiple biological processes implicated in cancer biology and the impact of NAMPT inhibition as therapeutic strategy for cancer treatment.
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Affiliation(s)
- Massimiliano Gasparrini
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Valentina Audrito
- Department of Molecular Biotechnology and Health Sciences & Molecular Biotechnology Center, University of Torino, Torino, Italy.
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30
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Li B, Chen Y, Liang L, Wang Y, Huang W, Zhao K, Liu S, Deng G, Chen J. Tumor-derived extracellular vesicles shuttle c-Myc to promote gastric cancer growth and metastasis via the KCNQ1OT1/miR-556-3p/CLIC1 axis. Cell Death Dis 2022; 13:217. [PMID: 35260554 PMCID: PMC8904444 DOI: 10.1038/s41419-021-04446-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 11/24/2021] [Accepted: 12/01/2021] [Indexed: 12/24/2022]
Abstract
Gastric cancer (GC) is a heterogeneous disease with poor prognosis. Tumor-derived extracellular vesicles (EVs) assume a role in intercellular communication by carrying various molecules, including proteins, RNA, and DNAs, which has been identified to exhibit oncogenic effect in GC. Therefore, this research aimed to figure out whether tumor-derived EVs transmit c-Myc to orchestrate the growth and metastasis of GC. KCNQ1OT1, microRNA (miR)-556-3p and CLIC1 expression of GC tissues was detected through RT-qPCR. EVs were isolated from GC cells, followed by RT-qPCR and Western blot analysis of c-Myc expression in EVs and GC cells. Next, GC cells were incubated with EVs or transfected with a series of mimic, inhibitor, or siRNAs to assess their effects on cell viability, migrative, invasive, and apoptotic potential. Relationship among c-Myc, KCNQ1OT1, miR-556-3p, and CLIC1 was evaluated by dual-luciferase reporter assay. PI3K/AKT pathway-related proteins were assessed through Western blot analysis. KCNQ1OT1 and CLIC1 were highly expressed but miR-556-3p in GC tissues. c-Myc was high-expressed in tumor-derived EVs and GC cells. Mechanistically, c-Myc could induce KCNQ1OT1 expression, and KCNQ1OT1 bound to miR-556-3p that negatively targeted CLIC1 to inactivate PI3K/AKT pathway. Tumor-derived EVs, EVs-c-Myc, KCNQ1OT1 or CLIC1 overexpression, or miR-556-3p inhibition promoted GC cell proliferative, invasive, and migrative capacities but repressed their apoptosis through activating PI3K/AKT pathway. Collectively, tumor-derived EVs carrying c-Myc activated KCNQ1OT1 to downregulate miR-556-3p, thus elevating CLIC1 expression to activate the PI3K/AKT pathway, which facilitated the growth and metastasis of GC.
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Affiliation(s)
- Bopei Li
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China.,Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, 530021, Nanning, P.R. China
| | - Yeyang Chen
- Departments of Gastrointestinal Surgery, The First People's Hospital of Yulin, 537000, Yulin, P.R. China
| | - Liang Liang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, 530007, Nanning, P.R. China
| | - Ye Wang
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China
| | - Weijia Huang
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China
| | - Kun Zhao
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China
| | - Siyu Liu
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China
| | - Guofei Deng
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China
| | - Junqiang Chen
- Departments of Gastrointestinal Surgery, The First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, P.R. China. .,Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, 530021, Nanning, P.R. China.
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Ren D, Sun Y, Li D, Wu H, Jin X. USP22-mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression. Mol Oncol 2022; 16:1200-1217. [PMID: 34743406 PMCID: PMC8895442 DOI: 10.1002/1878-0261.13137] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 09/25/2021] [Accepted: 11/05/2021] [Indexed: 12/14/2022] Open
Abstract
Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a dual lipid and protein phosphatase. Multiple mechanisms contributing to the regulation of PTEN levels have been identified thus far, including post-translational modifications, epigenetic mechanisms, and transcriptional mechanisms. In the present study, we identified ubiquitin-specific peptidase 22 (USP22) as a novel deubiquitination-modifying enzyme of PTEN. Furthermore, by inducing deubiquitination and inhibiting the degradation of PTEN, USP22 could induce cyclin-dependent kinase inhibitor 1A (CDKN1A, also symboled as p21) expression in pancreatic cancer. Besides, MDM2 proto-oncogene (MDM2) inhibitor enhanced the antipancreatic cancer effects of USP22 overexpression. In addition to its regulation of MDM2-tumor protein p53 (p53) signaling, we found that PTEN could induce p21 expression by interacting with ankyrin repeat and KH domain containing 1 (ANKHD1) and inhibiting ANKHD1 binding to the p21 promoter. Taken together, our results indicate that ANKHD1 and MDM2 might be novel therapeutic targets in pancreatic cancer.
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Affiliation(s)
- Dianyun Ren
- Department of Pancreatic SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Sino‐German Laboratory of Personalized Medicine for Pancreatic CancerUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yan Sun
- Department of Pancreatic SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Sino‐German Laboratory of Personalized Medicine for Pancreatic CancerUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Dan Li
- Cardiovascular Medicine DepartmentUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Heshui Wu
- Department of Pancreatic SurgeryUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Sino‐German Laboratory of Personalized Medicine for Pancreatic CancerUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xin Jin
- Department of UrologyThe Second Xiangya HospitalCentral South UniversityChangshaChina
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Choi HS, Baek KH. Pro-apoptotic and anti-apoptotic regulation mediated by deubiquitinating enzymes. Cell Mol Life Sci 2022; 79:117. [PMID: 35118522 PMCID: PMC11071826 DOI: 10.1007/s00018-022-04132-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/20/2021] [Accepted: 01/05/2022] [Indexed: 12/16/2022]
Abstract
Although damaged cells can be repaired, cells that are considered unlikely to be repaired are eliminated through apoptosis, a type of predicted cell death found in multicellular organisms. Apoptosis is a structured cell death involving alterations to the cell morphology and internal biochemical changes. This process involves the expansion and cracking of cells, changes in cell membranes, nuclear fragmentation, chromatin condensation, and chromosome cleavage, culminating in the damaged cells being eaten and processed by other cells. The ubiquitin-proteasome system (UPS) is a major cellular pathway that regulates the protein levels through proteasomal degradation. This review proposes that apoptotic proteins are regulated through the UPS and describes a unique direction for cancer treatment by controlling proteasomal degradation of apoptotic proteins, and small molecules targeted to enzymes associated with UPS.
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Affiliation(s)
- Hae-Seul Choi
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, 13488, Republic of Korea.
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Chang XT, Wu H, Li HL, Li HL, Zheng YB. PADI4 promotes epithelial-mesenchymal transition(EMT) in gastric cancer via the upregulation of interleukin 8. BMC Gastroenterol 2022; 22:25. [PMID: 35045833 PMCID: PMC8767667 DOI: 10.1186/s12876-022-02097-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/03/2022] [Indexed: 01/04/2023] Open
Abstract
Abstract
Background
Gastric cancer (GC) is one of the deadliest tumours due to its ability to metastasize. The Epithelial–to-mesenchymal transition plays a crucial role in promoting the GC metastasis, which increases the migration and metastasis of tumour cells. Peptidyl arginine deiminase IV (PADI4) is a susceptibility gene for gastric carcinoma. The aim of this study was to evaluate the functional roles of PADI4 in gastric cancer.
Methods
The expression of PADI4 was examined by qRT-PCR, western blot and immunohistochemistry. In addition, the functional roles of PADI4 were explored by over-expression PADI4 plasmids in gastric cancer cells.
Results
We found that the expression of PADI4 was up-regulated in GC. PADI4 overexpression in GC cells increased the proliferation, migration, metastasis, clone forming ability, and tumorigenic ability, but reduced the apoptosis ability. The Multi-Analyte ELISArray Kit results showed that interleukin 8 (IL-8) is upregulated in PADI4-overexpressing gastric cells. Using short interfering RNA (siRNA) to silence the expression of IL-8, we demonstrated that IL-8 silencing significantly inhibited the increased migratory capacity in PADI4-overexpressing GC cells.
Conclusions
Our data suggest that PADI4 accelerate metastasis by promoting IL-8 expression in gastric cancer cells, indicating that it is a new PADI4/IL-8 signalling pathway in metastatic GC.
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Yan J, Tan M, Yu L, Jin X, Li Y. Ring finger 220 promotes the stemness and progression of colon cancer cells via Ubiquitin specific peptidase 22-BMI1 axis. Bioengineered 2021; 12:12060-12069. [PMID: 34753387 PMCID: PMC8809949 DOI: 10.1080/21655979.2021.2003664] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/03/2022] Open
Abstract
Colorectal cancer (CRC) is ranked as the third most common malignancy worldwide. Therefore, it is urgent to screen novel and effective molecular drug targets for colorectal cancer therapeutics. In this study, the specific role and related mechanism underlying Ring finger (RNF) 220 in colon cancer were investigated. Firstly, RT-PCR assay was used to compare differences between expression levels of RNF220 in colorectal tumor and normal tissues. Western blot and RT-PCR assays were applied to examine the protein levels of RNF220 in normal colonic mucosa and colorectal cancer cells. We found that RNF220 was upregulated in colorectal cancer in patients and cell models. RNF220 promoted the proliferation and migration, invasion of colorectal cancer cells through BrdU incorporation, clone formation, transwell and wound healing assays. Spheroid formation and western blot assays illustrated that RNF220 promoted the stemness of colorectal cancer cells. Moreover, we found that RNF220 regulated BMI1 expression through USP22 by western blot. Finally, we discovered that RNF220 facilitated tumor growth in vivo through establishment of subcutaneous xenograft tumor mice model. In conclusion, RNF220 promoted the stemness and progression of colon cancer cells via the USP22-BMI1 axis.
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Affiliation(s)
- Jianwen Yan
- Department of Surgery 1, Guilin Tcm Hospital of China, Guilin City, Guangxi Zhuang Autonomous Region, China
| | - Min Tan
- Department of Surgery 1, Guilin Tcm Hospital of China, Guilin City, Guangxi Zhuang Autonomous Region, China
| | - Lin Yu
- Department of Surgery 1, Guilin Tcm Hospital of China, Guilin City, Guangxi Zhuang Autonomous Region, China
| | - Xichao Jin
- Department of Surgery 1, Guilin Tcm Hospital of China, Guilin City, Guangxi Zhuang Autonomous Region, China
| | - Yangcheng Li
- Department of General Surgery, Nantong Tumor Hospital, Nantong City, Jiangsu Province, China
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Deng YW, Shu YG, Sun SL. miR-376a inhibits glioma proliferation and angiogenesis by regulating YAP1/VEGF signalling via targeting of SIRT1. Transl Oncol 2021; 15:101270. [PMID: 34808462 PMCID: PMC8609063 DOI: 10.1016/j.tranon.2021.101270] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/31/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Glioma is the most common cancer in the central nervous system. Previous studies have revealed that the miR-376 family is crucial in tumour development; however, its detailed mechanism in glioma is not clear. METHODS Cellular mRNA or protein levels of miR-376a, SIRT1, VEGF and YAP1 were detected via qRT-PCR or Western blotting. We analysed the proliferation, angiogenesis and migration abilities of glioma cell lines using colony formation, tube formation and Transwell assays. A luciferase assay was performed to determine whether miR-376a could recognize SIRT1 mRNA. Xenograft experiments were performed to analyse the tumorigenesis capacity of glioma cell lines in nude mice. The angiogenesis marker CD31 in xenograft tumours was detected via immunohistochemistry (IHC). RESULTS miR-376a expression was lower in glioma cells than in normal astrocytes. miR-376a mimic inhibited SIRT1, YAP1, and VEGF expression and suppressed the proliferation, migration and angiogenesis abilities of the glioma cell lines LN229 and A172, whereas miR-376a inhibitor exerted the opposite functions. In a luciferase assay, miR-376a inhibited the luciferase activity of WT-SIRT1. SIRT1 overexpression upregulated YAP1 and VEGF in glioma cells and promoted proliferation, migration and angiogenesis. Xenografts with ectopic miR-376a expression exhibited lower volumes and weights and a slower growth curve. Overexpression of miR-376a inhibited YAP1/VEGF signalling and angiogenesis by inhibiting SIRT1 in xenograft tissues. CONCLUSION miR-376a directly targets and inhibits SIRT1 in glioma cells. Downregulation of SIRT1 resulted in decreased YAP1 and VEGF signalling, which led to suppression of glioma cell proliferation, migration and angiogenesis.
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Affiliation(s)
- Yong-Wen Deng
- Department of Neurosurgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), No.61, Jiefang West Road, Changsha, Hunan 410005, PR China
| | - Yu-Gao Shu
- Department of Neurosurgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), No.61, Jiefang West Road, Changsha, Hunan 410005, PR China
| | - Sheng-Li Sun
- Department of Neurosurgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), No.61, Jiefang West Road, Changsha, Hunan 410005, PR China.
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Halasa M, Adamczuk K, Adamczuk G, Afshan S, Stepulak A, Cybulski M, Wawruszak A. Deacetylation of Transcription Factors in Carcinogenesis. Int J Mol Sci 2021; 22:11810. [PMID: 34769241 PMCID: PMC8583941 DOI: 10.3390/ijms222111810] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins' properties and their biological functions. Some of the transcription factors, including tumor suppressors and oncoproteins, undergo this modification altering different cell signaling pathways. HDACs deacetylate their targets, which leads to either the upregulation or downregulation of proteins involved in the regulation of cell cycle and apoptosis, ultimately influencing tumor growth, invasion, and drug resistance. Therefore, epigenetic modifications are of great clinical importance and may constitute a new therapeutic target in cancer treatment. This review is aimed to present the significance of HDACs in carcinogenesis through their influence on functions of transcription factors, and therefore regulation of different signaling pathways, cancer progression, and metastasis.
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Affiliation(s)
- Marta Halasa
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Kamila Adamczuk
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Grzegorz Adamczuk
- Independent Medical Biology Unit, Medical University of Lublin, Kazimierza Jaczewskiego 8b St., 20-090 Lublin, Poland;
| | - Syeda Afshan
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, 20520 Turku, Finland;
| | - Andrzej Stepulak
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Marek Cybulski
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
| | - Anna Wawruszak
- Chair and Department of Biochemistry and Molecular Biology, Medical University of Lublin, Witolda Chodźki 1 St., 20-093 Lublin, Poland; (M.H.); (K.A.); (A.S.); (M.C.)
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Chen YH, Li CL, Chen WJ, Liu J, Wu HT. Diverse roles of FOXO family members in gastric cancer. World J Gastrointest Oncol 2021; 13:1367-1382. [PMID: 34721771 PMCID: PMC8529928 DOI: 10.4251/wjgo.v13.i10.1367] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/06/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fifth most diagnosed cancer and the third leading cause of cancer-related death worldwide. Although progress has been made in diagnosis, surgical resection, systemic chemotherapy, and immunotherapy, patients with GC still have a poor prognosis. The overall 5-year survival rate in patients with advanced GC is less than 5%. The FOXO subfamily, of the forkhead box family of transcription factors, consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6. This subfamily plays an important role in many cellular processes, such as cell cycle, cell growth, apoptosis, autophagy, stress resistance, protection from aggregate toxicity, DNA repair, tumor suppression, and metabolism, in both normal tissue and malignant tumors. Various studies support a role for FOXOs as tumor suppressors based on their ability to inhibit angiogenesis and metastasis, and promote apoptosis, yet several other studies have shown that FOXOs might also promote tumor progression in certain circumstances. To elucidate the diverse roles of FOXOs in GC, this article systematically reviews the cellular functions of FOXOs in GC to determine potential therapeutic targets and treatment strategies for patients with GC.
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Affiliation(s)
- Yu-Han Chen
- Department of Clinical Medicine, Shantou University Medical College, Shantou 515041, Guangdong Province, China
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Chun-Lan Li
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Changjiang Scholar's Laboratory, Department of Physiology, Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Wu W, Cao X, Wang Y. The role of miRNA-624-5p in congenital hypothyroidism and its molecular mechanism by targeting SIRT1. Genes Genomics 2021; 44:1137-1147. [PMID: 34609722 DOI: 10.1007/s13258-021-01171-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/23/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Accumulating reports evidenced that congenital hypothyroidism (CH) is a kind of endocrine diseases caused by thyroid hormone imperfection. MicroRNAs (miRNAs) were confirmed to exhibit protective functions in CH progression. However, the functions and latent mechanism of microRNA-624-5p (miR-624-5p) in CH remains unknown. OBJECTIVE This report was designed to illustrate the potential molecular mechanisms of miR-624-5p on CH. METHODS Rats were induced by 50 mg/day propylthiouracil to conduct CH models. Free thyroxine (fT4) and thyroid-Stimulating hormone (TSH) concentrations were measured to confirm CH model conduction. The direct target of miR-624-5p was predicted and verified by Starbase and dual luciferase reporter assay. Besides, the levels of miR-624-5p and sirtuin1 (SIRT1) in hippocampus or hippocampal neuronal cells were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot assays. Then CH rat behaviors were evaluated using open field test (OFT) and forced swim test (FST). Furthermore, neuronal cells viability and apoptosis were checked using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry. RESULTS qRT-PCR assay suggested that miR-624-5p was up-regulated and SIRT1 was low-expressed in hippocampus tissues of CH rats. SIRT1 was a direct target of miR-624-5p. MiR-624-5p inhibitor signally enhanced fT4 levels and reduced TSH levels in the plasma of CH rats, and improved CH rat depressive behaviors by targeting SIRT1. Moreover, our data also revealed that miR-624-5p inhibitor increased cell viability and reduced apoptotic neuronal cells, which was reversed by silencing of SIRT1. CONCLUSIONS Taken together, this research demonstrated that miR-624-5p serves as a promising target for CH treatment.
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Affiliation(s)
- Wanli Wu
- Department of Pediatrics, Yiwu Maternity and Children Hospital, No. C100 Xinke Road, Yiwu, 322000, China
| | - Xuying Cao
- Department of Pediatrics, Yiwu Maternity and Children Hospital, No. C100 Xinke Road, Yiwu, 322000, China
| | - Yuhong Wang
- Department of Pediatrics, Yiwu Maternity and Children Hospital, No. C100 Xinke Road, Yiwu, 322000, China.
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Jin JO, Puranik N, Bui QT, Yadav D, Lee PCW. The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer. Int J Mol Sci 2021; 22:9629. [PMID: 34502538 PMCID: PMC8431782 DOI: 10.3390/ijms22179629] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/03/2021] [Accepted: 09/03/2021] [Indexed: 12/25/2022] Open
Abstract
The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system.
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Affiliation(s)
- Jun-O Jin
- Shanghai Public Health Clinical Center & Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Nidhi Puranik
- Biological Sciences Department, Bharathiar University, Coimbatore 641046, Tamil Nadu, India;
| | - Quyen Thu Bui
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
| | - Dhananjay Yadav
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Peter Chang-Whan Lee
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea;
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Visfatin Promotes the Metastatic Potential of Chondrosarcoma Cells by Stimulating AP-1-Dependent MMP-2 Production in the MAPK Pathway. Int J Mol Sci 2021; 22:ijms22168642. [PMID: 34445345 PMCID: PMC8395530 DOI: 10.3390/ijms22168642] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/30/2021] [Accepted: 08/08/2021] [Indexed: 12/12/2022] Open
Abstract
Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.
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Liu J, Feng W, Liu M, Rao H, Li X, Teng Y, Yang X, Xu J, Gao W, Li L. Stomach-specific c-Myc overexpression drives gastric adenoma in mice through AKT/mammalian target of rapamycin signaling. Bosn J Basic Med Sci 2021; 21:434-446. [PMID: 33259779 PMCID: PMC8292868 DOI: 10.17305/bjbms.2020.4978] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/16/2020] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant cancers in the world. c-Myc, a well-known oncogene, is commonly amplified in many cancers, including gastric cancer. However, it is still not completely understood how c-Myc functions in GC. Here, we generated a stomach-specific c-Myc transgenic mouse model to investigate its role in GC. We found that overexpression of c-Myc in Atp4b+ gastric parietal cells could induce gastric adenoma in mice. Mechanistically, c-Myc promoted tumorigenesis via the AKT/mTOR pathway. Furthermore, AKT inhibitor (MK-2206) or mTOR inhibitor (Rapamycin) inhibited the proliferation of c-Myc overexpressing gastric cancer cell lines. Thus, our findings highlight that gastric tumorigenesis can be induced by c-Myc overexpression through activation of the AKT/mTOR pathway.
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Affiliation(s)
- Jing Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Wenxin Feng
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Min Liu
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Hanyu Rao
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoxue Li
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Teng
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Xiao Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing, China
| | - Jin Xu
- School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Weiqiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
| | - Li Li
- State Key Laboratory of Oncogenes and Related Genes, Renji Med-X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China
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Guo JN, Xia BR, Deng SH, Yang C, Pi YN, Cui BB, Jin WL. Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential. Front Cell Dev Biol 2021; 9:680100. [PMID: 34179009 PMCID: PMC8220152 DOI: 10.3389/fcell.2021.680100] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/17/2021] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.
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Affiliation(s)
- Jun-Nan Guo
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bai-Rong Xia
- Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Anhui Provincial Cancer Hospital, University of Science and Technology of China, Hefei, China
| | - Shen-Hui Deng
- Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chang Yang
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ya-Nan Pi
- Department of Gynecology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Wei-Lin Jin
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, Institute of Cancer Neuroscience, The First Clinical Medical College of Lanzhou University, Lanzhou, China
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Hong S, Li S, Bi M, Yu H, Yan Z, Liu T, Wang H. lncRNA ILF3-AS1 promotes proliferation and metastasis of colorectal cancer cells by recruiting histone methylase EZH2. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 24:1012-1023. [PMID: 34141456 PMCID: PMC8167202 DOI: 10.1016/j.omtn.2021.04.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 04/07/2021] [Indexed: 12/11/2022]
Abstract
The role of long non-coding RNA (lncRNA) has been displayed in colorectal cancer (CRC). Here, we aimed to discuss the role of lncRNA interleukin enhancer-binding factor 3-antisense RNA 1 (ILF3-AS1)/enhancer of zeste homolog 2 (EZH2)/cyclin-dependent kinase inhibitor 2 (CDKN2A)/histone 3 (H3) lysine 27 trimethylation (H3K27me3) in cell proliferation and metastasis of CRC. ILF3-AS1, EZH2, and CDKN2A levels in CRC tissues and cells were detected. The relationship between ILF3-AS1/EZH2 expression and the clinicopathological features of CRC was analyzed. High/low expression of ILF3-AS1/EZH2 plasmids were composed to explore the function of ILF3-AS1/EZH2 in invasion, migration, proliferation, colony formation, and apoptosis of CRC cells. The growth status of nude mice was observed to verify the in vitro results from in vivo experiment. ILF3-AS1 and EZH2 increased, whereas CDKN2A reduced in CRC tissues and cells. ILF3-AS1 and EZH2 expression was linked to Dukes stage, distant metastasis, vascular invasion, and lymph node metastasis of CRC patients. Depleted ILF3-AS1 or reduced EZH2 suppressed proliferation, migration, colony-formation, and invasion ability, as well as facilitated apoptosis of CRC cells and attenuated the tumor growth in CRC mice. ILF3-AS1 accelerates the proliferation and metastasis of CRC cells by recruiting histone methylase EZH2 to induce trimethylation of H3K27 and downregulate CDKN2A.
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Affiliation(s)
- Sen Hong
- Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China
| | - Shiquan Li
- Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China
| | - Miaomiao Bi
- Department of Ophthalmology, The China-Japan Union Hospital of Jilin University, Jilin University, Changchun 130022, Jilin, People’s Republic of China
| | - Haiyao Yu
- Chief Pharmacist, Changchun Food and Drug Inspection Center, Changchun, Jilin, People’s Republic of China
| | - Zhenkun Yan
- Endoscopy Center, The China-Japan Union Hospital of Jilin University, Changchun 130022, Jilin, People’s Republic of China
| | - Tao Liu
- Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China
| | - Helei Wang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun 130021, Jilin, People’s Republic of China
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Lee CS, Kim S, Hwang G, Song J. Deubiquitinases: Modulators of Different Types of Regulated Cell Death. Int J Mol Sci 2021; 22:4352. [PMID: 33919439 PMCID: PMC8122337 DOI: 10.3390/ijms22094352] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 02/06/2023] Open
Abstract
The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.
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Affiliation(s)
- Choong-Sil Lee
- Integrated OMICS for Biomedical Science, World Class University, Yonsei University, Seoul 120-749, Korea;
| | - Seungyeon Kim
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; (S.K.); (G.H.)
| | - Gyuho Hwang
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; (S.K.); (G.H.)
| | - Jaewhan Song
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; (S.K.); (G.H.)
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Jin D, Wei W, Song C, Han P, Leng X. RETRACTED: Knockdown EZH2 attenuates cerebral ischemia-reperfusion injury via regulating microRNA-30d-3p methylation and USP22. Brain Res Bull 2021; 169:25-34. [PMID: 33388376 DOI: 10.1016/j.brainresbull.2020.12.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 11/30/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023]
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief as there are concerns about the reliability of the results. Concerns have been raised about a portion of Figure 5B, ‘DMSO’ group appears to contain image similarities with Figure 4e, ‘Inhibitor NC’ group, published in Yang et al., 2021 doi: 10.1080/15384101.2020.1856498. A portion of Figure 5B, ‘DZNeP+miR-30d-3p antagomir’ group appears to contain image similarities with Figure 4e, ‘Inhibitor NC’ group, published in Yang et al., 2021. Figure 7/G western blot bands have the same eyebrow shaped phenotype as many other publications as detailed here (https://pubpeer.com/publications/B26AE47AC0E71E0EF339B40893B2C2).
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Affiliation(s)
- Dianshi Jin
- The Affliated Dalian Central Hospital of Dalian Medical University, Dalian, 116033 Liaoning, China.
| | - Wei Wei
- The Affliated Dalian Central Hospital of Dalian Medical University, Dalian, 116033 Liaoning, China
| | - Chong Song
- The Affliated Dalian Central Hospital of Dalian Medical University, Dalian, 116033 Liaoning, China
| | - Peng Han
- The Affliated Dalian Central Hospital of Dalian Medical University, Dalian, 116033 Liaoning, China
| | - Xiaolei Leng
- The Affliated Dalian Central Hospital of Dalian Medical University, Dalian, 116033 Liaoning, China
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Cai W, Ni W, Jin Y, Li Y. TRIP13 promotes lung cancer cell growth and metastasis through AKT/mTORC1/c-Myc signaling. Cancer Biomark 2021; 30:237-248. [PMID: 33136091 DOI: 10.3233/cbm-200039] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) is a primary cause of cancer-patient mortality throughout the world. Thyroid hormone receptor interactor 13 (TRIP13) is a gene that expresses a protein involved in cell division, including tumorigenesis. Its expression is high in various human tumors; however, its role in LUAD cells remains undetermined. OBJECTIVE To investigate the TRIP13's role in the development of LUAD. METHODS Bioinformation analysis was used to analyze the expression of TRIP13 in LUAD tissues and the impact on the prognosis of LUAD; CRISPR/Cas9 was used to construct the cell lines; CCK-8 was used to explore the cell proliferation; Transwell assays was applied to exam the cell migration and cell invasion abilities; Western blot and immunoprecipitation was used to explore the relation between TRIP13 and AKT/mTORC1/c-Myc signaling pathway. RESULTS By analyzing LUAD data from The Cancer Genome Atlas and the Gene Expression Omnibus databases, we determined that TRIP13 is highly expressed in LUAD tissues and that this expression level has a negative impact on the patient mortality. TRIP13 has also proved to promote LUAD cell proliferation, migration, and invasion. In this study, we demonstrated that TRIP13 activates AKT/mTORC1/c-Myc signaling in these cells. CONCLUSION Our results have identified the role and potential mechanism by which TRIP13 affects LUAD cells, which may provide a useful marker for helping to diagnose this disease and create new therapies against it.
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Affiliation(s)
- Weiyang Cai
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Ni
- Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai, China.,Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yin Jin
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yanyan Li
- Department of Ultrasound, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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LeBlanc L, Ramirez N, Kim J. Context-dependent roles of YAP/TAZ in stem cell fates and cancer. Cell Mol Life Sci 2021; 78:4201-4219. [PMID: 33582842 PMCID: PMC8164607 DOI: 10.1007/s00018-021-03781-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/30/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Hippo effectors YAP and TAZ control cell fate and survival through various mechanisms, including transcriptional regulation of key genes. However, much of this research has been marked by conflicting results, as well as controversy over whether YAP and TAZ are redundant. A substantial portion of the discordance stems from their contradictory roles in stem cell self-renewal vs. differentiation and cancer cell survival vs. apoptosis. In this review, we present an overview of the multiple context-dependent functions of YAP and TAZ in regulating cell fate decisions in stem cells and organoids, as well as their mechanisms of controlling programmed cell death pathways in cancer.
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Affiliation(s)
- Lucy LeBlanc
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA. .,Interdisciplinary Life Sciences Graduate Program, The University of Texas at Austin, Austin, TX, 78712, USA.
| | - Nereida Ramirez
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.,Harvard Medical School, 25 Shattuck St, Boston, MA, 02115, USA
| | - Jonghwan Kim
- Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA. .,Interdisciplinary Life Sciences Graduate Program, The University of Texas at Austin, Austin, TX, 78712, USA. .,Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, TX, 78712, USA.
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Rong J, Li Z, Xu L, Lang L, Zheng G. microRNA-362-3p targets USP22 to retard retinoblastoma growth via reducing deubiquitination of LSD1. Cell Cycle 2021; 20:298-307. [PMID: 33475455 DOI: 10.1080/15384101.2021.1874685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Accumulating evidence has reported the role of microRNA (miR) in retinoblastoma (RB). Therefore, the objective was to discuss how miR-362-3p exerted its function in RB cell progression via regulating ubiquitin-specific protease 2 (USP22) and lysine-specific histone demethylase 1 (LSD1). MiR-362-3p, USP22 and LSD1 expression in RB cells and tissues were tested. The biological functions of RB cells were detected via over-expressing miR-362-3p and down-regulating USP22. The target relationship of USP22 and miR-362-3p as well as the interaction of USP22 and LSD1 in RB was verified. Down-regulated miR-362-3p and up-regulated USP22 and LSD1 were demonstrated in RB tissues and cells. Restoring miR-362-3p and depleting USP22 attenuated invasion, proliferation and migration, and facilitated apoptosis of RB cells. USP22 was a target gene of miR-362-3p. USP22 deubiquitinated LSD1 in RB. It is revealed that miR-362-3p targets USP22 and then restrains invasion, proliferation and migration while promotes apoptosis of RB via reducing LSD1 modified by deubiquitination.
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Affiliation(s)
- Junbo Rong
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan, China
| | - Zhigang Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan, China
| | - Limin Xu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan, China
| | - Lijuan Lang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan, China
| | - Guangying Zheng
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University , Zhengzhou, Henan, China
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Fu T, Ji K, Jin L, Zhang J, Wu X, Ji X, Fan B, Jia Z, Wang A, Liu J, Bu Z, Ji J. ASB16-AS1 up-regulated and phosphorylated TRIM37 to activate NF-κB pathway and promote proliferation, stemness, and cisplatin resistance of gastric cancer. Gastric Cancer 2021; 24:45-59. [PMID: 32572790 DOI: 10.1007/s10120-020-01096-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/28/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Long non-coding RNA (lncRNA) ASB16 antisense RNA 1 (ASB16-AS1) is recognized as an oncogene in several cancer types, but its relation to GC is unknown. Tripartite motif containing 37 (TRIM37) has been proven to accelerate the development of gastric cancer (GC), whereas the molecular mechanism assisted ASB16-AS1 and TRIM37 in regulating GC progression remains unclear. METHODS Differentially expressed lncRNAs in GC samples were analyzed based on Gene Expression Omnibus (GEO) data. CCK-8 and colony formation assays were applied to determine the proliferative ability of GC cells. Stem cell-like phenotype of GC cells was assessed by sphere formation assay and flow cytometry analysis. Luciferase reporter assay, RNA immunoprecipitation (RIP), pulldown, and co-immunoprecipitation (Co-IP) were performed to verify the interplay of RNA molecules. RESULTS ASB16-AS1 was upregulated in GC samples according to GEO data and qRT-PCR analysis. ASB16-AS1 strengthened the proliferative ability and stem cell-like characteristics in GC cells. More importantly, ASB16-AS1 encouraged GC cell growth in vivo. Mechanistically, ASB16-AS1 strengthened TRIM37 expression by sequestering miR-3918 and miR-4676-3p. ASB16-AS1 activated NF-kappa B (NF-κB) pathway by cooperating with ATM serine/threonine kinase (ATM) to induce TRIM37 phosphorylation. CONCLUSION In summary, ASB16-AS1 exerted oncogenic functions in GC through modulating TRIM37 expression at both mRNA and protein levels.
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Affiliation(s)
- Tao Fu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Ke Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Li Jin
- Department of Radiotherapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Ji Zhang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xiaojiang Wu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Xin Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Biao Fan
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Ziyu Jia
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Anqiang Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Jiaen Liu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Zhaode Bu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China.
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Xiang C, Cong S, Liang B, Cong S. Bioinformatic gene analysis for potential therapeutic targets of Huntington's disease in pre-symptomatic and symptomatic stage. J Transl Med 2020; 18:388. [PMID: 33054835 PMCID: PMC7559361 DOI: 10.1186/s12967-020-02549-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 09/27/2020] [Indexed: 01/18/2023] Open
Abstract
Background Huntington’s disease (HD) is a neurodegenerative disorder characterized by psychiatric symptoms, serious motor and cognitive deficits. Certain pathological changes can already be observed in pre-symptomatic HD (pre-HD) patients; however, the underlying molecular pathogenesis is still uncertain and no effective treatments are available until now. Here, we reanalyzed HD-related differentially expressed genes from the GEO database between symptomatic HD patients, pre-HD individuals, and healthy controls using bioinformatics analysis, hoping to get more insight in the pathogenesis of both pre-HD and HD, and shed a light in the potential therapeutic targets of the disease. Methods Pre-HD and symptomatic HD differentially expressed genes (DEGs) were screened by bioinformatics analysis Gene Expression Omnibus (GEO) dataset GSE1751. A protein–protein interaction (PPI) network was used to select hub genes. Subsequently, Gene Ontology (GO) enrichment analysis of DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of hub genes were applied. Dataset GSE24250 was downloaded to verify our hub genes by the Kaplan–Meier method using Graphpad Prism 5.0. Finally, target miRNAs of intersected hub genes involved in pre-HD and symptomatic HD were predicted. Results A total of 37 and 985 DEGs were identified in pre-HD and symptomatic HD, respectively. The hub genes, SIRT1, SUZ12, and PSMC6, may be implicated in pre-HD, and the hub genes, FIS1, SIRT1, CCNH, SUZ12, and 10 others, may be implicated in symptomatic HD. The intersected hub genes, SIRT1 and SUZ12, and their predicted target miRNAs, in particular miR-22-3p and miR-19b, may be significantly associated with pre-HD. Conclusion The PSMC6, SIRT1, and SUZ12 genes and their related ubiquitin-mediated proteolysis, transcriptional dysregulation, and histone metabolism are significantly associated with pre-HD. FIS1, CCNH, and their related mitochondrial disruption and transcriptional dysregulation processes are related to symptomatic HD, which might shed a light on the elucidation of potential therapeutic targets in HD.
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Affiliation(s)
- Chunchen Xiang
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Shengri Cong
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China
| | - Bin Liang
- Bioinformatics of Department, School of Life Sciences, China Medical University, Shenyang, China
| | - Shuyan Cong
- Department of Neurology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China.
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