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Kołodziejczak-Guglas I, Simões RLS, de Souza Santos E, Demicco EG, Lazcano Segura RN, Ma W, Wang P, Geffen Y, Storrs E, Petralia F, Colaprico A, da Veiga Leprevost F, Pugliese P, Ceccarelli M, Noushmehr H, Nesvizhskii AI, Kamińska B, Priebe W, Lubiński J, Zhang B, Lazar AJ, Kurzawa P, Mesri M, Robles AI, Ding L, Malta TM, Wiznerowicz M. Proteomic-based stemness score measures oncogenic dedifferentiation and enables the identification of druggable targets. CELL GENOMICS 2025:100851. [PMID: 40250426 DOI: 10.1016/j.xgen.2025.100851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/13/2024] [Accepted: 03/21/2025] [Indexed: 04/20/2025]
Abstract
Cancer progression and therapeutic resistance are closely linked to a stemness phenotype. Here, we introduce a protein-expression-based stemness index (PROTsi) to evaluate oncogenic dedifferentiation in relation to histopathology, molecular features, and clinical outcomes. Utilizing datasets from the Clinical Proteomic Tumor Analysis Consortium across 11 tumor types, we validate PROTsi's effectiveness in accurately quantifying stem-like features. Through integration of PROTsi with multi-omics, including protein post-translational modifications, we identify molecular features associated with stemness and proteins that act as active nodes within transcriptional networks, driving tumor aggressiveness. Proteins highly correlated with stemness were identified as potential drug targets, both shared and tumor specific. These stemness-associated proteins demonstrate predictive value for clinical outcomes, as confirmed by immunohistochemistry in multiple samples. The findings emphasize PROTsi's efficacy as a valuable tool for selecting predictive protein targets, a crucial step in customizing anti-cancer therapy and advancing the clinical development of cures for cancer patients.
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Affiliation(s)
- Iga Kołodziejczak-Guglas
- International Institute for Molecular Oncology, 60-203 Poznań, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Renan L S Simões
- School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil
| | - Emerson de Souza Santos
- School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil
| | - Elizabeth G Demicco
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON M5G 1X5, Canada
| | - Rossana N Lazcano Segura
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Weiping Ma
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Pei Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yifat Geffen
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA 02115, USA
| | - Erik Storrs
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Francesca Petralia
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Antonio Colaprico
- Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | | | - Pietro Pugliese
- Department of Science and Technology, University of Sannio, 82100 Benevento, Italy
| | - Michele Ceccarelli
- Sylvester Comprehensive Cancer Center and Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Houtan Noushmehr
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, MI 48202, USA
| | - Alexey I Nesvizhskii
- Departments of Pathology and Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Bożena Kamińska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland
| | - Waldemar Priebe
- Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 70-204 Szczecin, Poland
| | - Bing Zhang
- Lester and Sue Smith Breast Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander J Lazar
- Departments of Pathology & Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Paweł Kurzawa
- Department of Oncological Pathology, University Clinical Hospital in Poznan, Poznan University of Medical Sciences, 60-514 Poznań, Poland
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850, USA
| | - Li Ding
- Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Tathiane M Malta
- School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Ribeirão Preto 14040-903, Brazil; Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil.
| | - Maciej Wiznerowicz
- International Institute for Molecular Oncology, 60-203 Poznań, Poland; Department of Oncology, Institute of Oncology, University Clinical Hospital in Poznan, Poznan University of Medical Sciences, 60-659 Poznań, Poland.
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Saha G, Ghosh MK. The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2025; 1872:119908. [PMID: 39880128 DOI: 10.1016/j.bbamcr.2025.119908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/10/2025] [Accepted: 01/24/2025] [Indexed: 01/31/2025]
Abstract
The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.
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Affiliation(s)
- Gouranga Saha
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
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Jansen C, McAdams J, Kim C, De La Cruz P, Salaverria A, DaSilva NA, Grive K, James NE. Small molecule inhibition of ubiquitin C-terminal hydrolase L1 alters cell metabolism proteins and exerts anti- or pro-tumorigenic effects contingent upon chemosensitivity status in high grade serous ovarian cancer. Front Pharmacol 2025; 16:1547164. [PMID: 40078282 PMCID: PMC11897294 DOI: 10.3389/fphar.2025.1547164] [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: 12/17/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies in which the majority of patients eventually develop chemoresistant recurrent disease. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme canonically known for its involvement in neurodegeneration, but recently has been shown to play a key role in tumorigenesis. Furthermore, UCHL1 has garnered attention across a multitude of cancer subtypes as it has the ability to be targeted through small molecule inhibition. Therefore, the goal of this present study was to elucidate mechanistic consequences of small molecule UCHL1 inhibition in HGSOC. Comparative label-free proteomic analysis of HGSOC cell line, OVCAR8 revealed prominent changes in cell metabolism proteins upon treatment with UCHL1 small molecule inhibitor, LDN-57444. Further validation via Western blot analysis revealed that changes in cell metabolism proteins differed in matched chemosensitive versus chemoresistant HGSOC cells. Finally, cell viability analysis demonstrated that a combinatorial carboplatin and LDN-57444 blockade produced a promotion or conversely, inhibition of cell death, in chemoresistant, and chemosensitve HGSOC cells, respectively. This phenomenon was further corroborated by respective differences in activation levels of common tumor cell growth pathways STAT3, MAPK/ERK, and AKT in chemoresistant versus chemosensitive HGSOC cells. Overall, this investigation established that pharmacologic targeting of UCHL1 produces differential effects according to HGSOC chemosensitivity status.
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Affiliation(s)
- Corinne Jansen
- Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
| | - Julia McAdams
- Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
| | - Chloe Kim
- School of Public Health, Brown University, Providence, RI, United States
| | - Payton De La Cruz
- Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
| | - Angelica Salaverria
- Therapeutic Sciences Graduate Program, Brown University, Providence, RI, United States
| | - Nicholas A. DaSilva
- Division of Biology and Medicine, Proteomics Facility, Brown University, Providence, RI, United States
| | - Kathryn Grive
- Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
| | - Nicole E. James
- Program in Women’s Oncology, Women and Infants Hospital, Providence, RI, United States
- Department of Obstetrics and Gynecology, Warren-Alpert Medical School of Brown University, Providence, RI, United States
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Filipovich E, Gorodkova E, Shcherbakova A, Asaad W, Popov S, Melnichenko G, Mokrysheva N, Utkina M. The role of cell cycle-related genes in the tumorigenesis of adrenal and thyroid neuroendocrine tumors. Heliyon 2025; 11:e41457. [PMID: 39834406 PMCID: PMC11742855 DOI: 10.1016/j.heliyon.2024.e41457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/16/2024] [Accepted: 12/23/2024] [Indexed: 01/22/2025] Open
Abstract
The molecular mechanisms underlying adrenal and thyroid neuroendocrine tumors, including their tumorigenesis, progression, and metastasis, involve unique pathways regulating cell cycle progression. To better understand these mechanisms and pathways, extensive in-depth research on cell cycle-related genes is necessary. This review aims to describe and interpret current single-cell RNA sequencing studies on neuroblastoma, medullary thyroid cancer, and pheochromocytoma tumors. Our review summarizes differentially expressed cell cycle-related genes with distinct functions, highlighting their potential as therapeutic targets and components of panels used to determine tumor type or aggressiveness. Although some insights have been gained, there is still limited information on these topics, and further research is required to explore the regulatory mechanisms of these tumors.
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Affiliation(s)
- Ekaterina Filipovich
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Ekaterina Gorodkova
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Anastasia Shcherbakova
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Walaa Asaad
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Sergey Popov
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Galina Melnichenko
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Natalya Mokrysheva
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
| | - Marina Utkina
- Laboratory of General, Molecular and Population Genetics, Endocrinology Research Center, Moscow, 117292, Russia
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Du S, Wang Y, Tao W, Lu S. Differential effects of enzymatically modified Ougan (Citrus Suavissima Hort. ex Tanaka) peel pectins extracted with different methods on inhibiting the proliferation of Hela cells. Int J Biol Macromol 2024; 278:134463. [PMID: 39102920 DOI: 10.1016/j.ijbiomac.2024.134463] [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: 05/21/2024] [Revised: 07/24/2024] [Accepted: 08/01/2024] [Indexed: 08/07/2024]
Abstract
Previous studies have shown that modified citrus pectin (MCP) is an anti-tumor material of food grade. In this study, two enzymatically modified Ougan (Citrus Suavissima Hort. ex Tanaka) peel pectins (EMP1 and EMP2, the ones extracted by alkali and enzymatic methods) were used to investigate their differential effects on viability and physiology of Hela cells. The results showed that EMP1 and EMP2 had 88.00 % and 81.01 % galacturonic acid, 21.31 % and 20.25 % esterification degree, 10,417 g/mol and 6416 g/mol molecular weight (Mw), 82.86 % and 50.62 % RG-I, and 8.91 % and 15.70 % HG, respectively. EMP2 had higher intensities of absorption peaks than EMP1. They were irregularly shaped, with more holes on EMP1 but more wrinkles on EMP2. Both could inhibit the growth, proliferation, migration, and invasion of HeLa cells in a concentration-dependent manner, with better efficiency in EMP2. Meanwhile, EMP2 was more efficient than EMP1 in blocking the cell cycle in S phase, resulting in apoptosis. In conclusion, the variations caused by extraction resulted in differences in anti-tumor activity of MCP and EMP2 with lower Mw and higher HG exhibited better anti-tumor effects. This study would provide an experimental basis and reference for the research and development of anti-tumor supplements from citrus pectin.
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Affiliation(s)
- Shuangning Du
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Zhejiang Key Laboratory of Intelligent Food Logistic and Processing, Ministry of Agriculture and Rural Affairs Key Laboratory of Post-Harvest Handling of Fruits, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China; School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China
| | - Yangguang Wang
- School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
| | - Wenyang Tao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Zhejiang Key Laboratory of Intelligent Food Logistic and Processing, Ministry of Agriculture and Rural Affairs Key Laboratory of Post-Harvest Handling of Fruits, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Shengmin Lu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Zhejiang Key Laboratory of Intelligent Food Logistic and Processing, Ministry of Agriculture and Rural Affairs Key Laboratory of Post-Harvest Handling of Fruits, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China; School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan 316022, China.
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Duranti E, Villa C. Insights into Dysregulated Neurological Biomarkers in Cancer. Cancers (Basel) 2024; 16:2680. [PMID: 39123408 PMCID: PMC11312413 DOI: 10.3390/cancers16152680] [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: 06/20/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
The link between neurodegenerative diseases (NDs) and cancer has generated greater interest in biomedical research, with decades of global studies investigating neurodegenerative biomarkers in cancer to better understand possible connections. Tau, amyloid-β, α-synuclein, SOD1, TDP-43, and other proteins associated with nervous system diseases have also been identified in various types of solid and malignant tumors, suggesting a potential overlap in pathological processes. In this review, we aim to provide an overview of current evidence on the role of these proteins in cancer, specifically examining their effects on cell proliferation, apoptosis, chemoresistance, and tumor progression. Additionally, we discuss the diagnostic and therapeutic implications of this interconnection, emphasizing the importance of further research to completely comprehend the clinical implications of these proteins in tumors. Finally, we explore the challenges and opportunities in targeting these proteins for the development of new targeted anticancer therapies, providing insight into how to integrate knowledge of NDs in oncology research.
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Affiliation(s)
| | - Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy;
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Xu Z, Zhang N, Shi L. Potential roles of UCH family deubiquitinases in tumorigenesis and chemical inhibitors developed against them. Am J Cancer Res 2024; 14:2666-2694. [PMID: 39005671 PMCID: PMC11236784 DOI: 10.62347/oege2648] [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: 02/18/2024] [Accepted: 05/30/2024] [Indexed: 07/16/2024] Open
Abstract
Deubiquitinating enzymes (DUBs) are a large group of proteases that reverse ubiquitination process and maintain protein homeostasis. The DUBs have been classified into seven subfamilies according to their primary sequence and structural similarity. As a small subfamily of DUBs, the ubiquitin C-terminal hydrolases (UCHs) subfamily only contains four members including UCHL1, UCHL3, UCHL5, and BRCA1-associated protein-1 (BAP1). Despite sharing the deubiquitinase activity with a similar catalysis mechanism, the UCHs exhibit distinctive biological functions which are mainly determined by their specific subcellular localization and partner substrates. Besides, growing evidence indicates that the UCH enzymes are involved in human malignancies. In this review, the structural information and biological functions of the UCHs are briefly described. Meanwhile, the roles of these enzymes in tumorigenesis and the discovered inhibitors against them are also summarized to give an insight into the cancer therapy with the potential alternative strategy.
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Affiliation(s)
- Zhuo Xu
- State Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences555 Zu Chong Zhi Road, Shanghai 201203, China
- University of The Chinese Academy of Sciences19A Yuquan Road, Beijing 100049, China
| | - Naixia Zhang
- State Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences555 Zu Chong Zhi Road, Shanghai 201203, China
- University of The Chinese Academy of Sciences19A Yuquan Road, Beijing 100049, China
| | - Li Shi
- State Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of Sciences555 Zu Chong Zhi Road, Shanghai 201203, China
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Zheng LL, Wang LT, Pang YW, Sun LP, Shi L. Recent advances in the development of deubiquitinases inhibitors as antitumor agents. Eur J Med Chem 2024; 266:116161. [PMID: 38262120 DOI: 10.1016/j.ejmech.2024.116161] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/25/2024]
Abstract
Ubiquitination is a type of post-translational modification that covalently links ubiquitin to a target protein, which plays a critical role in modulating protein activity, stability, and localization. In contrast, this process is reversed by deubiquitinases (DUBs), which remove ubiquitin from ubiquitinated substrates. Dysregulation of DUBs is associated with several human diseases, such as cancer, inflammation, neurodegenerative disorders, and autoimmune diseases. Thus, DUBs have become promising targets for drug development. Although the physiological and pathological effects of DUBs are increasingly well understood, the clinical drug discovery of selective DUB inhibitors has been challenging. Herein, we summarize the structures and functions of main classes of DUBs and discuss the recent progress in developing selective small-molecule DUB inhibitors as antitumor agents.
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Affiliation(s)
- Li-Li Zheng
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li-Ting Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Ye-Wei Pang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Lei Shi
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
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Hoai Nga NT, Long TT, Ngoc TTB, Nguyen NHK, Thao DTP, Trinh NTM. Ethyl Acetate Extract from Romdoul ( Sphaerocoryne affinis) Fruit Induced Apoptosis in Human Promyelocytic Leukemia Cells. GLOBAL ADVANCES IN INTEGRATIVE MEDICINE AND HEALTH 2024; 13:27536130241296826. [PMID: 39494213 PMCID: PMC11528603 DOI: 10.1177/27536130241296826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/10/2024] [Accepted: 10/17/2024] [Indexed: 11/05/2024]
Abstract
Background Romdoul (Sphaerocoryne affinis) is a flowering plant of the Annonaceae family and has been used customarily in folk medicine. The bioactivities of this plant, especially the anti-cancer effect, however, remain surprisingly few. Objective this study aimed to elucidate the anti-leukemic effect of romdoul fruit extracts and their underlining mechanisms. Methods The extracts were prepared from fresh fruits and the phytochemical contents were evaluated by biochemical assays and HPLC method. The promising extract was identified via the inhibition of HL60 as well as normal NIH-3T3 cell densities utilizing MTT assay. The underline mechanism of the extract's effect was studied by accessing the treated HL60 cell population overtime (via MTT assay). The morphology of abnormal cells was examined by bright-field microscopic imaging. Hallmarks of apoptosis including nucleus characteristics and caspase 3 activation were analyzed by fluorescence imaging. The underline mechanisms of apoptosis and proliferation inhibition were accessed via RT-qPCR examination of involved genes. Results Our findings showed that the ethyl acetate extract of romdoul fruit (SA-EA) was found to be an exceptional anti-leukemic candidate (IC50 was as low as 4.11 μg/mL). More interestingly, the treated HL60 cells expressed nuclear fragmentation and caspase 3 activation, indicating the effect could follow an apoptotic mechanism. Importantly, the transcription assessment of apoptotic and proliferative genes suggested that SA-EA might suppress the growth of HL60 cells and induce p21-dependent apoptotic pathway. Conclusion This study demonstrated one of the first scientific evidence for the anti-cancer activity of Sphaerocoryne affinis fruit-derived extract. Thus, our findings exhibited a novel and promising anti-leukemic candidate for future studies.
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Affiliation(s)
- Nguyen Thi Hoai Nga
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
| | - Tran Thanh Long
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
| | - Truong Thi Bich Ngoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
- Laboratory of Molecular Biotechnology, VNUHCM- University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University, Ho Chi Minh City, Viet Nam
| | - Nguyen Hoang Khoi Nguyen
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
- Laboratory of Molecular Biotechnology, VNUHCM- University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University, Ho Chi Minh City, Viet Nam
| | - Dang Thi Phuong Thao
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
- Laboratory of Molecular Biotechnology, VNUHCM- University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University, Ho Chi Minh City, Viet Nam
- Laboratory of Cancer Research, VNUHCM- University of Science, Ho Chi Minh City, Viet Nam
| | - Nguyen Thi My Trinh
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNUHCM-University of Science, Ho Chi Minh City, Viet Nam
- Laboratory of Molecular Biotechnology, VNUHCM- University of Science, Ho Chi Minh City, Viet Nam
- Vietnam National University, Ho Chi Minh City, Viet Nam
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Du NH, Ngoc TTB, Cang HQ, Luyen NTT, Thuoc TL, Le Quan T, Thao DTP. KTt-45, a T-type calcium channel blocker, acts as an anticancer agent by inducing apoptosis on HeLa cervical cancer cell line. Sci Rep 2023; 13:22092. [PMID: 38086845 PMCID: PMC10716508 DOI: 10.1038/s41598-023-47199-1] [Citation(s) in RCA: 5] [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: 07/09/2023] [Accepted: 11/10/2023] [Indexed: 12/18/2023] Open
Abstract
The abnormal expression in the T-type calcium channels is involved in various cancer types, thus inhibiting T-type calcium channels is one of approaches in cancer treatment. The fact that KTt-45 acted as a T-type calcium channel inhibitor as well as a pain-relief agent prompts us to address if KTt-45 plays any role against cancer cells. The results showed that KTt-45 caused cytotoxic effects towards HeLa cervical, Raji lymphoma, MCF-7 breast cancer, and A549 lung cancer cell lines with IC50 values less than 100 μM, in which highly selective toxicity was against HeLa cells (IC50 = 37.4 μM, SI > 3.2). Strikingly, the KTt-45 induced an accumulation of cytoplasmic vacuoles after 48 h treatment and mitochondrial-dependent apoptosis activation as evidenced by morphological features, chromatin condensation, nuclear fragmentation, and significant activation of caspase-9 as well as caspase-3. In conclusion, KTt-45 could inhibit cell growth and trigger mitochondrial-dependent apoptosis in HeLa cervical cancer cells. The results, taken together, strongly demonstrated that KTt-45 is a potential agent for further study on anticancer drug development which not only targets cancer cells but also helps to relieve neuropathic pain in cancer patients.
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Affiliation(s)
- Nguyen Huy Du
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Truong Thi Bich Ngoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Huynh Qui Cang
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Nguyen Thi Thuy Luyen
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Hydro-Geology-Engineering Geology and Environmental Geology, Faculty of Geology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Medicinal Chemistry, Faculty of Chemistry, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Tran Linh Thuoc
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Tran Le Quan
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
- Central Laboratory of Analysis, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Hydro-Geology-Engineering Geology and Environmental Geology, Faculty of Geology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
- Department of Medicinal Chemistry, Faculty of Chemistry, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Dang Thi Phuong Thao
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.
- Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.
- Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.
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Ren J, Yu P, Liu S, Li R, Niu X, Chen Y, Zhang Z, Zhou F, Zhang L. Deubiquitylating Enzymes in Cancer and Immunity. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303807. [PMID: 37888853 PMCID: PMC10754134 DOI: 10.1002/advs.202303807] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/30/2023] [Indexed: 10/28/2023]
Abstract
Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.
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Affiliation(s)
- Jiang Ren
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Peng Yu
- Zhongshan Institute for Drug DiscoveryShanghai Institute of Materia MedicaChinese Academy of SciencesZhongshanGuangdongP. R. China
| | - Sijia Liu
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang ProvinceHangzhou310058China
| | - Ran Li
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Xin Niu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
| | - Yan Chen
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
| | - Zhenyu Zhang
- Department of NeurosurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan450003P. R. China
| | - Fangfang Zhou
- Institutes of Biology and Medical ScienceSoochow UniversitySuzhou215123P. R. China
| | - Long Zhang
- The Eighth Affiliated HospitalSun Yat‐sen UniversityShenzhen518033P. R. China
- International Biomed‐X Research CenterSecond Affiliated Hospital of Zhejiang University School of MedicineZhejiang UniversityHangzhouP. R. China
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling NetworkLife Sciences InstituteZhejiang UniversityHangzhou310058P. R. China
- Cancer CenterZhejiang UniversityHangzhouZhejiang310058P. R. China
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12
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Zheng Y, Shi D, Chen L, Yang Y, Yao M. UCHL1-PKM2 axis dysregulation is associated with promoted proliferation and invasiveness of urothelial bladder cancer cells. Aging (Albany NY) 2023; 15:10593-10606. [PMID: 37815895 PMCID: PMC10599732 DOI: 10.18632/aging.205097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/09/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND Bladder cancer is one of the most common type of cancers globally, and the majority of cases belong to urothelial bladder carcinoma (UBC) type. Current researches have demonstrated that multiple genomic abnormalities are related to the sensitivity of cisplatin-based chemotherapy in bladder cancer patients. Previous findings have indicated a controversial role of Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) in malignancy, so we aimed to further explore the role of UCHL1 in UBC. METHODS UBC cell lines and The Cancer Genome Atlas (TCGA) in-silico datasets were utilized to investigate UCHL1 expression pattern and functional as well as prognostic impacts in UBC cancer cell line models and patients. UCHL1 overexpression and silencing vectors and subsequent immunoprecipitation/ubiquitination experiments in combination of cellular functional assays were conducted to explore UCHL1-PKM2 interaction axis and its significance in UBC malignancy. RESULTS UCHL1 was significantly up-regulated in UBC cancer cells and UCHL1 high-expression was associated with higher pathology/clinical grade and significantly inferior overall prognosis of UBC patients. UCHL1 interacted with PKM2 and enhanced PKM2 protein level through inhibition of PKM2 protein degradation via ubiquitination process. UCHL1-PKM2 interaction significantly promoted UBC cellular proliferation, metastasis and invasion activities. CONCLUSION UCHL1-PKM2 interaction played an interesting role in UBC tumor cell proliferation, migration and metastasis. Our study suggests PKM2-targeted treatment might have a potential value in metastatic malignancy therapy development in the future.
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Affiliation(s)
- Yuhui Zheng
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
| | - Dongliang Shi
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
| | - Linlin Chen
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
| | - Yinghong Yang
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
| | - Meihong Yao
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, China
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13
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Epshtein Y, Mathew B, Chen W, Jacobson JR. UCHL1 Regulates Radiation Lung Injury via Sphingosine Kinase-1. Cells 2023; 12:2405. [PMID: 37830619 PMCID: PMC10572187 DOI: 10.3390/cells12192405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/14/2023] Open
Abstract
GADD45a is a gene we previously reported as a mediator of responses to acute lung injury. GADD45a-/- mice express decreased Akt and increased Akt ubiquitination due to the reduced expression of UCHL1 (ubiquitin c-terminal hydrolase L1), a deubiquitinating enzyme, while GADD45a-/- mice have increased their susceptibility to radiation-induced lung injury (RILI). Separately, we have reported a role for sphingolipids in RILI, evidenced by the increased RILI susceptibility of SphK1-/- (sphingosine kinase 1) mice. A mechanistic link between UCHL1 and sphingolipid signaling in RILI is suggested by the known polyubiquitination of SphK1. Thus, we hypothesized that the regulation of SphK1 ubiquitination by UCHL1 mediates RILI. Initially, human lung endothelial cells (EC) subjected to radiation demonstrated a significant upregulation of UCHL1 and SphK1. The ubiquitination of EC SphK1 after radiation was confirmed via the immunoprecipitation of SphK1 and Western blotting for ubiquitin. Further, EC transfected with siRNA specifically for UCHL1 or pretreated with LDN-5744, as a UCHL1 inhibitor, prior to radiation were noted to have decreased ubiquitinated SphK1 in both conditions. Further, the inhibition of UCHL1 attenuated sphingolipid-mediated EC barrier enhancement was measured by transendothelial electrical resistance. Finally, LDN pretreatment significantly augmented murine RILI severity. Our data support the fact that the regulation of SphK1 expression after radiation is mediated by UCHL1. The modulation of UCHL1 affecting sphingolipid signaling may represent a novel RILI therapeutic strategy.
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Affiliation(s)
| | | | | | - Jeffrey R. Jacobson
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL 60612, USA; (Y.E.); (W.C.)
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14
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Yano N, Fedulov AV. Targeted DNA Demethylation: Vectors, Effectors and Perspectives. Biomedicines 2023; 11:biomedicines11051334. [PMID: 37239005 DOI: 10.3390/biomedicines11051334] [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: 03/28/2023] [Revised: 04/21/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a great potential to demonstrate mechanistic importance, and even causality of epigenetic alterations, and may open novel avenues to epigenetic cures. However, existing methods based on DNA methyltransferase inhibitors that elicit genome-wide demethylation are not suitable for treatment of diseases with specific epimutations and provide a limited experimental value. Therefore, gene-specific epigenetic editing is a critical approach for epigenetic re-activation of silenced genes. Site-specific demethylation can be achieved by utilizing sequence-dependent DNA-binding molecules such as zinc finger protein array (ZFA), transcription activator-like effector (TALE) and clustered regularly interspaced short palindromic repeat-associated dead Cas9 (CRISPR/dCas9). Synthetic proteins, where these DNA-binding domains are fused with the DNA demethylases such as ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG) enzymes, successfully induced or enhanced transcriptional responsiveness at targeted loci. However, a number of challenges, including the dependence on transgenesis for delivery of the fusion constructs, remain issues to be solved. In this review, we detail current and potential approaches to gene-specific DNA demethylation as a novel epigenetic editing-based therapeutic strategy.
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Affiliation(s)
- Naohiro Yano
- Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA
| | - Alexey V Fedulov
- Department of Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, 593 Eddy Street, Providence, RI 02903, USA
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Wu F, He J, Deng Q, Chen J, Peng M, Xiao J, Zeng Y, Yi L, Li Z, Tian R, Jiang Z. Neuroglobin inhibits pancreatic cancer proliferation and metastasis by targeting the GNAI1/EGFR/AKT/ERK signaling axis. Biochem Biophys Res Commun 2023; 664:108-116. [PMID: 37141638 DOI: 10.1016/j.bbrc.2023.04.080] [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: 03/16/2023] [Revised: 04/11/2023] [Accepted: 04/23/2023] [Indexed: 05/06/2023]
Abstract
Pancreatic cancer is an extremely aggressive malignancy with a very disappointing prognosis. Neuroglobin (NGB), a member of the globin family, has been demonstrated to have a significant role in a variety of tumor forms. The possible role of NGB as a tumor suppressor gene in pancreatic cancer was investigated in this work. Information from the public dataset TCGA combined with GTEx was used to analyze the finding that NGB was commonly downregulated in pancreatic cancer cell lines and tissues, correlating with patient age and prognosis. The expression of NGB in pancreatic cancer was investigated via RT-PCR, qRT-PCR, and Western blot experiments. In-vitro and in-vivo assays, NGB elicited cell cycle arrest in the S phase and apoptosis, hindered migration and invasion, reversed the EMT process, and suppressed cell proliferation and development. The mechanism of action of NGB was predicted via bioinformatics analysis and validated using Western blot and co-IP experiments revealed that NGB inhibited the EGFR/AKT/ERK pathway by binding to and reducing expression of GNAI1 and p-EGFR. In addition, pancreatic cancer cells overexpressing NGB showed increased drug sensitivity to gefitinib (EGFR-TKI). In conclusion, NGB inhibits pancreatic cancer progression by specifically targeting the GNAI1/EGFR/AKT/ERK signaling axis.
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Affiliation(s)
- Fan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jin He
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Qianxi Deng
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Mingyu Peng
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jiayi Xiao
- West China School of Medicine and West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, PR China
| | - Yiwei Zeng
- CHINA MEDICAL UNIVERSITY, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China
| | - Lin Yi
- CHONGQING MEDICAL UNIVERSITY, 1 Yixueyuan Road, Yuzhong District, Chongqing, 400016, PR China
| | - Zhuoqing Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Rui Tian
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Zheng Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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16
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Wang X, Zhang N, Li M, Hong T, Meng W, Ouyang T. Ubiquitin C‑terminal hydrolase‑L1: A new cancer marker and therapeutic target with dual effects (Review). Oncol Lett 2023; 25:123. [PMID: 36844618 PMCID: PMC9950345 DOI: 10.3892/ol.2023.13709] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/08/2022] [Indexed: 02/11/2023] Open
Abstract
Ubiquitin C-terminal hydrolase-L1 (UCH-L1), a member of the lesser-known deubiquitinating enzyme family, has deubiquitinase and ubiquitin (Ub) ligase activity and the role of stabilizing Ub. UCH-L1 was first discovered in the brain and is associated with regulating cell differentiation, proliferation, transcriptional regulation and numerous other biological processes. UCH-L1 is predominantly expressed in the brain and serves a role in tumor promotion or inhibition. There is still controversy about the effect of UCH-L1 dysregulation in cancer and its mechanisms are unknown. Extensive research to investigate the mechanism of UCH-L1 in different types of cancer is key for the future treatment of UCH-L1-associated cancer. The present review details the molecular structure and function of UCH-L1. The role of UCH-L1 in different types of cancer is also summarized and how novel treatment targets provide a theoretical foundation in cancer research is discussed.
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Affiliation(s)
- Xiaowei Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Department of The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Na Zhang
- Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Tao Hong
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Wei Meng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Correspondence to: Dr Wei Meng or Dr Taohui Ouyang, Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi 330006, P.R. China, E-mail:
| | - Taohui Ouyang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China,Correspondence to: Dr Wei Meng or Dr Taohui Ouyang, Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yongwai Street, Nanchang, Jiangxi 330006, P.R. China, E-mail:
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17
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Comprehensive transcriptome analysis of sika deer antler using PacBio and Illumina sequencing. Sci Rep 2022; 12:16161. [PMID: 36171236 PMCID: PMC9519574 DOI: 10.1038/s41598-022-20244-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 09/12/2022] [Indexed: 11/09/2022] Open
Abstract
Antler is the fastest growing and ossifying tissue in animals and it is a valuable model for cartilage/bone development. To understand the molecular mechanisms of chondrogenesis and osteogenesis of antlers, the PacBio Sequel II and Illumina sequencing technology were combined and used to investigate the mRNA expression profiles in antler tip, middle, and base at six different developmental stages, i.e., at 15th, 25th, 45th, 65th, 100th and 130th growth days. Consequently, we identified 24,856 genes (FPKM > 0.1), including 8778 novel genes. Besides, principal component analysis (PCA) revealed a significant separation between the growth stage (25th, 45th and 65th days) and ossification stage (100th and 130th days). COL2A1 gene was significantly abundant in the growth stage, whereas S100A7, S100A12, S100A8, and WFDC18 genes were abundant at the ossification stage. Subsequently screened to 14,765 significantly differentially expressed genes (DEGs), WGCNA and GO functional enrichment analyses revealed that genes related to cell division and chondrocyte differentiation were up-regulated, whereas those with steroid hormone-mediated signaling pathways were down-regulated at ossification stages. Additionally, 25 tumor suppressor genes and 11 oncogenes were identified and were predicted to interact with p53. Co-regulation of tumor suppressor genes and oncogenes is responsible for the special growth pattern of antlers. Together, we constructed the most complete sika deer antler transcriptome database so far. The database provides data support for subsequent studies on the molecular mechanism of sika deer antler chondrogenesis and osteogenesis.
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Ning Y, Deng C, Li C, Peng W, Yan C, Ran J, Chen W, Liu Y, Xia J, Ye L, Wei Z, Xiang T. PCDH20 inhibits esophageal squamous cell carcinoma proliferation and migration by suppression of the mitogen-activated protein kinase 9/AKT/β-catenin pathway. Front Oncol 2022; 12:937716. [PMID: 36248995 PMCID: PMC9555239 DOI: 10.3389/fonc.2022.937716] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Aberrant protocadherins (PCDHs) expression trigger tumor invasion and metastasis. PCDH20 anti-tumor functions in various tumor have been identified. Tumor suppression is due to Wnt/β-catenin pathway antagonism and may be suppressed caused by PCDH20 downregulation through promotor methylation, whereas PCDH20 effects and regulation mechanism in esophageal squamous cell carcinoma (ESCC) remains elusive. We analyzed PCDH20 effects on ESCC and underlying action mechanisms for PCDH20. We test PCDH20 expression in ESCC tissues and cells by semi-quantitative PCR (RT-PCR) and q-PCR (real-time quantitative polymerase chain reaction). MSP (methylation-specific PCR) was carried out to assess the methylation of PCDH20 in ESCC cells and tissues. Anti-tumor effects of PCDH20 in vitro were assessed by clone formation assay, CCK8 assay, Transwell assay, and flow cytometry. Nude mice tumorigenicity was used to assess PCDH20 anti-tumor effect in vivo. Online database, qPCR, and Western blotting were used to identify the downregulation of MAP3K9 by PCDH20, associated with AKT/β-catenin signaling inactivation. We found that PCDH20 expression was dramatically attenuated in esophageal cancer tissues and cells, maybe due to promotor methylation, and ectopic PCDH20 expression suppressed ESCC malignant biological phenotypes. PCDH20 exerted anti-tumor effects by MAP3K9 downregulation, which suppressed AKT/β-catenin signaling in ESCC cells.ConclusionPCDH20 was a tumor suppressor gene, which antagonized AKT/β-catenin signaling pathway in ESCC by decreasing MAP3K9.
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Affiliation(s)
- Yijiao Ning
- Gastrointestinal Surgical Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chaoqun Deng
- Gastrointestinal Surgical Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chunhong Li
- Department of Oncology, Suining Central Hospital, Suining, China
- *Correspondence: Tingxiu Xiang, ; Chunhong Li,
| | - Weiyan Peng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chun Yan
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Ran
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China
| | - Weihong Chen
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yujia Liu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiuyi Xia
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Ye
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengqiang Wei
- Gastrointestinal Surgical Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Gastrointestinal Surgical Unit, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Tingxiu Xiang, ; Chunhong Li,
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Pyroptosis is related to immune infiltration and predictive for survival of colon adenocarcinoma patients. Sci Rep 2022; 12:9233. [PMID: 35655081 PMCID: PMC9163148 DOI: 10.1038/s41598-022-13212-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
Pyroptosis is a novel type of programmed cell death, initiated by inflammasome. Pyroptosis inhibits the development and metastasis of colon cancer and is associated with patients’ prognosis. However, how the pyroptosis-related genes predict the survival of patients is still unclear. In the study, colon adenocarcinoma (COAD) patients were divided into two groups according to the expression of pyroptosis-related regulators through consensus clustering. DEGs between two clusters were analyzed by using COX and Lasso regression. Then, regression coefficients in Lasso were used to calculate the risk score for every patient. Patients were classified into two types: low- and high-risk group according to their risk score. The difference of immune microenvironment infiltration and clinicopathological characteristics between subgroups was performed. Moreover, the nomogram model was built on the bases of risk model and clinicopathological factors. The TCGA-COAD cohort and GEO cohort were used as training and validating set respectively. 398 COAD patients in TCGA training set were identified as two regulation patterns via unsupervised clustering method. Patients in cluster 2 showed better prognosis (P = 0.002). Through differentiated expression analysis, COX and Lasso regression, a 5-gene prognostic risk model was constructed. This risk model was significantly associated with OS (HR: 2.088, 95% CI: 1.183–3.688, P = 0.011), validated in GEO set (HR:1.344, 95%CI: 1.061–1.704, P = 0.014), and patients with low risk had better prognosis (P < 0.001 in TCGA; P = 0.038 in GEO). Through ROC analysis, it can be found that this model presented better predictive accuracy for long-term survival. Clinical analyses demonstrated that high-risk group had more advanced N stage, higher risk of metastasis and later pathological stage. Immune-related analysis illustrated that low-risk group had more immune cell infiltration and more activated immune pathways. The pyroptosis-related risk model can be predictive for the survival of COAD patients. That patients with higher risk had poorer prognosis was associated with more advanced tumor stage and higher risk of metastasis, and resulted from highly activated pro-tumor pathways and inhibited immune system and poorer integrity of intestinal epithelial. This study proved the relationship between pyroptosis and immune, which offered basis for future studies.
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Zhang D, Fu Y, Tian G, Li J, Shang D, Zhou S. UCHL1 promotes proliferation and metastasis in head and neck squamous cell carcinoma and could be a potential therapeutic target. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 133:684-697. [PMID: 35165060 DOI: 10.1016/j.oooo.2021.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/10/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVE The purpose of this study was to research the physiological roles of ubiquitin carboxyl-terminal esterase L1 (UCHL1) in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN Ten HNSCC samples and matched normal oral mucosal tissues were collected. UCHL1 expression of these tissues was detected by the immunohistochemical staining and real-time quantitative polymerase chain reaction. The human HNSCC cell line HN6 UCHL1 knockout (UCHL1 KO) cell line was constructed using CRISPR/CAS9 gene editing and verified by western blotting. Wound healing assay, cell proliferation assay, cell invasion assay, and flow cytometric analysis of the cell cycle and apoptosis were applied to research the role of UCHL1 in HNSCC. Also, an RNAseq gene expression data set and HNSCC patient survival data from The Cancer Genome Atlas were analyzed. RESULTS UCHL1 was highly expressed in HNSCC tissues compared with normal oral mucosal tissues (P = .032). A decreased proliferation (P < .0001), migration (P < .0001), and invasion (P = .0049) ability of HN6 cells was exhibited after knockout of UCHL1. However, HN6 UCHL1 KO cells showed no significant differences in the cell cycle or apoptosis. The progression, nodal metastasis status, and stage of HNSCC had a positive correlation with the expression of UCHL1. CONCLUSIONS UCHL1 plays an important role in HNSCC, and we consider that targeting UCHL1 may be a feasible therapeutic strategy for HNSCC.
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Affiliation(s)
- Dahe Zhang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China
| | - You Fu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China
| | - Guocai Tian
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China
| | - Jiayi Li
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China
| | - Dihua Shang
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China
| | - Shanghui Zhou
- Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, Shanghai, China; National Center for Stomatology, Shanghai, Shanghai, China; National Clinical Research Center for Oral Diseases, Shanghai, Shanghai, China; Shanghai Key Laboratory of Stomatology, Shanghai, Shanghai, China.
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21
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Cheng Z, Yu R, Li L, Mu J, Gong Y, Wu F, Liu Y, Zhou X, Zeng X, Wu Y, Sun R, Xiang T. Disruption of ZNF334 promotes triple-negative breast carcinoma malignancy through the SFRP1/ Wnt/β-catenin signaling axis. Cell Mol Life Sci 2022; 79:280. [PMID: 35507080 PMCID: PMC11072843 DOI: 10.1007/s00018-022-04295-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/20/2022] [Accepted: 04/06/2022] [Indexed: 11/03/2022]
Abstract
Zinc-finger proteins (ZNFs) constitute the largest transcription factor family in the human genome. The family functions in many important biological processes involved in tumorigenesis. In our research, we identified ZNF334 as a novel tumor suppressor of triple-negative breast cancer (TNBC). ZNF334 expression was usually reduced in breast cancerv (BrCa) tissues and TNBC cell lines MDA-MB-231 (MB231) and YCCB1. We observed that promoter hypermethylation of ZNF334 was common in BrCa cell lines and tissues, which was likely responsible for its reduced expression. Ectopic expression of ZNF334 in TNBC cell lines MB231 and YCCB1 could suppress their growth and metastatic capacity both in vitro and in vivo, and as well induce cell cycle arrest at S phase and cell apoptosis. Moreover, re-expression of ZNF334 in TNBC cell lines could rescue Epithelial-Mesenchymal Transition (EMT) process and restrain stemness, due to up-regulation of SFRP1, which is an antagonist of Wnt/β-catenin signaling. In conclusion, we verified that ZNF334 had a suppressive function of TNBC cell lines by targeting the SFRP1/Wnt/β-catenin signaling axis, which might have the potentials to become a new biomarker for diagnosis and treatment of TNBC patients.
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Affiliation(s)
- Zhaobo Cheng
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renjie Yu
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Li Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junhao Mu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yijia Gong
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Wu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yujia Liu
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiangyi Zhou
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaohua Zeng
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Yongzhong Wu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China
| | - Ran Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
| | - Tingxiu Xiang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China.
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22
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Mondal M, Conole D, Nautiyal J, Tate EW. UCHL1 as a novel target in breast cancer: emerging insights from cell and chemical biology. Br J Cancer 2022; 126:24-33. [PMID: 34497382 PMCID: PMC8727673 DOI: 10.1038/s41416-021-01516-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/25/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer has the highest incidence and death rate among cancers in women worldwide. In particular, metastatic estrogen receptor negative (ER-) breast cancer and triple-negative breast cancer (TNBC) subtypes have very limited treatment options, with low survival rates. Ubiquitin carboxyl terminal hydrolase L1 (UCHL1), a ubiquitin C-terminal hydrolase belonging to the deubiquitinase (DUB) family of enzymes, is highly expressed in these cancer types, and several key reports have revealed emerging and important roles for UCHL1 in breast cancer. However, selective and potent small-molecule UCHL1 inhibitors have been disclosed only very recently, alongside chemical biology approaches to detect regulated UHCL1 activity in cancer cells. These tools will enable novel insights into oncogenic mechanisms driven by UCHL1, and identification of substrate proteins deubiquitinated by UCHL1, with the ultimate goal of realising the potential of UCHL1 as a drug target in breast cancer.
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Affiliation(s)
- Milon Mondal
- Department of Chemistry, Imperial College London, London, UK
| | - Daniel Conole
- Department of Chemistry, Imperial College London, London, UK
| | - Jaya Nautiyal
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK
| | - Edward W Tate
- Department of Chemistry, Imperial College London, London, UK.
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23
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Tam TDT, Ngoc TTB, Nga NTH, Trinh NTM, Thuoc TL, Thao DTP. Ethyl acetate extract of Elephantopus mollis Kunth induces apoptosis in human gastric cancer cells. BMC Complement Med Ther 2021; 21:273. [PMID: 34717604 PMCID: PMC8557499 DOI: 10.1186/s12906-021-03444-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 10/15/2021] [Indexed: 11/10/2022] Open
Abstract
Background Gastric cancer is one of the most leading causes of cancer death worldwide. Therefore, treatment studies have been being conducted, one of which is screening of novel agents from medicinal herbs. Elephantopus mollis Kunth (EM) belonging to Asteraceae family is a perennial herb with several therapeutic properties including anticancer activity. However, the effect of this species on gastric cancer has not been reported yet. In this study, cytotoxicity of different EM crude extracts was investigated on AGS gastric cancer cell line. Besides, the effects of extract on nuclear morphology, caspase-3 activation, and gene expression were also explored. Results The results showed that ethyl acetate extract exhibited a remarkably inhibitory ability (IC50 = 27.5 μg/ml) on the growth of AGS cells, while causing less toxicity to normal human fibroblasts. The extract also induced apoptotic deaths in AGS cells as evidenced by cell shrinkage, formation of apoptotic bodies, nuclear fragmentation, caspase-3 activation, and the upregulation of BAK and APAF-1 pro-apoptotic genes related to mitochondrial signaling pathway. Specifically, BAK and APAF-1 mRNA expression levels showed 2.57 and 2.71-fold increases respectively. Conclusions The current study not only proved the anti-gastric cancer activity of EM ethyl acetate extract but also proposed its molecular mechanism. The extract could be a potential candidate for further investigation.
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Affiliation(s)
- Tran Dang Thanh Tam
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam
| | - Truong Thi Bich Ngoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Nguyen Thi Hoai Nga
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Nguyen Thi My Trinh
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Tran Linh Thuoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam.,Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.,Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam
| | - Dang Thi Phuong Thao
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam. .,Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Vietnam. .,Laboratory of Cancer Research, VNU-HCM, University of Science, Duong so 4, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam. .,Vietnam National University, Ho Chi Minh City, Vo Truong Toan, Linh Trung, Thu Duc, Ho Chi Minh City, 700000, Vietnam.
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24
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Ciregia F, Cetani F, Pardi E, Soggiu A, Piras C, Zallocco L, Borsari S, Ronci M, Caruso V, Marcocci C, Mazzoni MR, Lucacchini A, Giusti L. Parathyroid Carcinoma and Adenoma Co-existing in One Patient: Case Report and Comparative Proteomic Analysis. Cancer Genomics Proteomics 2021; 18:781-796. [PMID: 34697069 DOI: 10.21873/cgp.20297] [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] [Received: 04/24/2021] [Revised: 09/02/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIM The lack of specific parathyroid carcinoma (PC) biomarkers in clinical practice points out the importance of analyzing the proteomic signature of this cancer. We performed a comparative proteomic analysis of PC and parathyroid adenoma (PA) co-existing in the same patient. PATIENTS AND METHODS PC and PA were taken from a 63-year-old patient. Using two-dimensional differential gel electrophoresis (2D-DIGE) coupled to mass spectrometry we examined the differences between PC and PA proteins. For validation, additional PC and PA samples were obtained from 10 patients. Western blot analysis was used to validate the difference of expression observed with 2D-DIGE analysis. Bioinfomatic analysis was performed using QIAGEN's Ingenuity Pathways Analysis (IPA) to determine the predominant canonical pathways and interaction networks involved. RESULTS Thirty-three differentially expressed proteins were identified in PC compared to PA. Among these, ubiquitin C-terminal hydrolase-L1 (UCH-L1) was highly overexpressed in PC. The result was confirmed by Western Blot analysis in additional PC samples. CONCLUSION Our comparative proteomic analysis of co-existing neoplasms allowed detecting specific and peculiar differences between PC and PA overcoming population biological variability.
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Affiliation(s)
- Federica Ciregia
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.,Department of Rheumatology, GIGA Research, Centre Hospitalier Universitaire (CHU) de Liège, University of Liège, Liège, Belgium
| | - Filomena Cetani
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Elena Pardi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Alessio Soggiu
- Surgical and Dental Sciences-One Health Unit, Department of Biomedical, University of Milano, Milan, Italy
| | - Cristian Piras
- Department of Health Sciences, Campus Universitario "S. Venuta", University "Magna Græcia" of Catanzaro, Catanzaro, Italy
| | | | - Simona Borsari
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Maurizio Ronci
- Department of Pharmacy, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Vanni Caruso
- School of Pharmacy & Pharmacology - College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Antonio Lucacchini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Laura Giusti
- School of Pharmacy, University of Camerino, Camerino, Italy
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25
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Thai SF, Jones CP, Robinette BL, Ren H, Vallant B, Fisher A, Kitchin KT. Effects of Copper Nanoparticles on mRNA and Small RNA Expression in Human Hepatocellular Carcinoma (HepG2) Cells. JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY 2021; 21:5083-5098. [PMID: 33875094 PMCID: PMC10803003 DOI: 10.1166/jnn.2021.19328] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
With the advancement of nanotechnology, nanoparticles are widely used in many different industrial processes and consumer products. Copper nanoparticles (Cu NPs) are among the most toxic nanomaterials. We investigated Cu NPs toxicity in Human Hepatocellular carcinoma (HepG2) cells by examining signaling pathways, and microRNA/mRNA interactions. We compared the effects of exposures to Cu NPs at various concentrations and CuCl₂ was used as a control. The number of differentially expressed mRNA did not follow a linear dose-response relationship for either Cu NPs or CuCl₂ treatments. The most significantly altered genes and pathways by Cu NPs exposure were NRF2 (nuclear factor erythroid 2 related factor 2)-mediated oxidative stress response, protein ubiquitination, Tumor protein p53 (p53), phase I and II metabolizing enzymes, antioxidant proteins and phase III detoxifying gene pathways.Messenger RNA-microRNA interaction from MicroRNA Target Filter Analyses revealed more signaling pathways altered in Cu NPs treated samples than transcriptomics alone, including cell proliferation, DNA methylation, endoplasmic reticulum (ER) stress, apoptosis, autophagy, reactive oxygen species, inflammation, tumorigenesis, extracellular matrix/angiogenesis and protein synthesis. In contrast, in the control (CuCl₂) treated samples showed mostly changes in inflammation mainly through regulation of the Nuclear Factor Kappa-light-chain-enhancer of Activated B-cells (NFκB). Further, some RNA based parameters that showed promise as biomarkers of Cu NPs exposure including both well and lesser known genes: heme oxygenase 1 (HMOX1), heat shock protein, c-Fos proto-oncogene, DNA methyltransferases, and glutamate-cysteine ligase modifier subunit (GCLM, part of the glutathione synthesis pathway). The differences in signaling pathways altered by the Cu NPs and CuCl₂ treatments suggest that the effects of the Cu NPs were not the results of nanomaterial dissolution to soluble copper ions.
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Affiliation(s)
- Sheau-Fung Thai
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Carlton P Jones
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Brian L Robinette
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Hongzu Ren
- Center for Public Health and Environmental Assessment, US Environmental Production Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Beena Vallant
- Center for Computational Toxicology and Exposure, US Environmental Protection Agency, 109 TW Alexander Dr., Durham NC 27709, USA
| | - Anna Fisher
- Center for Public Health and Environmental Assessment, US Environmental Production Agency, 109 TW Alexander Dr., Durham NC 27709, USA
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26
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Tangri A, Lighty K, Loganathan J, Mesmar F, Podicheti R, Zhang C, Iwanicki M, Drapkin R, Nakshatri H, Mitra S. Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7-APEH-Proteasome Axis in High-grade Serous Ovarian Carcinoma. Mol Cancer Res 2021; 19:1168-1181. [PMID: 33753553 DOI: 10.1158/1541-7786.mcr-20-0883] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/10/2021] [Accepted: 03/17/2021] [Indexed: 11/16/2022]
Abstract
High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the in vivo metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress-induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7-APEH-proteasome axis. IMPLICATIONS: This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.
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Affiliation(s)
- Apoorva Tangri
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kinzie Lighty
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jagadish Loganathan
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Fahmi Mesmar
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, Indiana
| | - Ram Podicheti
- Center for Genomics and Bioinformatics, Indiana University, Bloomington, Indiana
| | - Chi Zhang
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Marcin Iwanicki
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, New Jersey
| | - Ronny Drapkin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Harikrishna Nakshatri
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana
| | - Sumegha Mitra
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana.
- Indiana University Simon Comprehensive Cancer Center, Indianapolis, Indiana
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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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28
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Kamseng P, Siriboonpiputtana T, Puavilai T, Chuncharunee S, Paisooksantivatana K, Chareonsirisuthigul T, Junking M, Chiraphapphaiboon W, Yenchitsomanus PT, Rerkamnuaychoke B. Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14). Pathol Oncol Res 2021; 27:606567. [PMID: 34257568 PMCID: PMC8262241 DOI: 10.3389/pore.2021.606567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/11/2021] [Indexed: 11/13/2022]
Abstract
Multiple myeloma (MM) patients considered to be at high cytogenetic risk commonly fail to respond to standard treatment. A thorough understanding of the molecular mechanism of MM development is, therefore, needed. We endeavored to explore the transcriptional signature among different subgroups of newly diagnosed MM using gene chip-based expression microarray. Bone marrow samples of 15 newly diagnosed Thai MM patients were included. The chromosomal translocation t(4;14) was the most frequently identified genetic alteration in the high-risk subgroup. Cluster analysis from expression profiling demonstrated that high-risk MM have a distinctly different expression pattern compared to standard-risk patients. The most significant differentially expressed gene was UCHL1. Functional enrichment analysis by Gene Set Enrichment Analysis, FUNRICH, and Gene Ontology Panther pathway revealed the gene sets involved in cell cycle control to be enriched in the t(4;14) high-risk group. Interestingly, among the well-established downstream targets of UCHL1, only CCND2 was significantly expressed in the t(4;14) high-risk group. Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines. These findings shed light on the molecular mechanism of UCHL1 in t(4;14) high-risk MM and support the evidence that alteration of the UCHL1 pathway may play a role in the pathogenesis of high-risk MM.
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Affiliation(s)
- Parin Kamseng
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | - Teeraya Puavilai
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suporn Chuncharunee
- Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Karan Paisooksantivatana
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Takol Chareonsirisuthigul
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Mutita Junking
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wannasiri Chiraphapphaiboon
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Budsaba Rerkamnuaychoke
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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Rong C, Zhou R, Wan S, Su D, Wang SL, Hess J. Ubiquitin Carboxyl-Terminal Hydrolases and Human Malignancies: The Novel Prognostic and Therapeutic Implications for Head and Neck Cancer. Front Oncol 2021; 10:592501. [PMID: 33585209 PMCID: PMC7878561 DOI: 10.3389/fonc.2020.592501] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/07/2020] [Indexed: 12/24/2022] Open
Abstract
Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), have been found in a variety of tumor entities and play distinct roles in the pathogenesis and development of various cancers including head and neck cancer (HNC). HNC is a heterogeneous disease arising from the mucosal epithelia of the upper aerodigestive tract, including different anatomic sites, distinct histopathologic types, as well as human papillomavirus (HPV)-positive and negative subgroups. Despite advances in multi-disciplinary treatment for HNC, the long-term survival rate of patients with HNC remains low. Emerging evidence has revealed the members of UCHs are associated with the pathogenesis and clinical prognosis of HNC, which highlights the prognostic and therapeutic implications of UCHs for patients with HNC. In this review, we summarize the physiological and pathological functions of the UCHs family, which provides enlightenment of potential mechanisms of UCHs family in HNC pathogenesis and highlights the potential consideration of UCHs as attractive drug targets.
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Affiliation(s)
- Chao Rong
- Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
- Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Ran Zhou
- Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shan Wan
- Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
| | - Dan Su
- Department of Pharmacy, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shou-Li Wang
- Department of Pathology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China
| | - Jochen Hess
- Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Research Group Molecular Mechanisms of Head and Neck Tumors, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
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Bich Ngoc TT, Hoai Nga NT, My Trinh NT, Thuoc TL, Phuong Thao DT. Elephantopus mollis Kunth extracts induce antiproliferation and apoptosis in human lung cancer and myeloid leukemia cells. JOURNAL OF ETHNOPHARMACOLOGY 2020; 263:113222. [PMID: 32763415 DOI: 10.1016/j.jep.2020.113222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/01/2020] [Accepted: 07/25/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Elephantopus mollis Kunth (EM), which belongs to Asteraceae family, has been used as a folk medicine with diverse therapeutic properties. Previous studies reported that crude extracts of this plant could inhibit several cancer cell lines, including breast carcinoma MCF-7, liver carcinoma HepG2, colorectal carcinoma DLD-1, lung carcinoma NCI-H23, etc. AIM: In this study, the anticancer activity and associated molecular mechanism of EM which is distributed in Vietnam were investigated. MATERIALS AND METHODS The cytotoxicity of various EM extracts was evaluated on different cell lines by MTT assay. In addition, the effects of EM extracts on cell growth, cell morphology, nuclear morphology, caspase-3 activation, and mRNA expression levels of apoptosis-related genes were also examined. RESULTS Our results demonstrated that ethyl acetate extract (EM-EA) caused proliferative inhibition and apoptotic induction towards A549 lung cancer cells (IC50 = 18.66 μg/ml, SI = 5.8) and HL60 leukemia cells (IC50 = 7.45 μg/ml, SI = 14.5) while petroleum ether extract (EM-PE) showed high toxicity to HL60 cell line (IC50 = 11.14 μg/ml, SI = 6.7). Notably, Raji lymphoma cells were also affected by these extracts (IC50 < 20 μg/ml, SI > 4), which has not been reported yet. Furthermore, mechanisms of EM extracts were elucidated. The significant downregulation of PCNA mRNA level induced by EM-EA/PE extracts contributed to the cell-growth restraint. EM-EA extract might activate apoptosis in A549 cells through both extrinsic and intrinsic signaling pathways by causing a 1.55-fold increase in BID, 3.65-fold increase in BAK and 3.11-fold decrease in BCL-2 expression level. Meanwhile, with EM-EA-extract treatment, HL60 cells might encounter P53-dependent apoptotic deaths. CONCLUSIONS The combination of antiproliferation and apoptosis activation contributed to the high efficacy of EM extracts. These findings not only proved the anticancer potential of EM but also provided further insights into the mechanisms of EM extracts.
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Affiliation(s)
- Truong Thi Bich Ngoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam
| | - Nguyen Thi Hoai Nga
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Cancer Research, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam
| | - Nguyen Thi My Trinh
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam
| | - Tran Linh Thuoc
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam
| | - Dang Thi Phuong Thao
- Department of Molecular and Environmental Biotechnology, Faculty of Biology and Biotechnology, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Molecular Biotechnology, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Laboratory of Cancer Research, VNU-HCM, University of Science, 227 Nguyen Van Cu, Ho Chi Minh City, 700000, Viet Nam; Vietnam National University, Ho Chi Minh City, Viet Nam.
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31
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Ariya S, James AR, Joseph B. Identification of lung cancer master genes triggered by smoking and their key pathways based on gene expression profiling. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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32
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Serna-García M, Peiró R, Serna E, Santacreu MA. Ovarian Transcriptomic Analysis Reveals Differential Expression Genes Associated with Cell Death Process after Selection for Ovulation Rate in Rabbits. Animals (Basel) 2020; 10:ani10101924. [PMID: 33092110 PMCID: PMC7593938 DOI: 10.3390/ani10101924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/16/2020] [Accepted: 10/17/2020] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Transcriptomic analysis showed nineteen potential biomarkers in ovarian tissue from females belonged to a rabbit line selected for ovulation rate for 10 generations and the control line. These females differed not only in ovulation rate but also in prenatal survival since similar litter size were observed. Abstract Litter size is an essential trait in rabbit meat production but with low heritability. A selection experiment for ovulation rate has been performed for 10 generations to improve litter size in rabbits. The selected line increased two ova more than the control line but nevertheless a negative correlation was observed with prenatal survival. A transcriptomic study was performed, using microarrays, in ovarian tissue from females belonging to the selected line and the control line. Our results showed 1357 differential expressed genes and nineteen potential biomarkers associated with prenatal mortality, which could explain differences between litter size in rabbits. Cell death was the most relevant process.
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Affiliation(s)
- Marta Serna-García
- Instituto de Ciencia y Tecnología Animal, Universitat Politècnica de València, 46022 Valencia, Spain;
- Faculty of Agricultural and Veterinary Sciences, São Paulo State University, FCAV/UNESP, Jaboticabal 14884-900, São Paulo, Brazil
| | - Rosa Peiró
- Instituto de Conservación y Mejora de la Agrodiversidad Valenciana, Universitat Politècnica de València, 46022 Valencia, Spain;
| | - Eva Serna
- Department of Physiology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
- Correspondence: (E.S.); (M.A.S.); Tel.: +34-963864100 (ext. 83171) (E.S.); +34-963879436 (M.A.S.)
| | - María Antonia Santacreu
- Instituto de Ciencia y Tecnología Animal, Universitat Politècnica de València, 46022 Valencia, Spain;
- Correspondence: (E.S.); (M.A.S.); Tel.: +34-963864100 (ext. 83171) (E.S.); +34-963879436 (M.A.S.)
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33
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Boonsri B, Yacqub-Usman K, Thintharua P, Myint KZ, Sae-Lao T, Collier P, Suriyonplengsaeng C, Larbcharoensub N, Balasubramanian B, Venkatraman S, Egbuniwe IU, Gomez D, Mukherjee A, Kumkate S, Janvilisri T, Zaitoun AM, Kuakpaetoon T, Tohtong R, Grabowska AM, Bates DO, Wongprasert K. Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells. Cancer Res Treat 2020; 53:457-470. [PMID: 33070556 PMCID: PMC8053863 DOI: 10.4143/crt.2020.585] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/05/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. Results CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.
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Affiliation(s)
- Boonyakorn Boonsri
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kiren Yacqub-Usman
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Pakpoom Thintharua
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Kyaw Zwar Myint
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Thannicha Sae-Lao
- Department of Anatomy, Faculty of Medicine, Siam University, Bangkok, Thailand
| | - Pam Collier
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | | | - Noppadol Larbcharoensub
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Brinda Balasubramanian
- Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Simran Venkatraman
- Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Isioma U Egbuniwe
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.,Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Dhanwant Gomez
- Department of Hepatobiliary and Pancreatic Surgery, and NIHR Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, UK
| | - Abhik Mukherjee
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.,Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Supeecha Kumkate
- Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Abed M Zaitoun
- Department of Cellular Pathology, Queen's Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | | | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Anna M Grabowska
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - David O Bates
- Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Kanokpan Wongprasert
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
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Peng M, Ye L, Yang L, Liu X, Chen Y, Huang G, Jiang Y, Wang Y, Li D, He J, Qiu Z, Xiang T, Guo S. CAVIN2 is frequently silenced by CpG methylation and sensitizes lung cancer cells to paclitaxel and 5-FU. Epigenomics 2020; 12:1793-1810. [PMID: 33016107 DOI: 10.2217/epi-2020-0157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Aim: To explore the biological functions and clinical significance of CAVIN2 in lung cancer. Materials & methods: Methylation-specific PCR was used to measure promoter methylation of CAVIN2. The function of CAVIN2 was tested by Cell Counting Kit-8, colony formation, Transwell, flow cytometric analysis, acridine orange/ethidium bromide, chemosensitivity assay and xenograft assay. Results: CAVIN2 is significantly downregulated by promoter methylation in lung cancer. CAVIN2 overexpression inhibits lung cancer cell migration and invasion. Furthermore, ectopic expression of CAVIN2 inhibits cell proliferation in vivo and in vitro by inducing G2/M cell cycle arrest, which sensitizes the chemosensitivity of lung cancer cells to paclitaxel and 5-fluorouracil, but not cisplatin. Conclusion: CAVIN2 is a tumor suppressor in non-small-cell lung cancer and can sensitize lung cancer cells to paclitaxel and 5-fluorouracil.
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Affiliation(s)
- Mingyu Peng
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Lin Ye
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Li Yang
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xinzhu Liu
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yuhan Chen
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Guichuan Huang
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yu Jiang
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yan Wang
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dairong Li
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jin He
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhu Qiu
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology & Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Shuliang Guo
- Department of Respiratory & Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
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35
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Gutkin DW, Shurin MR, El Azher MA, Shurin GV, Velikokhatnaya L, Prosser D, Shin N, Modugno F, Stemmer P, Elishaev E, Lokshin A. Novel protein and immune response markers of human serous tubal intraepithelial carcinoma of the ovary. Cancer Biomark 2020; 26:471-479. [PMID: 31658047 DOI: 10.3233/cbm-190528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Ovarian cancer is the leading cause of death among gynecologic diseases in the USA and Europe. High-grade serous carcinoma (HGSC) of the ovary, the most aggressive type of ovarian cancer, is typically diagnosed at advanced stages when the 5-year survival is dismal. Since the cure rate for stage I HGSC is high, early detection of localized initial disease may improve patient outcomes. Serous tubal intraepithelial carcinoma (STIC) is considered to be a precursor lesion of HGSC. Discovery of biomarkers associated with STIC could aid in the development of an HGSC screening algorithm. Using immunohistochemical staining, we have demonstrated overexpression of UCHL1, ADAMTS13, and GAPDH in patients' STIC lesions, but not in cancer-free fallopian tubes. We additionally demonstrated a marked increase of T cells in perineoplastic stroma surrounding STIC lesions (largely CD4 + cells), but not in normal fallopian tubes and HGSC. FOXP3 + T regulatory cells are absent in STIC lesions but are present in HGSC. These observations indicate the microenvironment surrounding a STIC lesion may be immune promoting in contrast to the immune suppressive microenvironment of invasive carcinoma. In summary, we have identified UCHL1, ADAMTS13, and GAPDH as novel potentially useful markers associated with early stages of HGSC tumorigenesis and possibly contribute to STIC immunogenicity. The lack of immune suppression in the STIC microenvironment indicates that the immune system can still recognize and keep STIC controlled at this stage of the tumor development.
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Affiliation(s)
- Dmitriy W Gutkin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Michael R Shurin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Mounia Alaoui El Azher
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Galina V Shurin
- Departments of Immunology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Liudmila Velikokhatnaya
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Denise Prosser
- Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Namhee Shin
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA
| | - Francesmary Modugno
- Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Paul Stemmer
- Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA
| | - Esther Elishaev
- Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Anna Lokshin
- Departments of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Medicine, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.,Departments of Obstetrics and Gynecology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
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He J, Wu M, Xiong L, Gong Y, Yu R, Peng W, Li L, Li L, Tian S, Wang Y, Tao Q, Xiang T. BTB/POZ zinc finger protein ZBTB16 inhibits breast cancer proliferation and metastasis through upregulating ZBTB28 and antagonizing BCL6/ZBTB27. Clin Epigenetics 2020; 12:82. [PMID: 32517789 PMCID: PMC7285556 DOI: 10.1186/s13148-020-00867-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Breast cancer remains in urgent need of reliable diagnostic and prognostic markers. Zinc finger and BTB/POZ domain-containing family proteins (ZBTBs) are important transcription factors functioning as oncogenes or tumor suppressors. The role and regulation of ZBTB16 in breast cancer remain to be established. Methods Reverse-transcription PCR and methylation-specific PCR were applied to detect expression and methylation of ZBTB16 in breast cancer cell lines and tissues. The effects of ZBTB16 in breast cancer cells were examined via cell viability, CCK8, Transwell, colony formation, and flow cytometric assays. Xenografts and immunohistochemistry analyses were conducted to determine the effects of ZBTB16 on tumorigenesis in vivo. The specific mechanisms of ZBTB16 were further investigated using Western blot, qRT-PCR, luciferase assay, and co-IP. Results ZBTB16 was frequently downregulated in breast cancer cell lines in correlation with its promoter CpG methylation status. Restoration of ZBTB16 expression led to induction of G2/M phase arrest and apoptosis, inhibition of migration and invasion, reversal of EMT, and suppression of cell proliferation, both in vitro and in vivo. Furthermore, ectopically expressed ZBTB16 formed heterodimers with ZBTB28 or BCL6/ZBTB27 and exerted tumor suppressor effects through upregulation of ZBTB28 and antagonistic activity on BCL6. Conclusions Low expression of ZBTB16 is associated with its promoter hypermethylation and restoration of ZBTB16 inhibits tumorigenesis. ZBTB16 functions as a tumor suppressor through upregulating ZBTB28 and antagonizing BCL6. Our findings also support the possibility of ZBTB16 being a prognostic biomarker for breast cancer.
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Affiliation(s)
- Jin He
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingjun Wu
- Institute of Life Science, Chongqing Medical University, Chongqing, China
| | - Lei Xiong
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yijia Gong
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Renjie Yu
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyan Peng
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Li Li
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shaorong Tian
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Wang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Tao
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. .,Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
| | - Tingxiu Xiang
- Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Singh N, Rashid S, Rashid S, Dash NR, Gupta S, Saraya A. Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients. J Cancer Res Clin Oncol 2020; 146:897-907. [PMID: 32146565 DOI: 10.1007/s00432-020-03169-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 02/27/2020] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.
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Affiliation(s)
- Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sumaira Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Safoora Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Matuszczak E, Tylicka M, Komarowska MD, Debek W, Hermanowicz A. Ubiquitin carboxy-terminal hydrolase L1 - physiology and pathology. Cell Biochem Funct 2020; 38:533-540. [PMID: 32207552 DOI: 10.1002/cbf.3527] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/20/2020] [Accepted: 03/11/2020] [Indexed: 12/12/2022]
Abstract
Ubiquitin C-terminal hydrolase 1 (UCHL1) is an enzyme unique for its multiple activity - both ligase and hydrolase. UCHL1 was first identified as an abundant protein found in the brain and testes, however its expression is not limited to the neuronal compartment. UCHL1 is also highly expressed in carcinomas of various tissue origins, including those from brain, lung, breast, kidney, colon, prostate, pancreas and mesenchymal tissues. Loss-of-function studies and an inhibitor for UCHL1 confirmed the importance of UCHL1 for cancer therapy. So far biological significance of UCHL1 was described in the following processes: spermatogenesis, oncogenesis, angiogenesis, cell proliferation and differentiation in skeletal muscle, inflammation, tissue injury, neuronal injury and neurodegeneration.
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Affiliation(s)
- Ewa Matuszczak
- Pediatric Surgery Department, Medical University of Bialystok, Bialystok, Poland
| | - Marzena Tylicka
- Biophysics Department, Medical University of Bialystok, Bialystok, Poland
| | | | - Wojciech Debek
- Pediatric Surgery Department, Medical University of Bialystok, Bialystok, Poland
| | - Adam Hermanowicz
- Pediatric Surgery Department, Medical University of Bialystok, Bialystok, Poland
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Proteomic sift through serum and endometrium profiles unraveled signature proteins associated with subdued fertility and dampened endometrial receptivity in women with polycystic ovary syndrome. Cell Tissue Res 2020; 380:593-614. [PMID: 32052139 DOI: 10.1007/s00441-020-03171-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 01/10/2020] [Indexed: 01/20/2023]
Abstract
The objective of this study is to discern the proteomic differences responsible for hampering the receptivity of endometrium and subduing the fertility of females with polycystic ovary syndrome in analogy to healthy fertile females. This study was designed in collaboration with Hakeem Abdul Hameed Centenary Hospital affiliated to Jamia Hamdard, New Delhi, India. Serum samples were taken from infertile PCOS subjects (n = 6) and fertile control subjects (n = 6) whereas endometrial tissue samples were recruited from ovulatory PCOS (n = 4), anovulatory PCOS (n = 4) and normal healthy fertile control subjects (n = 4) for proteomic studies. Additionally, endometrial biopsies from healthy fertile control (n = 8), PCOS with infertility (n = 6), unexplained infertility (n = 3) and endometrial hyperplasia (n = 3) were taken for validation studies. Anthropometric, biochemical and hormonal evaluation was done for all the subjects enrolled in this study. Protein profiles were generated through 2D-PAGE and differential proteins analyzed with PD-QUEST software followed by identification with MALDI-TOF MS protein mass fingerprinting. Validation of identified proteins was done through RT-PCR relative expression analysis. Protein profiling of serum revealed differential expression of proteins involved in transcriptional regulation, embryogenesis, DNA repair, decidual cell ploidy, immunomodulation, intracellular trafficking and degradation processes. Proteins involved in cell cycle regulation, cellular transport and signaling, DNA repair, apoptotic processes and mitochondrial metabolism were found to be differentially expressed in endometrium. The findings of this study revealed proteins that hold strong candidature as potential drug targets to regulate the cellular processes implicating infertility and reduced receptivity of endometrium in women with polycystic ovary syndrome.
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Sun R, Xiang T, Tang J, Peng W, Luo J, Li L, Qiu Z, Tan Y, Ye L, Zhang M, Ren G, Tao Q. 19q13 KRAB zinc-finger protein ZNF471 activates MAPK10/JNK3 signaling but is frequently silenced by promoter CpG methylation in esophageal cancer. Theranostics 2020; 10:2243-2259. [PMID: 32089740 PMCID: PMC7019175 DOI: 10.7150/thno.35861] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 12/04/2019] [Indexed: 12/15/2022] Open
Abstract
Zinc-finger proteins (ZFPs) are the largest transcription factor family in mammals, involved in the regulation of multiple physiologic processes including cell differentiation, proliferation, apoptosis and neoplastic transformation. Approximately one-third of ZFPs are Krüppel-associated box domain (KRAB)-ZFPs. Methods: ZNF471 expression and methylation were detected by reverse-transcription PCR and methylation-specific PCR. The impact and mechanism of ectopic ZNF471 expression in esophageal squamous cell carcinoma (ESCC) cells was evaluated in vitro and in vivo. Results: We identified a 19q13 KRAB-ZFP, ZNF471, as a methylated target in ESCC. We further found that ZNF471 is significantly downregulated in ESCC tissues compared with adjacent non-cancer tissues, due to its aberrant promoter CpG methylation, and further confirmed by methylation analysis and treatment with demethylation agent. Restoration of ZNF471 expression in silenced ESCC cells significantly altered cell morphology, induced apoptosis and G0/G1 arrest, and inhibited tumor cell colony formation, viability, migration and invasion. Importantly, ZNF471 was found to activate the expression of MAPK10/JNK3 and PCDH family genes, and further enhance MAPK10 signaling and downstream gene expression through binding to the MAPK10/JNK3 promoter. Conclusion: Our results demonstrate that ZNF471 is an important tumor suppressor and loss of ZNF471 functions hampers MAPK10/JNK3 signaling during esophageal carcinogenesis.
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Kwan SY, Au-Yeung CL, Yeung TL, Rynne-Vidal A, Wong KK, Risinger JI, Lin HK, Schmandt RE, Yates MS, Mok SC, Lu KH. Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression. Cancers (Basel) 2020; 12:cancers12010118. [PMID: 31906456 PMCID: PMC7016780 DOI: 10.3390/cancers12010118] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 12/23/2019] [Indexed: 11/16/2022] Open
Abstract
Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.
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Affiliation(s)
- Suet-Ying Kwan
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Chi-Lam Au-Yeung
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Tsz-Lun Yeung
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Angela Rynne-Vidal
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Kwong-Kwok Wong
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - John I. Risinger
- Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 48824, USA
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan
- Department of Biotechnology, Asia University, Taichung 413, Taiwan
| | - Rosemarie E. Schmandt
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Melinda S. Yates
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
| | - Samuel C. Mok
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
- Correspondence: ; Tel.: +1-713-792-1442
| | - Karen H. Lu
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
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Khetani S, Kollath VO, Eastick E, Debert C, Sen A, Karan K, Sanati-Nezhad A. Single-step functionalization of poly-catecholamine nanofilms for ultra-sensitive immunosensing of ubiquitin carboxyl terminal hydrolase-L1 (UCHL-1) in spinal cord injury. Biosens Bioelectron 2019; 145:111715. [DOI: 10.1016/j.bios.2019.111715] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/17/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023]
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Ryskalin L, Gaglione A, Limanaqi F, Biagioni F, Familiari P, Frati A, Esposito V, Fornai F. The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies. Int J Mol Sci 2019; 20:ijms20153824. [PMID: 31387280 PMCID: PMC6695733 DOI: 10.3390/ijms20153824] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 07/26/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology.
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Affiliation(s)
- Larisa Ryskalin
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy
| | | | - Fiona Limanaqi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy
| | | | | | - Alessandro Frati
- I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy
| | - Vincenzo Esposito
- I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy
- Sapienza University of Rome, 00185 Roma, Italy
| | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126, Pisa, Italy.
- I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy.
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Alur VC, Raju V, Vastrad B, Vastrad C. Mining Featured Biomarkers Linked with Epithelial Ovarian CancerBased on Bioinformatics. Diagnostics (Basel) 2019; 9:diagnostics9020039. [PMID: 30970615 PMCID: PMC6628368 DOI: 10.3390/diagnostics9020039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/31/2019] [Accepted: 04/05/2019] [Indexed: 11/16/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the18th most common cancer worldwide and the 8th most common in women. The aim of this study was to diagnose the potential importance of, as well as novel genes linked with, EOC and to provide valid biological information for further research. The gene expression profiles of E-MTAB-3706 which contained four high-grade ovarian epithelial cancer samples, four normal fallopian tube samples and four normal ovarian epithelium samples were downloaded from the ArrayExpress database. Pathway enrichment and Gene Ontology (GO) enrichment analysis of differentially expressed genes (DEGs) were performed, and protein-protein interaction (PPI) network, microRNA-target gene regulatory network and TFs (transcription factors) -target gene regulatory network for up- and down-regulated were analyzed using Cytoscape. In total, 552 DEGs were found, including 276 up-regulated and 276 down-regulated DEGs. Pathway enrichment analysis demonstrated that most DEGs were significantly enriched in chemical carcinogenesis, urea cycle, cell adhesion molecules and creatine biosynthesis. GO enrichment analysis showed that most DEGs were significantly enriched in translation, nucleosome, extracellular matrix organization and extracellular matrix. From protein-protein interaction network (PPI) analysis, modules, microRNA-target gene regulatory network and TFs-target gene regulatory network for up- and down-regulated, and the top hub genes such as E2F4, SRPK2, A2M, CDH1, MAP1LC3A, UCHL1, HLA-C (major histocompatibility complex, class I, C), VAT1, ECM1 and SNRPN (small nuclear ribonucleoprotein polypeptide N) were associated in pathogenesis of EOC. The high expression levels of the hub genes such as CEBPD (CCAAT enhancer binding protein delta) and MID2 in stages 3 and 4 were validated in the TCGA (The Cancer Genome Atlas) database. CEBPD andMID2 were associated with the worst overall survival rates in EOC. In conclusion, the current study diagnosed DEGs between normal and EOC samples, which could improve our understanding of the molecular mechanisms in the progression of EOC. These new key biomarkers might be used as therapeutic targets for EOC.
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Affiliation(s)
- Varun Chandra Alur
- Department of Endocrinology, J.J. M Medical College, Davanagere, Karnataka 577004, India.
| | - Varshita Raju
- Department of Obstetrics and Gynecology, J.J. M Medical College, Davanagere, Karnataka 577004, India.
| | - Basavaraj Vastrad
- Department of Pharmaceutics, SET`S College of Pharmacy, Dharwad, Karnataka 580002, India.
| | - Chanabasayya Vastrad
- Biostatistics and Bioinformatics,Chanabasava Nilaya, Bharthinagar,Dharwad, Karanataka 580001, India.
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Finnerty BM, Moore MD, Verma A, Aronova A, Huang S, Edwards DP, Chen Z, Seandel M, Scognamiglio T, Du YCN, Elemento O, Zarnegar R, Min IM, Fahey TJ. UCHL1 loss alters the cell-cycle in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer 2019; 26:411-423. [PMID: 30689542 DOI: 10.1530/erc-18-0507] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 01/28/2019] [Indexed: 01/04/2023]
Abstract
Loss of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) expression by CpG promoter hypermethylation is associated with metastasis in gastroenteropancreatic neuroendocrine tumors; however, the mechanism of how UCHL1 loss contributes to metastatic potential remains unclear. In this study, we first confirmed that loss of UCHL1 expression on immunohistochemistry was significantly associated with metastatic tumors in a translational pancreatic neuroendocrine tumor (PNET) cohort, with a sensitivity and specificity of 78% and 89%, respectively. To study the mechanism driving this aggressive phenotype, BON and QGP-1 metastatic PNET cell lines, which do not produce UCHL1, were stably transfected to re-express UCHL1. In vitro assays, RNA-sequencing, and reverse-phase protein array (RPPA) analyses were performed comparing empty-vector negative controls and UCHL1-expressing cell lines. UCHL1 re-expression is associated with lower anchorage-independent colony growth in BON cells, lower colony formation in QGP cells, and a higher percentage of cells in the G0/G1 cell-cycle phase in BON and QGP cells. On RPPA proteomic analysis, there was an upregulation of cell-cycle regulatory proteins CHK2 (1.2 fold change, p=0.004) and P21 (1.2 fold change, p=0.023) in BON cells expressing UCHL1; western blot confirmed upregulation of phosphorylated CHK2 and P21. There were no transcriptomic differences detected on RNA-Sequencing between empty-vector negative controls and UCHL1-expressing cell lines. In conclusion, UCHL1 loss correlates with metastatic potential in PNETs and its re-expression induces a less aggressive phenotype in vitro, in part by inducing cell-cycle arrest through post-translational regulation of phosphorylated CHK2. UCHL1 re-expression should be considered as a functional biomarker in detecting PNETs capable of metastasis.
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Affiliation(s)
| | - Maureen D Moore
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Akanksha Verma
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA
| | - Anna Aronova
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Shixia Huang
- Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
| | - Dean P Edwards
- Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
| | - Zhengming Chen
- Department of Healthcare Policy & Research, Weill Cornell Medicine, New York, New York, USA
| | - Marco Seandel
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Theresa Scognamiglio
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Yi-Chieh Nancy Du
- Department of Pathology & Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA
| | - Rasa Zarnegar
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Irene M Min
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
| | - Thomas J Fahey
- Department of Surgery, Weill Cornell Medicine, New York, New York, USA
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Xiang Q, He X, Mu J, Mu H, Zhou D, Tang J, Xiao Q, Jiang Y, Ren G, Xiang T, Peng W. The phosphoinositide hydrolase phospholipase C delta1 inhibits epithelial-mesenchymal transition and is silenced in colorectal cancer. J Cell Physiol 2019; 234:13906-13916. [PMID: 30618183 DOI: 10.1002/jcp.28073] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 12/18/2018] [Indexed: 12/21/2022]
Abstract
In this study, we found that the phospholipase C delta1 (PLCD1) protein expression is reduced in colorectal tumor tissues compared with paired surgical margin tissues. PLCD1-promoted CpG methylation was detected in 29/64 (45%) primary colorectal tumors, but not in nontumor tissues. The PLCD1 RNA expression was also reduced in three out of six cell lines, due to PLCD1 methylation. The ectopic expression of PLCD1 resulted in inhibited proliferation and attenuated migration of colorectal tumor cells, yet promoted colorectal tumor cell apoptosis in vitro. We also observed that PLCD1 suppressed proliferation and promoted apoptosis in vivo. In addition, PLCD1 induced G1/S phase cell cycle arrest. Furthermore, we found that PLCD1 led to the downregulation of several factors downstream of β-catenin, including c-Myc and cyclin D1, which are generally known to be promoters of tumorigenesis. This downregulation was caused by an upregulation of E-cadherin in colorectal tumor cells. Our findings provide insights into the role of PLCD1 as a tumor suppressor gene in colorectal cancer (CRC), and demonstrate that it plays significant roles in proliferation, migration, invasion, cell cycle progression, and epithelial-mesenchymal transition. On the basis of these results, tumor-specific methylation of PLCD1 could be used as a novel biomarker for early detection and prognostic prediction in CRC.
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Affiliation(s)
- Qin Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqian He
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Junhao Mu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haixi Mu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dishu Zhou
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Tang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Xiao
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Jiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyan Peng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Zhang Y, Xu H, Mu J, Guo S, Ye L, Li D, Peng W, He X, Xiang T. Inactivation of ADAMTS18 by aberrant promoter hypermethylation contribute to lung cancer progression. J Cell Physiol 2018; 234:6965-6975. [PMID: 30417422 DOI: 10.1002/jcp.27439] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 08/28/2018] [Indexed: 12/19/2022]
Abstract
Lung cancer is the most frequently diagnosed cancer worldwide. Epigenetic regulation contributes to lung cancer pathogenesis. The ADAMTS18 tumor suppressor gene is inactivated in some cancers, but its involvement in lung cancer has not been shown. Immunohistochemistry, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and methylation-specific PCR were used to assay ADAMTS18 expression and promoter methylation in lung tumor tissues and adjacent tissues. Cell viability, transwell, and wound-healing assays, as well as flow cytometry were used to characterize the biological activity of ADAMTS18. The influence of ADAMTS18 on protein expression was assayed using western blots analysis, and its effect on chemosensitivity was assayed by the response to cisplatin. We found that ADAMTS18 was silenced in lung cancer cells by promoter methylation. Demethylation by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, with or without the histone deacetylase inhibitor trichostatin A, restored ADAMTS18 expression. Compared with normal lung tissue, ADAMTS18 in lung tumors was frequently methylated. Overexpression of ADAMTS18 in lung cancer cells inhibited cell proliferation, migration, and invasiveness and induced G0/G1 cell cycle arrest. Furthermore, ADAMTS18 suppressed epidermal growth factor receptor/protein kinase B (EGFR/AKT) signaling, which sensitized lung cancer cells to cisplatin. Thus, our results demonstrated that the tumor suppressor gene ADAMTS18 was downregulated in lung cancer by promoter CpG methylation, and it promoted sensitivity to cisplatin via EGFR/AKT signaling. Our study suggests that ADAMTS18 promoter methylation is a potential epigenetic biomarker for early detection of lung cancer and warrants investigation as a therapeutic target for early-stage lung cancer.
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Affiliation(s)
- Yan Zhang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongying Xu
- Department of Respiratory Medicine, The Sixth People's Hospital of Chongqing, Chongqing, China
| | - Junhao Mu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuliang Guo
- Department of Respiratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Ye
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dairong Li
- Department of Respiratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Weiyan Peng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoqian He
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Sun R, Ye L, Zhang M, Qiu Z, Xiang T, Tang J, Wang X, Li L, Luo J, Zhang D, Ren G. Prognostic significance of interferon regulating factor 4 in esophageal squamous cell carcinoma. Biochem Biophys Res Commun 2018; 506:685-691. [PMID: 30376993 DOI: 10.1016/j.bbrc.2018.10.142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/23/2018] [Indexed: 12/09/2022]
Abstract
BACKGROUND Aberrant expression of interferon regulatory factor 4 (IRF4) has been reported in several hematologic malignancies. However, the prognostic significance of IRF4 expression in esophageal squamous cell carcinoma (ESCC) remains unknown. METHODS IRF4 protein expression in ESCC tumor specimens was determined immunohistochemically. The correlation of IRF4 expression with clinico-pathological features was assessed from a cohort of 100 patients with primary ESCC. Kaplan-Meier and Cox proportional regression analyses were used to evaluate the association between IRF4 expression and patient survival. RESULTS A Kaplan-Meier analysis indicated that patients with high IRF4 expression had a significantly longer overall survival rate than those with low IRF4 expression (p = 0.0006). Furthermore, multi-variate analyses revealed that IRF4 protein expression is an independent prognostic indicator for ESCC patients. CONCLUSION Our results suggest that increased IRF4 protein expression correlates with improved outcome in ESCC. IRF4 may therefore represent a promising prognostic biomarker and potential immuno-therapeutic target for patients with ESCC.
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Affiliation(s)
- Ran Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lin Ye
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Zhang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhu Qiu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Tang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiangyu Wang
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Jie Luo
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
| | - Dongsheng Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Gu Y, Lv F, Xue M, Chen K, Cheng C, Ding X, Jin M, Xu G, Zhang Y, Wu Z, Zheng L, Wu Y. The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:258. [PMID: 30359286 PMCID: PMC6203192 DOI: 10.1186/s13046-018-0931-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 10/17/2018] [Indexed: 11/25/2022]
Abstract
Background Neuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive. Methods The correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro. Results Based on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What’s more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest. Conclusion Our findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB. Electronic supplementary material The online version of this article (10.1186/s13046-018-0931-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuting Gu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.,Department of Stomatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fan Lv
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Mingxing Xue
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Science, Chinese Academy of Sciences, Shanghai, China
| | - Kai Chen
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Cheng Cheng
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China
| | - Xinyuan Ding
- Department of Pharmacy, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Min Jin
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Science, Chinese Academy of Sciences, Shanghai, China
| | - Guofeng Xu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China
| | - Yanyun Zhang
- Shanghai Institutes for Biological Sciences, University of Chinese Academy of Science, Chinese Academy of Sciences, Shanghai, China
| | - Zhixiang Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. .,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China. .,Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, China.
| | - Leizhen Zheng
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
| | - Yeming Wu
- Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China. .,Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, China. .,Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, China.
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Yue Y, Zhou K, Li J, Jiang S, Li C, Men H. MSX1 induces G0/G1 arrest and apoptosis by suppressing Notch signaling and is frequently methylated in cervical cancer. Onco Targets Ther 2018; 11:4769-4780. [PMID: 30127625 PMCID: PMC6091477 DOI: 10.2147/ott.s165144] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE The objectives of this study were to investigate the expression of MSX1 in cervical cells and tissues, the methylation status of the MSX1 promoter, the influence of overexpression of gene MSX1 on the proliferation, migration, and invasion of HeLa and SiHa cells, and finally the possible molecular mechanisms responsible for the suppressive effects of MSX1 upon cervical cancer cells. PATIENTS AND METHODS Semi-quantitative and quantitative reverse transcription-polymerase chain reactions were used to investigate the expression levels of MSX1, and methylation-specific polymerase chain reaction (MSP) was performed to investigate promoter methylation status in cervical cancer cell lines, primary cervical tissues, and normal cervical tissues. Clone formation, Cell Counting Kit-8 (CCK-8), cell wound scratch, and transwell assays were performed to verify whether MSX1 could inhibit the proliferation and migration of cervical cancer cells. Western blot was used to analyze the effect of MSX1 upon Notch1, Jagged1, c-Myc, cleaved PARP, cleaved caspse-3, and cyclin D1 (CCND1). RESULTS MSX1 was frequently downregulated or silenced in 60.0% (3/5) of cervical cancer cell lines. The promoter methylation of MSX1 was detected in 42.0% (42/100) of primary tumor tissues, while no methylation was observed in normal cervical tissues. Pharmacological demethylation reduced MSX1 promoter methylation levels and restored the expression of MSX1. The overexpression of MSX1 in cervical cancer cells thus inhibited the proliferation and migration of cervical cancer cells. The overexpression of MSX1 in cervical cancer cells downregulated the expression levels of Notch1, Jagged1, and c-Myc but upregulated the expression levels of CCND1, cleaved PARP, and cleaved caspase-3. CONCLUSION MSX1 appears to be a functional tumor suppressor that regulates tumorigenesis in cervical cancer by antagonizing Notch signaling.
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Affiliation(s)
- Yujuan Yue
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Kun Zhou
- Clinical Center for Tumor Therapy, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China,
| | - Jiachu Li
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Shan Jiang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Chunyan Li
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Haitao Men
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
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