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Li J, Yong T, Chen Y, Zeng T, Zhang K, Wang S, Zhang Y. Targeting PCNA/PARP1 axis inhibits the malignant progression of hepatocellular carcinoma. Front Pharmacol 2025; 16:1571786. [PMID: 40313621 PMCID: PMC12043649 DOI: 10.3389/fphar.2025.1571786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
Introduction Proliferating cell nuclear antigen (PCNA) is associated with the proliferation and recurrence of various cancers, and its high expression is associated with poor prognosis in hepatocellular carcinoma (HCC) patients. However, the mechanistic role of PCNA in HCC progression remains poorly understood. This study aimed to investigate how PCNA regulates DNA damage repair and cell cycle progression in HCC, with a focus on its interaction with poly (ADP-ribose) polymerase 1 (PARP1) and therapeutic implications. Methods PCNA was targeted genetically and pharmacologically in HCC cells to assess its effects on DNA damage repair and cell cycle arrest. Protein-protein interactions between PCNA and PARP1 were validated through co-immunoprecipitation and functional assays. The sensitivity of HCC cells to the PARP1 inhibitor Olaparib was evaluated under PCNA inhibition. Synergistic effects of AOH1160 (a PCNA inhibitor) and Olaparib were tested in vitro and in vivo using proliferation assays, DNA damage quantification, and cell cycle analysis. Prognostic relevance of PCNA expression was analyzed using TCGA datasets. Results Targeting PCNA suppressed DNA damage repair and induced cell cycle arrest in HCC cells. Mechanistically, PARP1 was identified as a downstream target of PCNA and directly interacted with PCNA. Inhibiting the expression or activity of PCNA increased the sensitivity of HCC cells to the PARP1 inhibitor, Olaparib. In addition, AOH1160 and Olaparib synergistically inhibited the proliferation, DNA damage repair and cell cycle progression of HCC cells. Elevated PCNA levels correlated with unfavorable HCC prognosis, supporting its role as a therapeutic biomarker. In vivo experiments also confirmed that repression of the PCNA/PARP1 axis significantly reduced HCC tumor growth. Discussion This study elucidates the relationship between PCNA and PARP1 in regulating the malignant progression of HCC, and highlight the pivotal role of PCNA/PARP1 axis in DNA damage repair and cell cycle progression. The correlation between elevated PCNA levels and unfavorable prognosis underscores its potential as a therapeutic biomarker. Repression of PCNA/PARP1 axis significantly inhibits the malignant proliferation of HCC cells both in vitro and in vivo. Collectively, the study provides a mechanistic foundation for therapies targeting PCNA/PARP1 axis.
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Affiliation(s)
- Jipin Li
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Tao Yong
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Yali Chen
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Tingyu Zeng
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Kaifeng Zhang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Shuping Wang
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Youcheng Zhang
- Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
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Cavelius PM, Haack M, Awad D, Brueck TB, Mehlmer N. Rhodosporidium toruloides-a new surrogate model to study rapamycin induced effects on human aging and cancer. Cell Mol Life Sci 2025; 82:153. [PMID: 40205123 PMCID: PMC11982011 DOI: 10.1007/s00018-025-05662-4] [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: 09/26/2024] [Revised: 02/07/2025] [Accepted: 03/17/2025] [Indexed: 04/11/2025]
Abstract
The haploid, olegenious yeast Rhodosporidium toruloides accumulates intracellular lipids and carotenoids upon metabolic stress. Target of Rapamycin (TOR) signaling, essential for cell proliferation, is known to affect cellular lipid accumulation. In contrast to the conventional surrugate cell model S. cerevisiae, which harbours two TOR kinases within its TOR complex, R. toruloides only harbours one TOR kinase, mimicking mammalian systems. We used a proteomics centered approach to probe the cellular response, of the two R. toruloides haplotypes, IFO0559 and IFO0880 upon treatment with the TOR inhibitor rapamycin, with an original focus on difference in carotenoid and lipid accumulation. Unexpectedly, IFO0880 displayed severe growth arrest in response to rapamycin, while IFO0559 did not. Proteomic anaysis revealed differential expression of several proteins involved in cell cycle control, lipogensis, amino acid metabolism and autophagy between the two haplotypes. Among those we identified several proteins previously described in both mammalian oncogenic and aging contexts. This differential haplotype response to rapamycin treatment positions R. toruloides as a promising cell surrugate model to study cellular mechanisms underlying rapamycin response especially for systems with high lipid contents, an emerging hallmark of different forms of mammalian cancer and age related disease.
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Affiliation(s)
- Philipp M Cavelius
- Department of Chemistry, Werner Siemens-Chair of Synthetic Biotechnology, Technical University of Munich (TUM), Garching, Germany
| | - Martina Haack
- Department of Chemistry, Werner Siemens-Chair of Synthetic Biotechnology, Technical University of Munich (TUM), Garching, Germany
| | - Dania Awad
- Department of Chemistry, Werner Siemens-Chair of Synthetic Biotechnology, Technical University of Munich (TUM), Garching, Germany
| | - Thomas B Brueck
- Department of Chemistry, Werner Siemens-Chair of Synthetic Biotechnology, Technical University of Munich (TUM), Garching, Germany.
| | - Norbert Mehlmer
- Department of Chemistry, Werner Siemens-Chair of Synthetic Biotechnology, Technical University of Munich (TUM), Garching, Germany.
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Du D, Zhang W, Zhang D, Liu L, Li J, Chen Z, Yu X, Ye M, Wang W, Li Z, Shao J. NUB1 reduction promotes PCNA-mediated tumor growth by disturbing the PCNA polyubiquitination/NEDDylation in hepatocellular carcinoma cells. Cell Death Dis 2025; 16:228. [PMID: 40164590 PMCID: PMC11958677 DOI: 10.1038/s41419-025-07567-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/08/2025] [Accepted: 03/18/2025] [Indexed: 04/02/2025]
Abstract
Negative regulator of ubiquitin-like protein 1 (NUB1), an inhibitor of neural precursor cells expressed developmentally downregulated 8 (NEDD8), is implicated in tumor growth. However, the expression of NUB1 in hepatocellular carcinoma (HCC) and its effects on HCC growth remain unclear. In this study, our findings revealed reduced NUB1 protein expression in HCC tissues and cells, leading to increased proliferating cell nuclear antigen (PCNA) protein stability through upregulating NEDD8 to promote HCC cell growth. Mechanistically, NUB1 reduction upregulated NEDD8 to promote PCNA NEDDylation at lysine 164 (Lys164), in turn, antagonized PCNA K48-linked polyubiquitination, thereby increasing the stability of PCNA in HCC cells. Finally, the results of the in vitro and in vivo experiments revealed that the NEDDylation inhibitor TAS4464 could inhibit PCNA NEDDylation to decrease PCNA protein expression, thereby suppressing HCC cell growth. Collectively, our results identified NUB1 as a negative regulator of HCC proliferation and confirmed that PCNA NEDDylation promotes PCNA protein stability by antagonizing PCNA polyubiquitination. This study provides a new perspective on the specific mechanism of HCC growth. It expands our understanding of the role of NEDDylation in the regulation of substrate proteins and their functions.
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Affiliation(s)
- Dongnian Du
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Wenming Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Dandan Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Lingpeng Liu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Jiajuan Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Zehao Chen
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Xuzhe Yu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Miao Ye
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Wei Wang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Zijing Li
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China
| | - Jianghua Shao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
- Jiangxi Province Key Laboratory of Molecular Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
- Liver Cancer Institute, Nanchang University, Nanchang, 330000, China.
- Jiangxi Province Clinical Research Center of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Nanchang University, Nanchang, China.
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Luo S, Bai Y, Wang B, Xu H, Zhang S, Guo G, Li X, Sun H, Cui X. HOXA1 Promotes Migration, Invasion and Cell Cycle, and Suppresses Cisplatin Sensitivity of Laryngeal Cancer Cells By Mediating AKT/mTOR Pathway. TOHOKU J EXP MED 2025; 265:161-171. [PMID: 39085122 DOI: 10.1620/tjem.2024.j073] [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] [Indexed: 08/02/2024]
Abstract
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
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Affiliation(s)
- Shaohao Luo
- Graduate School, Inner Mongolia Medical University
| | - Yunfei Bai
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Boqian Wang
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Haixia Xu
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Shu Zhang
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Gang Guo
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Xin Li
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Hongyang Sun
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
| | - Xiaobo Cui
- Department of Otolaryngology, Head and Neck Surgery, the Affiliated Hospital of Inner Mongolia Medical University
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Soltanipur M, Rohani Bastami M, Shahshenas S, Ghorbanniadelavar Z, Barouh A, Shadmand A, Karimi Nemch M, Yarmohammadi H, Siadat SD, Jalali Nadoushan M. Expression of Proliferating Cell Nuclear Antigen (PCNA) in Nasal Polyp: A Systematic Review and Meta-analysis. Indian J Otolaryngol Head Neck Surg 2025; 77:608-619. [PMID: 40066409 PMCID: PMC11890497 DOI: 10.1007/s12070-024-05172-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 10/24/2024] [Indexed: 05/10/2025] Open
Abstract
UNLABELLED Nasal polyp (NP) is a pathological benign mass that affects the nasal cavity and paranasal sinuses. This lesion is occasionally associated with chronic rhinosinusitis (CRS), which is named chronic rhinosinusitis with nasal polyps (CRSwNP). Proliferating cell nuclear antigen (PCNA) indicates abnormal cell proliferation which may help assess the nasopharyngeal lesions and upper airway cancers. This study aimed to examine the PCNA expression in NP tissue. This study was conducted under the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A thorough search using relevant keywords was performed on the electronic database to identify studies examining the PCNA expression in NP. Meta-analysis on pooled single group proportion and means of PCNA expression was conducted by the metamean and metaprop functions in R software (version 4.4.0). Quality assessment was done according to the Joanna Briggs Institute (JBI) checklist. Ten articles were included in this study. The PCNA expression in NP was higher than in normal nasal mucosa (NNM), while its expression in NP was lower than in inverted papilloma (IP). The mean percentage of PCNA expression in NP was 15.73% (95%-CI[2.87-28.58]) with considerable heterogeneity (I 2 = 97%[96-98%],p-value < 0.01). Based on a cutoff staining (> 5%), 64% of NP samples were PCNA-positive (95%-CI[42-81%]) with high heterogeneity (I 2 = 76%[47-89%], p-value < 0.01). NP tissue has a relatively high expression of the PCNA oncoprotein based on the immunohistochemistry (IHC) staining. Although more than half of NP samples were positive for PCNA, still the mean expression of this marker in NP was lower than in IP tissue. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12070-024-05172-y.
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Affiliation(s)
- Masood Soltanipur
- Quality of Life Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- General Practitioner (GP), Avicenna Hospital, Tehran, Iran
| | | | - Sina Shahshenas
- Student Research Committee, Faculty of Medicine, Shahed University, Tehran, Iran
| | | | - Alireza Barouh
- Student Research Committee, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Alireza Shadmand
- Faculty of Economics and Social Sciences, Heidelberg University, Heidelberg, Germany
| | | | - Hossein Yarmohammadi
- Quality of Life Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
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Chen H, Zhang W, Shi J, Tang Y, Chen X, Li J, Yao X. Study on the mechanism of S100A4-mediated cancer oncogenesis in uveal melanoma cells through the integration of bioinformatics and in vitro experiments. Gene 2024; 911:148333. [PMID: 38431233 DOI: 10.1016/j.gene.2024.148333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/13/2024] [Accepted: 02/28/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND The elevated metastasis rate of uveal melanoma (UM) is intricately correlated with patient prognosis, significantly affecting the quality of life. S100 calcium-binding protein A4 (S100A4) has tumorigenic properties; therefore, the present study investigated the impact of S100A4 on UM cell proliferation, apoptosis, migration, and invasion using bioinformatics and in vitro experiments. METHODS Bioinformatic analysis was used to screen S100A4 as a hub gene and predict its possible mechanism in UM cells, and the S100A4 silencing cell line was constructed. The impact of S100A4 silencing on the proliferative ability of UM cells was detected using the Cell Counting Kit-8 and colony formation assays. Annexin V-FITC/PI double fluorescence and Hoechst 33342 staining were used to observe the effects of apoptosis on UM cells. The effect of S100A4 silencing on the migratory and invasive capabilities of UM cells was assessed using wound healing and Transwell assays. Western blotting was used to detect the expression of related proteins. RESULTS The present study found that S100A4 is a biomarker of UM, and its high expression is related to poor prognosis. After constructing the S100A4 silencing cell line, cell viability, clone number, proliferating cell nuclear antigen, X-linked inhibitor of apoptosis protein, and survivin expression were decreased in UM cells. The cell apoptosis rate and relative fluorescence intensity increased, accompanied by increased levels of Bax and caspase-3 and decreased levels of Bcl-2. Additionally, a decrease in the cell migration index and relative invasion rate was observed with increased E-cadherin expression and decreased N-cadherin and vimentin protein expression. CONCLUSION S100A4 silencing can inhibit the proliferation, migration, and invasion and synchronously induces apoptosis in UM cells.
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Affiliation(s)
- Huimei Chen
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Wenqing Zhang
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Jian Shi
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Yu Tang
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Xiong Chen
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Jiangwei Li
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Xiaolei Yao
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China.
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Tiberio L, Laffranchi M, Zucchi G, Salvi V, Schioppa T, Sozzani S, Del Prete A, Bosisio D. Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer. Front Immunol 2024; 15:1360291. [PMID: 38504978 PMCID: PMC10948453 DOI: 10.3389/fimmu.2024.1360291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/22/2024] [Indexed: 03/21/2024] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an "innate checkpoint", reminiscent of the function of "classical" adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.
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Affiliation(s)
- Laura Tiberio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Mattia Laffranchi
- Department of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, Italy
| | - Giovanni Zucchi
- Department of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, Italy
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Tiziana Schioppa
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Silvano Sozzani
- Department of Molecular Medicine, Laboratory Affiliated to Institute Pasteur-Italia, Sapienza University of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, IS, Italy
| | - Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- IRCCS Humanitas Research Hospital, Milan, Italy
| | - Daniela Bosisio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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Malta TM, Sabedot TS, Morosini NS, Datta I, Garofano L, Vallentgoed W, Varn FS, Aldape K, D'Angelo F, Bakas S, Barnholtz-Sloan JS, Gan HK, Hasanain M, Hau AC, Johnson KC, Cazacu S, deCarvalho AC, Khasraw M, Kocakavuk E, Kouwenhoven MC, Migliozzi S, Niclou SP, Niers JM, Ormond DR, Paek SH, Reifenberger G, Sillevis Smitt PA, Smits M, Stead LF, van den Bent MJ, Van Meir EG, Walenkamp A, Weiss T, Weller M, Westerman BA, Ylstra B, Wesseling P, Lasorella A, French PJ, Poisson LM, Verhaak RG, Iavarone A, Noushmehr H. The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen. Cancer Res 2024; 84:741-756. [PMID: 38117484 PMCID: PMC10911804 DOI: 10.1158/0008-5472.can-23-2093] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 09/15/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023]
Abstract
Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. SIGNIFICANCE Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.
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Affiliation(s)
- Tathiane M. Malta
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Thais S. Sabedot
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
| | | | - Indrani Datta
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
| | - Luciano Garofano
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | - Wies Vallentgoed
- Neurology Department, The Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Frederick S. Varn
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
| | | | - Fulvio D'Angelo
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Spyridon Bakas
- Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Hui K. Gan
- Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Melbourne, Australia
| | - Mohammad Hasanain
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | | | - Kevin C. Johnson
- Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut
| | - Simona Cazacu
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
| | - Ana C. deCarvalho
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
| | | | - Emre Kocakavuk
- Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center (WTZ), National Center for Tumor Diseases (NCT) West, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Mathilde C.M. Kouwenhoven
- Department of Neurology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Simona Migliozzi
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
| | | | - Johanna M. Niers
- Department of Neurology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - D. Ryan Ormond
- University of Colorado School of Medicine, Department of Neurosurgery, Aurora, Colorado
| | - Sun Ha Paek
- Department of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute, Seoul National University, Seoul, Republic of Korea (South)
| | - Guido Reifenberger
- Institute of Neuropathology, Heinrich Heine University, Dusseldorf, Germany
| | - Peter A. Sillevis Smitt
- Department of Neurology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- The Brain Tumour Centre, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Marion Smits
- Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Lucy F. Stead
- Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
| | - Martin J. van den Bent
- Department of Neurology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- The Brain Tumour Centre, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Erwin G. Van Meir
- Department of Neurosurgery and O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama
| | | | - Tobias Weiss
- Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Michael Weller
- Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Bart A. Westerman
- Department of Neurology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Bauke Ylstra
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Pieter Wesseling
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
- Brain Tumor Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands
- Laboratory for Childhood Cancer Pathology, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Anna Lasorella
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Pim J. French
- Neurology Department, The Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Laila M. Poisson
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
| | - Roel G.W. Verhaak
- Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut
- Department of Neurosurgery, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Antonio Iavarone
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Houtan Noushmehr
- Hermelin Brain Tumor Center, Henry Ford Health System, Detroit, Michigan
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9
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Wu M, Mu C, Yang H, Wang Y, Ma P, Li S, Wang Z, Lan T. 8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer. Mol Biol Rep 2024; 51:140. [PMID: 38236447 DOI: 10.1007/s11033-023-09037-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 11/28/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I), a serine/threonine kinase, is important in tumor development. The present study determines that the cGMP/PKG I pathway is essential for promoting cell proliferation and survival in human ovarian cancer cells, whereas cGMP analog has been shown to lead to growth inhibition and apoptosis of various cancer cells. The role of cGMP/PKG I pathway in epithelial ovarian cancer (EOC), therefore, remains controversial. We investigated the effect of cGMP/PKG I pathway and the underlying mechanism in EOC. METHODS AND RESULTS The results showed that exogenous 8-Bromoguanosine-3', 5'-cyclic monophosphate (8-Br-cGMP) (cGMP analog) could antagonize the effects by EGF, including suppressing proliferation, invasion and migration of EOC cells. In vivo, 8-Br-cGMP hampered the growth of the xenograft tumor. Additionally, the expressions of epidermal growth factor receptor (EGFR), matrix metallopeptidase 9 (MMP9), proliferating cell nuclear antigen and Ki67 in xenograft tumor were decreased after 8-Br-cGMP intervention. Further research demonstrated that 8-Br-cGMP decreased the phosphorylation of EGFR (Y992) and downstream proteins phospholipase Cγ1 (PLC γ1) (Y783), calmodulin kinase II (T286) and inhibited cytoplasmic Ca2+ release as well as PKC transferring to cell membrane. It's worth noting that the inhibition was 8-Br-cGMP dose-dependent and 8-Br-cGMP showed similar inhibitory effect on EOC cells compared with U-73122, a specific inhibitor of PLC γ1. CONCLUSIONS The activation of endogenous PKG I by addition of exogenous 8-Br-cGMP could inhibit EOC development probably via EGFR/PLCγ1 signaling pathway. 8-Br-cGMP/PKG I provide a new insight and strategy for EOC treatment.
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Affiliation(s)
- Min Wu
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Chunyan Mu
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Huiwen Yang
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Yue Wang
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
| | - Ping Ma
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Shibao Li
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhongcheng Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China.
| | - Ting Lan
- Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu, China.
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, People's Republic of China.
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10
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Liang K, Pan X, Chen Y, Huang S. Anti-ovarian cancer actions and pharmacological targets of plumbagin. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1205-1210. [PMID: 36692828 DOI: 10.1007/s00210-023-02393-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 01/10/2023] [Indexed: 01/25/2023]
Abstract
Ovarian cancer is a gynecological malignancy characterized with increasing death rate in the world. It is clinically reported that chemotherapy against ovarian cancer is still found with poor curative effect and potential side effect. Plumbagin is an emerging anti-cancer compound. Although some experimental findings of plumbagin anti-ovarian cancer activity are described, the pharmacological targets should be further explored. In this study, we aimed to investigate the underlying pharmacological activities and targets of plumbagin against ovarian cancer in vitro. As results, in silico docking analysis suggested plumbagin potently treating ovarian cancer through regulating pharmacological targets, including octamer-binding transcription factor 4 (OCT4) and Kruppel-like factor 4 (KLF4). The preliminary experimental data showed that plumbagin treatment inhibited cell growth and induced apoptosis in cancer cells. In addition, decreased mRNA expressions of intracellular OCT4, PCNA, and elevated KLF4 mRNA activation were detected in plumbagin-treated cancer cells. Furthermore, immunostaining determination showed reduced OCT4-positive cells and increased KLF4-positive cells were observed following plumbagin treatments. To sum up, our current findings have preliminarily showed the anti-ovarian cancer benefits of plumbagin, and the pharmacological targets may be identified as KLF4 and OCT4 pathway. Thus, we conclude that plumbagin may be a bioactive compound for ovarian cancer treatment.
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Affiliation(s)
- Kai Liang
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Guangxi, Nanning, People's Republic of China
| | - Xinwei Pan
- Department of Pharmacy, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Guangxi, Nanning, People's Republic of China.
| | - Yumei Chen
- Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, People's Republic of China
| | - Shaode Huang
- Guangxi Vocational University of Agriculture, Nanning, People's Republic of China
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11
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NKp44-Derived Peptide Used in Combination Stimulates Antineoplastic Efficacy of Targeted Therapeutic Drugs. Int J Mol Sci 2022; 23:ijms232214054. [PMID: 36430528 PMCID: PMC9692391 DOI: 10.3390/ijms232214054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022] Open
Abstract
Lung cancer cells in the tumor microenvironment facilitate immune evasion that leads to failure of conventional chemotherapies, despite provisionally decided on the genetic diagnosis of patients in a clinical setup. The current study follows three lung cancer patients who underwent "personalized" chemotherapeutic intervention. Patient-derived xenografts (PDXs) were subjected to tumor microarray and treatment screening with chemotherapies, either individually or in combination with the peptide R11-NLS-pep8; this peptide targets both membrane-associated and nuclear PCNA. Ex vivo, employing PDX-derived explants, it was found that combination with R11-NLS-pep8 stimulated antineoplastic effect of chemotherapies that were, although predicted based on the patient's genetic mutation, inactive on their own. Furthermore, treatment in vivo of PDX-bearing mice showed an exactly similar trend in the result, corroborating the finding to be translated into clinical setup.
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12
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The Comparative Experimental Study of Sodium and Magnesium Dichloroacetate Effects on Pediatric PBT24 and SF8628 Cell Glioblastoma Tumors Using a Chicken Embryo Chorioallantoic Membrane Model and on Cells In Vitro. Int J Mol Sci 2022; 23:ijms231810455. [PMID: 36142368 PMCID: PMC9499689 DOI: 10.3390/ijms231810455] [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: 08/16/2022] [Revised: 08/31/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
In this study, pyruvate dehydrogenase kinase-1 inhibition with dichloroacetate (DCA) was explored as an alternative cancer therapy. The study’s aim was to compare the effectiveness of NaDCA and MgDCA on pediatric glioblastoma PBT24 and SF8628 tumors and cells. The treatment effects were evaluated on xenografts growth on a chicken embryo chorioallantoic membrane. The PCNA, EZH2, p53, survivin expression in tumor, and the SLC12A2, SLC12A5, SLC5A8, CDH1, and CDH2 expression in cells were studied. The tumor groups were: control, cells treated with 10 mM and 5 mM of NaDCA, and 5 mM and 2.5 mM of MgDCA. The cells were also treated with 3 mM DCA. Both the 10 mM DCA preparations significantly reduced PBT24 and SF8624 tumor invasion rates, while 5 mM NaDCA reduced it only in the SF8628 tumors. The 5 mM MgDCA inhibited tumor-associated neoangiogenesis in PBT24; both doses of NaDCA inhibited tumor-associated neoangiogenesis in SF8628. The 10 mM DCA inhibited the expression of markers tested in PBT24 and SF8628 tumors, but the 5 mM DCA affect on their expression depended on the cation. The DCA treatment did not affect the SLC12A2, SLC12A5, and SLC5A8 expression in cells but increased CDH1 expression in SF8628. The tumor response to DCA at different doses indicated that a contrast between NaDCA and MgDCA effectiveness reflects the differences in the tested cells’ biologies.
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13
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Bagheri R, Rassouli FB, Gholamhosseinian H, Ebrahimi K, Mahdavi S, Goudarzi S, Iranshahi M, Rafatpanah H, Keramati MR. Radiation Response of Human Leukemia/Lymphoma Cells was Improved by 7-Geranyloxycoumarin. Dose Response 2022; 20:15593258221124479. [PMID: 36158737 PMCID: PMC9500271 DOI: 10.1177/15593258221124479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Objectives Adult T-cell leukemia/lymphoma (ATLL) is a blood neoplasm with specific geographic distribution. Although radiotherapy is a palliative treatment that provides long-term local control, single use of radiation leads to complications for patients. To introduce a novel multimodal approach against ATLL, we investigated combinatorial effects of 7-geranyloxycoumarin and radiation in vitro. Methods Viability of MT-2 cells was determined by resazurin assay upon administration of 7-geranyloxycoumarin alone and followed by radiation. Then, apoptosis was detected by annexin V and propidium iodide, and the expression of candidate genes was analyzed by qPCR. Results Findings revealed significant (P<.0001) improvement in radiation effects upon 7-geranyloxycoumarin pretreatment, most notably when cells were pretreated with 5 µg/ml 7-geranyloxycoumarin for 96 h, exposed to 6 Gy radiation and recovered for 48 h. These results were confirmed by flow cytometry, as the percentage of early and late apoptotic cells was increased after combinatorial treatment. In addition, significant (P< .0001) changes in CD44, c-MYC, cFLIPL, BMI-1, NF-κB (Rel A), and P53 expression was induced by 7-geranyloxycoumarin and radiation. Conclusions Current research indicated, for the first time, that combinatorial use of 7-geranyloxycoumarin and ionizing radiation could be considered as an effective therapeutic modality for ATLL.
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Affiliation(s)
- Ramin Bagheri
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B. Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hamid Gholamhosseinian
- Department of Medical Physics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Keyhan Ebrahimi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Shakiba Mahdavi
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Sajad Goudarzi
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Houshang Rafatpanah
- Immunology Research Center, Inflammation and inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keramati
- Cancer Molecular Pathology Research Center, Department of Hematology and Blood Bank, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Ring finger protein 6 enhances chemo-resistance by transcriptionally activating proliferating cell nuclear antigen expression and attenuating DNA damage in lung adenocarcinoma. Cancer Lett 2022; 534:215609. [DOI: 10.1016/j.canlet.2022.215609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/15/2022] [Accepted: 02/24/2022] [Indexed: 11/20/2022]
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15
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Wang H, Jiang Y, Liang Y, Wei L, Zhang W, Li L. Observation of the cervical microbiome in the progression of cervical intraepithelial neoplasia. BMC Cancer 2022; 22:362. [PMID: 35379200 PMCID: PMC8981842 DOI: 10.1186/s12885-022-09452-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 03/21/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE Cervical microbial community in the cervical intraepithelial neoplasia and cervical cancer patients was analysed to study its composition, diversity and signalling pathways by high-throughput 16S rDNA sequencing,and the candidate genes associated with occurrence and progression of cervical intraepithelial neoplasia were screened out and the model was established to predict the evolution of cervical intraepithelial neoplasia malignant transformation from the cervical microbial genes aspect. METHODS Cervical tissues of normal, cervical intraepithelial neoplasia and cervical cancer patients without receiving any treatment were collected. The correlation between candidate genes and cervical intraepithelial neoplasia progression was initially determined by analyzing the microbial flora. Real-time fluorescence quantitative PCR was used to detect the expression of candidate genes in different cervical tissues, ROC curve and logistic regression was used to analyse and predict the risk factors related to the occurrence and progression of cervical intraepithelial neoplasia. Finally, the early warning model of cervical intraepithelial neoplasia occurrence and progression is established. RESULTS Cervical tissues from normal, cervical intraepithelial neoplasia and cervical cancer patients were collected for microbial community high-throughput 16S rDNA sequencing. The analysis revealed five different pathways related to cervical intraepithelial neoplasia. 10 candidate genes were selected by further bioinformatics analysis and preliminary screening. Real time PCR, ROC curve and Logistic regression analysis showed that human papillomavirus infection, TCT severity, ABCG2, TDG, PCNA were independent risk factors for cervical intraepithelial neoplasia. We used these indicators to establish a random forest model. Seven models were built through different combinations. The model 4 (ABCG2 + PCNA + TDG) was the best early warning model for the occurrence and progression of CIN. CONCLUSIONS A total of 5 differential pathways and 10 candidate genes related to occurrence and progression of cervical intraepithelial neoplasia were found in cervical microbial community. This study firstly identified the genes from cervical microbial community that play an important role in the occurrence and progression of cervical intraepithelial neoplasia. At the same time, the early warning model including ABCG2 + PCNA+TDG genes provided a new idea and target for clinical prediction and blocking the evolution of cervical intraepithelial neoplasia malignant transformation from the aspect of cervical microbiological related genes.
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Affiliation(s)
- He Wang
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China
| | - Yanming Jiang
- Department of Obstetrics and Gynecology, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yuejuan Liang
- Department of Obstetrics and Gynecology, Liuzhou People's Hospital, Liuzhou, China
| | - Lingjia Wei
- Department of Obstetrics and Gynecology, Guangxi Medical University, Nanning, China
| | - Wei Zhang
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China
| | - Li Li
- Department of gynecologic oncology, Guangxi Medical University Cancer Hospital, 71 He Di Road, Nanning, 530021, Guangxi, China.
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16
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The Anti-Proliferative and Apoptotic Effects of Rutaecarpine on Human Esophageal Squamous Cell Carcinoma Cell Line CE81T/VGH In Vitro and In Vivo. Int J Mol Sci 2022; 23:ijms23052843. [PMID: 35269987 PMCID: PMC8911365 DOI: 10.3390/ijms23052843] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023] Open
Abstract
The overall five-year survival rate for patients with esophageal cancer is low (15 to 25%) because of the poor prognosis at earlier stages. Rutaecarpine (RTP) is a bioalkaloid found in the traditional Chinese herb Evodia rutaecarpa and has been shown to exhibit anti-proliferative effect on tumor cells. However, the mechanisms by which RTP confer these effects and its importance in esophageal squamous cell carcinoma treatment remain unclear. Thus, in the present study, we first incubated human esophageal squamous cell carcinoma cell line, CE81T/VGH, with RTP to evaluate RTP’s effects on tumor cell growth and apoptosis. We also performed a xenograft study to confirm the in vitro findings. Furthermore, we determined the expression of p53, Bax, bcl-2, caspase-3, caspase-9, and PCNA in CE81T/VGH cells or the tumor tissues to investigate the possible mechanisms. All the effects of TRP were compared with that of cisplatin. The results showed that RTP significantly inhibits CE81T/VGH cell growth, promotes arrest of cells in the G2/M phase, and induces apoptosis. Consistently, the in vivo study showed that tumor size, tumor weight, and proliferating cell nuclear antigen protein expression in tumor tissue are significantly reduced in the high-dose RTP treatment group. Furthermore, the in vitro and in vivo studies showed that RTP increases the expression of p53 and Bax proteins, while inhibiting the expression of Bcl-2 in cancer cells. In addition, RTP significantly increases the expression of cleaved caspase-9 and cleaved caspase-3 proteins in tumor tissues in mice. These results suggest that RTP may trigger the apoptosis and inhibit growth in CE81T/VGH cells by the mechanisms associated with the regulation of the expression of p53, Bax, Bcl-2, as well as caspase-9 and caspase-3.
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Qufeng Xuanbi Formula Ameliorates Airway Remodeling in Asthmatic Mice by Suppressing Airway Smooth Muscle Cell Proliferation through MEK/ERK Signaling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:1525110. [PMID: 35186095 PMCID: PMC8849894 DOI: 10.1155/2022/1525110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/19/2021] [Accepted: 01/12/2022] [Indexed: 11/20/2022]
Abstract
Asthma is a common chronic respiratory disease. The Qufeng Xuanbi formula (QFXBF), a Chinese herbal decoction, has shown efficacy in the management of asthma. The purpose of this study was to investigate the potential therapeutic effects of QFXBF in the treatment of asthma both in vitro and in vivo. Platelet-derived growth factor (PDGF)-induced airway smooth muscle cell (ASMC) proliferation and MTT assays were used to explore the effects of QFXBF on the proliferation of ASMCs. Moreover, 40 female BALB/c mice were randomly divided into five groups: control group, ovalbumin (OVA) group, high QFXBF group, low QFXBF group, and dexamethasone (DEX) group (n = 8 per group). A mouse allergic asthma model was established using the intranasally administered OVA sensitization method. Morphological changes in the lung tissue were examined by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Finally, the protein expression of alpha-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), phospho-mitogen-activated protein kinase (p-MEK1/2), mitogen-activated protein kinase (MEK1/2), phospho-extracellular signal-regulated kinases (p-ERK1/2), and extracellular signal-regulated kinases (ERK1/2) in ASMCs and lung tissue were determined by western blotting and immunofluorescent staining assays. PDGF significantly increased the viability of ASMCs. Compared with mice in the control group, the airway walls and airway smooth muscle of mice in the OVA group were thickened, and the number of inflammatory cells around the bronchus significantly increased. Moreover, the administration of QFXBF markedly inhibited the proliferation of ASMCs and alleviated the pathological changes induced by OVA. Furthermore, the protein expressions of p-ERK1/2, p-MEK1/2, PCNA, and α-SMA were significantly increased in OVA-treated mice and PDGF-treated ASMCs. Finally, treatment with QFXBF also significantly decreased the protein expression of p-ERK1/2, p-MEK1/2, α-SMA, and PCNA. QFXBF inhibited the proliferation of ASMCs by suppressing MEK/ERK signaling in PDGF-induced ASMCs and OVA-induced mice.
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Hou W, Xue Y, Qian Y, Pan H, Xu M, Shen Y, Li X, Yu Y. Application of Intravoxel Incoherent Motion Diffusion-Weighted Imaging in Predicting and Monitoring Early Efficacy of Anti-Angiogenic Therapy in the C6 Glioma Rat Model. Front Oncol 2022; 11:842169. [PMID: 35155219 PMCID: PMC8831888 DOI: 10.3389/fonc.2021.842169] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 12/31/2021] [Indexed: 12/30/2022] Open
Abstract
Objective To investigate the feasibility of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) in evaluating early effects of anti-angiogenic therapy in the C6 glioma rat model. Methods Twenty-six rats of the C6 glioma model were randomly divided into a treatment group (received bevacizumab) and a control group (physiological saline). IVIM-DWI was performed on days 0, 1, 3, 5, and 7 after anti-angiogenic therapy and tumor growth and IVIM-DWI parameters were dynamically observed. Hematoxylin and eosin, CD34 microvessel density (MVD), proliferation of cell nuclear antigen (PCNA), and Hif-α staining were performed on day 7. One-way ANOVA was used to compare intra-group differences and an independent-samples t-test was used to compare inter-group differences of MRI parameters. Correlations between IVIM-DWI parameters, tumor size, and pathological results were analyzed. Results The relative change in tumor volume (ΔVolume) in the two groups differed significantly on days 5 and 7 (p = 0.038 and p < 0.001). The perfusion-related parameters D*- and f-values decreased in the treatment group and demonstrated significant differences compared with the control group on days 3, 5, and 7 (p = 0.033, p < 0.001, and p < 0.001, respectively). The diffusion-related parameters ADC and D-values increased in the treatment group and were found to be significantly differently different from the control group on days 5 and 7 (both p < 0.001). The initial D-value showed a negative correlation with ΔVolume (γ = −0.744, p < 0.001), whereas the initial D*-value and relative change of D-value had a positive correlation with ΔVolume (γ = 0.718, p < 0.001 and γ = 0.800, p < 0.001, respectively). MVD was strongly positively correlated with D*-value (r = 0.886, p = 0.019), PCNA was negatively correlated with ADC- and D-values (r = −0.848, p = 0.033; and r = −0.928 p = 0.008, respectively), and Hif-1α was strongly negatively correlated with D*-value (r = −0.879, p = 0.010). Conclusion IVIM-DWI was sensitive and accurate in predicting and monitoring the effects of early anti-angiogenesis therapy in a C6 glioma rat model.
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Affiliation(s)
- Weishu Hou
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yangyang Xue
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Nuclear Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yinfeng Qian
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hongli Pan
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Man Xu
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yujun Shen
- Department of Basic Medical Sciences, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Xiaohu Li
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Xiaohu Li, ; Yongqiang Yu,
| | - Yongqiang Yu
- Department of Radiology, First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Xiaohu Li, ; Yongqiang Yu,
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Balaraman G, Sundaram J, Mari A, Krishnan P, Salam S, Subramaniam N, Sirajduddin I, Thiruvengadam D. Farnesol alleviates diethyl nitrosamine induced inflammation and protects experimental rat hepatocellular carcinoma. ENVIRONMENTAL TOXICOLOGY 2021; 36:2467-2474. [PMID: 34473392 DOI: 10.1002/tox.23359] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/16/2021] [Accepted: 08/22/2021] [Indexed: 06/13/2023]
Abstract
Hepatocellular carcinoma is a well-known internal malignancy with increased worldwide mortality. The increased progression rate is closely associated with chronic liver diseases such as cirrhosis. Chemical carcinogens cause tumor advocacy over free radical metabolites to causes numerous biochemical and molecular changes that bring oxidative stress. In addition, inflammatory cells and its growth factor promotes the progression of liver cancer through deregulates the numerous cellular signaling pathways involved in normal cellular proliferation. Plant derived phytochemicals have a better complimentary potency to defend against a wide array of free radical mediated diseases such as cancer. More recently, we have evaluated the anticancer effect of Farnesol against DEN induced hepatocellular carcinoma in male wistar albino rats. However, the possible mechanism in which Farnesol attributes its anticancer effect against DEN induced liver cancer remains unknown. Hence in the present study, an attempt has been made to reduce the oxidative stress by appraise the antioxidant effect by Farnesol in DEN induced hepatocellular carcinoma. Elevated oxidative stress markers with concomitant decreased cellular antioxidants levels were observed in DEN induced hepatic tissues. Further, proliferating nuclei with increased proliferating cell nucleolar antigen (PCNA) and inflammatory mediator expression were observed in DEN induced rats. Oral supplementation of Farnesol to DEN induced rats significantly decrease the oxidative stress markers and increase the cellular antioxidant status. Moreover, Farnesol treatment decreases the argyrophilic nuclear organizer region and PCNA along with decreased expression of inflammatory mediators suggest that Farnesol treatment restores DEN induced hepatic abnormalities and protects liver from cancer progression.
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Affiliation(s)
| | - Jagan Sundaram
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
| | - Ashok Mari
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
| | - Palanisamy Krishnan
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
| | - Sharmila Salam
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
| | - Nirmala Subramaniam
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India
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Sherif DA, Makled MN, Suddek GM. The HIV reverse transcriptase Inhibitor Tenofovir suppressed DMH/HFD-induced colorectal cancer in Wistar rats. Fundam Clin Pharmacol 2021; 35:940-954. [PMID: 33829539 DOI: 10.1111/fcp.12679] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/29/2021] [Accepted: 04/06/2021] [Indexed: 12/30/2022]
Abstract
Colon rectal cancer (CRC) is the second commonest malignancy in developed countries and a significant cause of mortality. Tenofovir reportedly reduces the risk of hepatocellular carcinoma and interferes with cell cycle and cell proliferation. The current study investigated the potential antitumor effect of tenofovir against experimentally induced CRC. CRC was induced by 1,2-dimethylhydrazine (DMH, 20 mg/kg, once a week) and high-fat diet (HFD) in Wistar rats. Rats received tenofovir at a dose of 25 or 50 mg/kg (i.p.) for 24 weeks. Tenofovir-25 failed to significantly decrease the total number of dysplasia, adenoma and adenocarcinoma and to improve histopathological changes; however, tenofovir-50 resulted in no tumors seen in the colon lumen and a significant decrease in the total number of dysplasia and no adenoma or adenocarcinoma observed compared to DMH/HFD group. Tenofovir-25 failed to attenuate DMH/HFD-induced cell proliferation, whereas tenofovir-50 significantly decreased cell proliferation revealed by the decreased PCNA expression. Tenofovir-25 also failed to attenuate DMH/HFD-induced oxidative stress, whereas tenofovir-50 significantly attenuated oxidative stress as indicated by the decreased MDA concentration and SOD activity along with the increased GSH concentrations. Moreover, tenofovir-50 decreased Bcl-2 and cyclin D1 expressions in colon tissues compared with DMH/HFD group. Tenofovir-50 also significantly decreased INF-ɤ concentration in colon tissues. These findings suggest that the high dose of tenofovir (50 mg/kg) has antitumor potential against DMH/HFD-induced CRC, which might be mediated through the inhibition of cell proliferation, oxidative stress, and inflammation.
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Affiliation(s)
- Dana A Sherif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.,Clinical Pharmacy Department, Gastrointestinal Surgery Center (GISC), Mansoura University, Mansoura, Egypt
| | - Mirhan N Makled
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Lin T, Zhang Y, Lin Z, Peng L. ZWINT is a Promising Therapeutic Biomarker Associated with the Immune Microenvironment of Hepatocellular Carcinoma. Int J Gen Med 2021; 14:7487-7501. [PMID: 34744456 PMCID: PMC8566006 DOI: 10.2147/ijgm.s340057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/20/2021] [Indexed: 12/15/2022] Open
Abstract
Background The prognosis of patients with advanced hepatocellular carcinoma (HCC) is still poor, effective therapeutic targets are needed. ZW10 interacting kinetochore protein (Zwint) is an essential component of the mitotic spindle checkpoint and is upregulated in cancers. Disappointing, the role of ZWINT in HCC has not been fully illuminated. Methods Multiple tools, including TIMER2.0, Oncomine, GEPIA2, UALCAN, LinkedOmics, Kaplan-Meier Plotter, cBioPortal, and MethSurv, etc. were applied to comprehensively analyze the expression, genetic alternations, clinicopathological relevance, prognostic value, and DNA methylation of ZWINT, along with its correlations with immune infiltration in HCC. Besides, gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) analysis were performed for the correlated genes of ZWINT, closely interconnected clusters and hub proteins in the PPI network were discovered to learn the underlying biological mechanisms. Results We found ZWINT was significantly upregulated in diverse cancers including HCC, compared with the corresponding normal controls. ZWINT upregulation was significantly associated with unfavorable clinicopathological features and survivals of HCC patients. Genetic alternations of ZWINT frequently occurred, which were linked to worse outcomes of HCC patients. The results of GSEA displayed ZWINT and its correlated genes might be components of condensed chromosomes and spindles, which participated in biological processes and signaling pathways involving DNA replication, cytokinesis, and cell cycle checkpoint, etc. Three highly interconnected clusters and 10 hub proteins were identified from the PPI network constructed with the correlated genes of ZWINT. Moreover, ZWINT expression was found positively correlated with infiltration levels of various immune cells, especially myeloid-derived suppressor cells. Conclusion This study demonstrated ZWINT might be a promising unfavorable prognostic biomarker and a therapeutic target of HCC, which could regulate HCC progression through cell division and immunosuppression.
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Affiliation(s)
- Tong Lin
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, People's Republic of China
| | - Yingzhao Zhang
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, People's Republic of China
| | - Zhimei Lin
- The Fourth Clinical Medical School, Guangzhou University of Chinese Medicine, Shenzhen, People's Republic of China
| | - Lisheng Peng
- Department of Science and Education, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People's Republic of China
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Research Progress of PCNA in Reproductive System Diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:2391917. [PMID: 34721621 PMCID: PMC8553460 DOI: 10.1155/2021/2391917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/11/2021] [Accepted: 09/24/2021] [Indexed: 11/26/2022]
Abstract
Reproductive system diseases have become a public health problem that endangers human physical and mental health. The causes of reproductive diseases are complex and diverse. From a biological point of view, abnormal cell proliferation may affect important physiological functions of reproductive organs and cause various gynecological or andrological diseases. Proliferating cell nuclear antigen (PCNA) is the most commonly used indicator for detecting cell proliferation activity. The up- or downregulation of its expression is of great significance in reproductive system diseases. This review summarizes the significance of the latest research on PCNA expression in reproductive system diseases.
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Susini T, Saccardin G, Renda I, Giani M, Tartarotti E, Nori J, Vanzi E, Pasqualini E, Bianchi S. Immunohistochemical Evaluation of FGD3 Expression: A New Strong Prognostic Factor in Invasive Breast Cancer. Cancers (Basel) 2021; 13:cancers13153824. [PMID: 34359725 PMCID: PMC8345064 DOI: 10.3390/cancers13153824] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/17/2021] [Accepted: 07/25/2021] [Indexed: 12/14/2022] Open
Abstract
Among new prognostic factors for breast cancer, the most promising one seems to be FGD3 (Facio-Genital Dysplasia 3) gene, whose expression improves outcome by inhibiting cell migration. The aim of the study was to evaluate the prognostic role of FGD3 in invasive breast cancer in a series of 401 women, treated at our unit, by evaluating the expression of this gene by immunohistochemistry. Patients with high FGD3 expression showed a significantly better disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). The prognostic value of FGD3 expression was stronger than that of classical pathologic parameters such as histological grade of differentiation, Ki-67 index and molecular subtype. By multivariate Cox analysis, FGD3 expression was confirmed as significant and independent prognostic factor, ranking second after age at diagnosis (≤40 years) for DFS (p = 0.003) and the second strongest predictor of OS, after AJCC Stage (p < 0.001). Our data suggest that inclusion of FGD3 evaluation in the routine workup of breast cancer patients may result in a more accurate stratification of the individual risk. The possibility to assess FGD3 expression by a simple and cheap technique such as immunohistochemistry may enhance the spread of its use in the clinical practice.
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Affiliation(s)
- Tommaso Susini
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (G.S.); (I.R.); (M.G.); (E.T.)
- Correspondence: ; Tel.: +39-055-275-1752
| | - Giulia Saccardin
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (G.S.); (I.R.); (M.G.); (E.T.)
| | - Irene Renda
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (G.S.); (I.R.); (M.G.); (E.T.)
| | - Milo Giani
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (G.S.); (I.R.); (M.G.); (E.T.)
| | - Enrico Tartarotti
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (G.S.); (I.R.); (M.G.); (E.T.)
| | - Jacopo Nori
- Diagnostic Senology Unit, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy; (J.N.); (E.V.)
| | - Ermanno Vanzi
- Diagnostic Senology Unit, Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy; (J.N.); (E.V.)
| | - Elisa Pasqualini
- Pathology Unit, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (E.P.); (S.B.)
| | - Simonetta Bianchi
- Pathology Unit, Department of Health Sciences, University of Florence, 50134 Florence, Italy; (E.P.); (S.B.)
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The γ-tubulin meshwork assists in the recruitment of PCNA to chromatin in mammalian cells. Commun Biol 2021; 4:767. [PMID: 34158617 PMCID: PMC8219688 DOI: 10.1038/s42003-021-02280-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 05/28/2021] [Indexed: 12/27/2022] Open
Abstract
Changes in the location of γ-tubulin ensure cell survival and preserve genome integrity. We investigated whether the nuclear accumulation of γ-tubulin facilitates the transport of proliferating cell nuclear antigen (PCNA) between the cytosolic and the nuclear compartment in mammalian cells. We found that the γ-tubulin meshwork assists in the recruitment of PCNA to chromatin. Also, decreased levels of γ-tubulin reduce the nuclear pool of PCNA. In addition, the γ-tubulin C terminus encodes a PCNA-interacting peptide (PIP) motif, and a γ-tubulin–PIP-mutant affects the nuclear accumulation of PCNA. In a cell-free system, PCNA and γ-tubulin formed a complex. In tumors, there is a significant positive correlation between TUBG1 and PCNA expression. Thus, we report a novel mechanism that constitutes the basis for tumor growth by which the γ-tubulin meshwork maintains indefinite proliferation by acting as an opportune scaffold for the transport of PCNA from the cytosol to the chromatin. Corvaisier et al discover that γ-tubulin and replication protein PCNA forms a complex and that this facilitates recruitment of PCNA to chromatin both during cell division and during the DSB repair response. They identify a PCNA binding motif in γ-tubulin, which when mutated affects replication fork progression, providing insights into the role of the nuclear γ-tubulin meshwork.
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Pan B, Liu C, Zhan X, Li J. Protegrin-1 Regulates Porcine Granulosa Cell Proliferation via the EGFR-ERK1/2/p38 Signaling Pathway in vitro. Front Physiol 2021; 12:673777. [PMID: 34093234 PMCID: PMC8176212 DOI: 10.3389/fphys.2021.673777] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/28/2021] [Indexed: 11/13/2022] Open
Abstract
Antimicrobial peptides (AMPs) are traditionally known to be essential components in host defense via their broad activities against bacteria, fungi, viruses, and protozoa. Their immunomodulatory properties have also recently received considerable attention in mammalian somatic tissues of various species. However, little is known regarding the role of AMPs in the development and maturation of ovarian follicles. Protegrin-1 (PG-1) is an antimicrobial peptide which is known to have potent antimicrobial activity against both gram positive and negative bacteria. Here we report that the PG-1 is present in the porcine ovarian follicular fluid. Treatment of granulosa cell with PG-1 enhanced granulosa cell proliferation in a dose-dependent manner. This is accompanied by increased expression of cell-cycle progression-related genes such as cyclin D1(CCND1), cyclin D2 (CCND2), and cyclin B1(CCNB1). Additionally, Western blot analysis showed that PG-1 increased phosphorylated epidermal growth factor receptor (EGFR), and the phosphorylated-/total extracellular signal-regulated kinase (ERK)1/2 ratio. Pretreatment with either U0126, a specific ERK1/2 phosphorylation inhibitor, or EGFR kinase inhibitor, AG1478, blocked the PG-1 induced proliferation. Moreover, luciferase reporter assay revealed that ETS domain-containing protein-1 (Elk1) C/EBP homologous protein (CHOP), and the transcription activators downstream of the MAPK pathway, were activated by PG-1. These data collectively suggest that PG-1 may regulate pig granulosa cell proliferation via EGFR-MAPK pathway., Hence, our finding offers insights into the role of antimicrobial peptides on follicular development regulation.
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Affiliation(s)
- Bo Pan
- Department of Animal BioSciences, University of Guelph, Guelph, ON, Canada
| | - Canying Liu
- Department of Animal BioSciences, University of Guelph, Guelph, ON, Canada.,Department of Life Science and Engineering, Foshan University, Foshan, China
| | - Xiaoshu Zhan
- Department of Animal BioSciences, University of Guelph, Guelph, ON, Canada.,Department of Life Science and Engineering, Foshan University, Foshan, China
| | - Julang Li
- Department of Animal BioSciences, University of Guelph, Guelph, ON, Canada
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Stakišaitis D, Damanskienė E, Curkūnavičiūtė R, Juknevičienė M, Alonso MM, Valančiūtė A, Ročka S, Balnytė I. The Effectiveness of Dichloroacetate on Human Glioblastoma Xenograft Growth Depends on Na+ and Mg2+ Cations. Dose Response 2021; 19:1559325821990166. [PMID: 33716589 PMCID: PMC7923996 DOI: 10.1177/1559325821990166] [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: 12/03/2020] [Revised: 01/02/2021] [Accepted: 01/05/2021] [Indexed: 01/03/2023] Open
Abstract
The study's aim was to investigate the effectiveness of sodium dichloroacetate (NaDCA) or magnesium dichloroacetate (MgDCA) on adult U87 MG and pediatric PBT24 cell lines glioblastoma (GB) xenografts in a chicken chorioallantoic membrane (CAM) model. The study groups were: treated with 10 mM, 5 mM of NaDCA, and 5 mM, 2.5 mM of MgDCA, and controls. The U87 MG and PBT24 xenografts growth, frequency of tumor invasion into CAM, CAM thickening, and the number of blood vessels in CAM differed depending on the dichloroacetate salt treatment. NaDCA impact on U87 MG and PBT24 tumor on proliferating cell nunclear antigen (PCNA) and enhancer of zeste homolog 2 (EZH2) expression in the tumor was different, depending on the NaDCA dose. The 5 mM MgDCA impact was more potent and had similar effects on U87 MG and PBT24 tumors, and its impact was also reflected in changes in PCNA and EZH2 expression in tumor cells. The U87 MG and PBT24 tumor response variations to treatment with different NaDCA concentration on tumor growth or a contrast between NaDCA and MgDCA effectiveness may reflect some differences in U87 MG and PBT24 cell biology.
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Affiliation(s)
- Donatas Stakišaitis
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.,Laboratory of Molecular Oncology, National Cancer Institute, Vilnius, Lithuania
| | - Eligija Damanskienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rūta Curkūnavičiūtė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Milda Juknevičienė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Marta Maria Alonso
- Department of Pediatrics, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain
| | - Angelija Valančiūtė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Saulius Ročka
- Centre of Neurosurgery, Clinic of Neurology and Neurosurgery, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ingrida Balnytė
- Department of Histology and Embryology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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Ge S, Shi Y, Zhu G, Li S, Cai Y, Ji P, Liu J, Guo W, Gong L, Lou M, Feng F, Wang Y, Zhai Y, Qu Y, Wang L. Molecular Pathological Markers Correlated With the Recurrence Patterns of Glioma. Front Oncol 2021; 10:565045. [PMID: 33585189 PMCID: PMC7873968 DOI: 10.3389/fonc.2020.565045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 11/24/2020] [Indexed: 01/03/2023] Open
Abstract
Purpose Glioma is one of the most common tumors of the central nervous system, and many patients suffer from recurrence even after standard comprehensive treatment. However, little is known about the molecular markers that predict the recurrence patterns of glioma. This study aimed to demonstrate the correlations between molecular markers and glioma recurrence patterns, which included local/nonlocal recurrence and paraventricular/nonparaventricular recurrence. Methods Immunohistochemical techniques were used to assess the molecular markers of 88 glioma tissues following surgical resection. The recurrence patterns were divided into local recurrence, marginal recurrence, distant recurrence, multirecurrence, and subarachniod recurrence, with the last four recurrence patterns being collectively called nonlocal recurrence. According to whether the recurrence invaded ventricles, the nonlocal recurrence patterns were divided into paraventricular and nonparaventricular recurrence. Then, we compared the different recurrence patterns and their clinical characteristics, focusing on the expression of molecular markers. Results More patients in the nonlocal recurrence group received combined radiotherapy and chemotherapy than patients in the local recurrence group (p=0.019). Sex, age, extent of surgery, time to recurrence, tumor location, size, and WHO grade were not different in the defined groups (P>0.05). Recurrent tumor volume and WHO grade were significantly different between the paraventricular and nonparaventricular recurrence groups (p=0.046 and 0.033). The expression of Ki-67, P53, and PCNA in the nonlocal recurrence group was significantly higher than that in the local recurrence group (p=0.015, 0.009, and 0.037), while the expression of S-100 in the nonlocal recurrence group was significantly lower than that in the local recurrence group (p=0.015). Cox regression indicated hazard ratio (HR) for high expression level of PCNA associated with non-local recurrence was 3.43 (95% CI, 1.15, 10.24), and HR for high expression level of MGMT associated with paraventricular recurrence was 2.64 (95% CI, 1.15,6.08). Conclusions Ki-67, P53, PCNA, and MGMT might be important clinical markers for nonlocal recurrence and paraventricular recurrence.
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Affiliation(s)
- Shunnan Ge
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yingwu Shi
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Gang Zhu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Songlun Li
- Medical Department of Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yaning Cai
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Peigang Ji
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinghui Liu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Wei Guo
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Li Gong
- Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Miao Lou
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Fuqiang Feng
- Department of Neurosurgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yuan Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yulong Zhai
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yan Qu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Liang Wang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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TOP2A/MCM2, p16 INK4a, and cyclin E1 expression in liquid-based cytology: a biomarkers panel for progression risk of cervical premalignant lesions. BMC Cancer 2021; 21:39. [PMID: 33413211 PMCID: PMC7792307 DOI: 10.1186/s12885-020-07740-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/15/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND To improve the efficiency of early diagnosis systems for cervical cancer, the use of cellular and viral markers for identifying precancerous lesions with a greater probability to progress to cancer has been proposed. Several cellular proteins and markers of oxidative DNA damage have been suggested as possible biomarkers of cervical carcinogenesis; however, they have not been evaluated together. In this study, we analyzed the expression of the cellular markers p16INK4a, Ki-67, CyclinE1, TOP2A/MCM2, and telomerase, as well as the DNA oxidative damage markers ROS and 8-OHdG. The analyses were performed in liquid-based cervical cytology samples or biopsies with premalignant lesions or cervical cancer diagnosis, with the purpose of selecting a panel of biomarkers that allow the identification of precursor lesions with greater risk of progression to cervical cancer. METHODS We analyzed 1485 liquid-based cytology samples, including 239 non-squamous intraepithelial lesions (NSIL), 901 low-grade squamous intraepithelial lesions (LSIL), 54 high-grade squamous intraepithelial lesions (HSIL), and 291 cervical cancers (CC). The biomarkers were analyzed by immunocytochemistry and Human Papilloma Virus (HPV) genotyping with the INNO-LiPA genotyping Extra kit. RESULTS We found that all tested cellular biomarkers were overexpressed in samples with high risk-HPV infection, and the expression levels increased with the severity of the lesion. TOP2A/MCM2 was the best biomarker for discriminating between LSIL and HSIL, followed by p16INK4a and cyclinE1. Statistical analysis showed that TOP2A/MCM2 provided the largest explanation of HSIL and CC cases (93.8%), followed by p16INK4a (91%), cyclin E1 (91%), Ki-67 (89.3%), and telomerase (88.9%). CONCLUSIONS We propose that the detection of TOP2A/MCM2, p16INK4a and cyclin E1 expression levels is useful as a panel of biomarkers that allow identification of cervical lesions with a higher risk for progression to CC with high sensitivity and precision; this can be done inexpensively, in a single and non-invasive liquid-based cytology sample.
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Shi H, Wang Y, Yao M, Zhang D, Fang W, Zhou T, Gan D, Yue S, Qian H, Chen T. Honokiol inhibits the growth of SKBR3 cells. Transl Cancer Res 2020; 9:7596-7604. [PMID: 35117359 PMCID: PMC8797426 DOI: 10.21037/tcr-20-3110] [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: 09/18/2020] [Accepted: 11/24/2020] [Indexed: 12/04/2022]
Abstract
BACKGROUND Breast cancer is one of the most malignant tumors in the reproductive system and has a poor prognosis. Finding drugs with high efficiency, low side-effects, and low cost has become a research hotspot. METHODS In the present study, we treated SK-BR-3 cells with different doses of honokiol. Crystal violet staining method was used to detect changes in the total number of living cells; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to detect the effect of honokiol on SK-BR-3 cell proliferation. Cell migration ability change was determined by wound healing assay. Cell invasion ability change was determined by Transwell migration assay. Flow cytometry was used to detect the apoptotic rate of SK-BR-3 cells, and Western blot was used to detect the expression levels of proliferation-associated protein (PCNA); migration- and invasion-related protein matrix metalloproteinase-2 (MMP-2); vimentin; apoptosis-related proteins Bcl-xl, caspase 3, and cleaved caspase 3 (CC3); and β-catenin and its downstream target molecule c-Myc. RESULTS Compared with the control group, different doses of honokiol have different degrees of inhibitory effects on cells, including proliferation and invasion and migration (P<0.01). After treatment with 50 or 60 µmol·L-1 honokiol, the apoptotic rate of SK-BR-3 cells increased (both P<0.01); PCNA expression was significantly downregulated (P<0.01). Intracellular accumulation of apoptosis-related proteins Bcl-xl and caspase-3 decreased but C-C3 increased. We also found downregulation of MMP-2 expression, a protein related to invasion and migration (P<0.01), and a decrease in the expression levels of the Wnt/β-catenin signaling pathway-related proteins β-catenin and c-Myc (P<0.01). CONCLUSIONS Honokiol can promote the apoptosis of SK-BR-3 cells and can inhibit the proliferation, migration, and invasion of human breast cancer SK-BR-3 cells. The underlying mechanism may be through inhibiting the activation of the Wnt signaling pathway.
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Affiliation(s)
- He Shi
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Yange Wang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Mengli Yao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Dian Zhang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Wenli Fang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Ting Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Delu Gan
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Shujun Yue
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Husun Qian
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
| | - Tingmei Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, China
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Xiong Y, Lei J, Zhao J, Lu Q, Feng Y, Qiao T, Xin S, Han Y, Jiang T. A gene-based survival score for lung adenocarcinoma by multiple transcriptional datasets analysis. BMC Cancer 2020; 20:1046. [PMID: 33129284 PMCID: PMC7603718 DOI: 10.1186/s12885-020-07473-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 09/29/2020] [Indexed: 02/06/2023] Open
Abstract
Background Lung adenocarcinoma (LUAD) remains a crucial factor endangering human health. Gene-based clinical predictions could be of great help for cancer intervention strategies. Here, we tried to build a gene-based survival score (SS) for LUAD via analyzing multiple transcriptional datasets. Methods We first acquired differentially expressed genes between tumors and normal tissues from intersections of four LUAD datasets. Next, survival-related genes were preliminarily unscrambled by univariate Cox regression and further filtrated by LASSO regression. Then, we applied PCA to establish a comprehensive SS based on survival-related genes. Subsequently, we applied four independent LUAD datasets to evaluate prognostic prediction of SS. Moreover, we explored associations between SS and clinicopathological features. Furthermore, we assessed independent predictive value of SS by multivariate Cox analysis and then built prognostic models based on clinical stage and SS. Finally, we performed pathway enrichments analysis and investigated immune checkpoints expression underlying SS in four datasets. Results We established a 13 gene-based SS, which could precisely predict OS and PFS of LUAD. Close relations were elicited between SS and canonical malignant indictors. Furthermore, SS could serve as an independent risk factor for OS and PFS. Besides, the predictive efficacies of prognostic models were also reasonable (C-indexes: OS, 0.7; PFS, 0.7). Finally, we demonstrated enhanced cell proliferation and immune escape might account for high clinical risk of SS. Conclusions We built a 13 gene-based SS for prognostic prediction of LUAD, which exhibited wide applicability and could contribute to LUAD management.
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Affiliation(s)
- Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Jie Lei
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Qiang Lu
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Yangbo Feng
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Tianyun Qiao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Shaowei Xin
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China
| | - Yong Han
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China. .,Department of Thoracic Surgery, Air Force Medical Center, PLA, 30 Fucheng Road, Haidian District, Beijing, 100142, China.
| | - Tao Jiang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Baqiao District, Xi'an City, 710038, Shaanxi Province, China.
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Galvão MLTDC, Coimbra EC. Long noncoding RNAs (lncRNAs) in cervical carcinogenesis: New molecular targets, current prospects. Crit Rev Oncol Hematol 2020; 156:103111. [PMID: 33080526 DOI: 10.1016/j.critrevonc.2020.103111] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/15/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
Aberrant expression of lncRNAs has been seen as a key factor in a wide range of diseases including cancer. The role of lncRNAs in cervical cancer has not been clearly explained, and has been the subject of recent studies. In this review, we have compiled an updated list of previously reported lncRNAs and established a general profile of these transcripts in accordance with the role they play in cervical carcinogenesis. Thus, information here includes the influence of lncRNAs on cervical tumorigenic process through a disturbance of cellular activities. Additionally, we described recent discoveries about how HPV contributes to lncRNAs expression in cervical cancer and we summarized exploratory studies of strategies adopted to modulate the expression levels of lncRNAs to treat cervical neoplasia, by drawing attention to radio and chemo-resistance. Finally, this paper provides a broad overview that sets out new research directions about the role of lncRNAs in cervical cancer.
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Affiliation(s)
- Maria Luiza Tabosa de Carvalho Galvão
- Faculty of Medical Sciences, University of Pernambuco, Brazil; Laboratory of Molecular Biology of Viruses, Biological Sciences Institute, University of Pernambuco, Brazil
| | - Eliane Campos Coimbra
- Laboratory of Molecular Biology of Viruses, Biological Sciences Institute, University of Pernambuco, Brazil.
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Liu C, Pan B, Yang L, Wang B, Li J. Beta defensin 3 enhances ovarian granulosa cell proliferation and migration via ERK1/2 pathway in vitro†. Biol Reprod 2020; 100:1057-1065. [PMID: 30445521 DOI: 10.1093/biolre/ioy246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/26/2018] [Accepted: 11/15/2018] [Indexed: 12/14/2022] Open
Abstract
Antimicrobial peptides (AMPs) are regarded as host defense peptides that possess bactericidal activity as well as immunomodulatory function. However, the role of AMP in the mammalian ovary is unknown. In the present study, porcine granulosa cells were utilized in a cell model to study the role of porcine beta defensin 2 (pBD2; pDEFB4B) and 3 (pBD3; pDEFB103A) during ovarian follicular development. Granulosa cells were cultured in the absence and presence of 1, 10, and 50 μg/ml of pDEFB4B or pDEFB103A. After 24 h of treatment, pDEFB103A but not pDEFB4B stimulated granulosa cell proliferation in a concentration-dependent manner (P < 0.05). This effect was dependent on the stage of follicular development. In addition, transwell cell migration assay showed that in the presence of pDEFB103A (10 μg/ml), a 2.5-fold increase in cell migration was achieved. Furthermore, further study revealed that pDEFB103A increased the mRNA levels of cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA), both associated with cell proliferation. To study the potential pathway involved in pDEFB103A-induced cell proliferation and migration, western blots were performed. It was found that pDEFB103A significantly increased the phosphorylated-ERK1/2 to nonphosphorylated ratio. Moreover, pretreatment with the U0126, a specific ERK1/2 phosphorylation inhibitor, suppressed PDEFB103A inducing GCs ERK1/2 phosphorylation, as well as proliferation and migration, suggesting that PDEFB103A may act via activating the ERK1/2 pathway. Furthermore, using a signal transduction pathway Elk-1 trans-reporting system, the activation of ERK1/2 pathway by PDEFB103A was further confirmed. Our data suggest that AMP may play a physiological role in the mammalian ovary.
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Affiliation(s)
- Canying Liu
- Department of Life Science and Engineering, Foshan University, Foshan, China
- Department of Animal and Poultry Science, University of Guelph, Guelph, Canada
| | - Bo Pan
- Department of Animal and Poultry Science, University of Guelph, Guelph, Canada
| | - Lu Yang
- Shanghai Academy of Agriculture Sciences, Shanghai, China
| | - Bingyun Wang
- Department of Life Science and Engineering, Foshan University, Foshan, China
| | - Julang Li
- Department of Animal and Poultry Science, University of Guelph, Guelph, Canada
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Zhou Q, Wu H, Liu Y, Zhang N, Liang H, Gu M, Liu H, Wang H. Effects of different doses of propofol on the growth and expression of PCNA, CD34 and pAKT proteins in xenografted tumor of BALB/C mice with liver cancer. Clin Transl Oncol 2020; 22:1741-1749. [PMID: 32052381 DOI: 10.1007/s12094-020-02311-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 01/27/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To observe the effects of different doses of propofol on the growth of transplanted liver tumor in BALB/C mice and check the expression of PCNA, CD34 and pAKT proteins to clarify the mechanism on molecule level. METHOD Human primary liver cancer cells SMMC-7721 were subcutaneously cultured in BALB/C mice, and the transplanted tumor model of BALB/C mice was constructed. Forty mice successfully modeled were randomly divided into 5 groups (n = 8): the blank control group (group C), low-fat milk group (group I), low-dose (50 mg/kg) propofol group (P1), middle-dose (100 mg/kg) propofol group (P2) and high dose (150 mg/kg) propofol group (P3). Tumor volume changes were observed at 3, 6, 9, 12, 15 and 18 days (T1, T2, T3, T4, T5, T6 and T7) before and after administration of the drug, and tumor growth curves were plotted. After 19 days of administration, all mice were killed for tumor collection, tumor weight was measured, and the tumor inhibition rate of propofol was calculated. The protein expression of cluster of differentiation 34 (CD34) in transplanted tumor was detected by immunohistochemistry, and the protein expression of proliferating cell nuclear antigen (PCNA) and phospho-Akt (pAKT) was detected by immunofluorescence. RESULTS Compared with group C, there was no significant difference in tumor volume in group I. At T2 ~ 7, the tumor volume of group P1, P2 and P3 decreased successively (P < 0.05). There was no significant difference in the inhibitory rate of tumor in group I, and the inhibitory rate of tumor in group P1, P2 and P3 increased successively (P < 0.05). There was no significant difference in PCNA, CD34, and pAKT protein expression in group I, while PCNA, CD34, and pAKT protein content in P1, P2, P3 groups were successively decreased (P < 0.05). CONCLUSION Propofol had a dose-dependent effect on the growth of liver cancer xenografts in mice, inhibiting the expression of PCNA, CD34 and pAKT proteins, and the effect was most obvious in the 150 mg/kg propofol group.
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Affiliation(s)
- Q Zhou
- Department of Anaesthesiology, Affiliated Foshan Hospital of Sun Yat-sen University, 81# North, Linnandadao Road, Chancheng, Foshan City, 528000, Guangdong Province, China.
| | - H Wu
- Department of Anaesthesiology, Affiliated Foshan Hospital of Sun Yat-sen University, 81# North, Linnandadao Road, Chancheng, Foshan City, 528000, Guangdong Province, China
| | - Y Liu
- Department of Anesthesiology, LinZi People's Hospital, Linzi, Shandong, China
| | - N Zhang
- Department of Anesthesiology, LinZi People's Hospital, Linzi, Shandong, China
| | - H Liang
- Department of Anaesthesiology, Affiliated Foshan Hospital of Sun Yat-sen University, 81# North, Linnandadao Road, Chancheng, Foshan City, 528000, Guangdong Province, China
| | - M Gu
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - H Liu
- Department of Anaesthesiology, Affiliated Foshan Hospital of Sun Yat-sen University, 81# North, Linnandadao Road, Chancheng, Foshan City, 528000, Guangdong Province, China
| | - H Wang
- Department of Anaesthesiology, Affiliated Foshan Hospital of Sun Yat-sen University, 81# North, Linnandadao Road, Chancheng, Foshan City, 528000, Guangdong Province, China
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Lu E, Hu X, Pan C, Chen J, Xu Y, Zhu X. Up-regulation of peroxiredoxin-1 promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer. J Cancer 2020; 11:1170-1181. [PMID: 31956363 PMCID: PMC6959069 DOI: 10.7150/jca.37147] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 10/26/2019] [Indexed: 02/07/2023] Open
Abstract
Objective: To investigate the effect of peroxiredoxin 1 (PRDX1) on the biological behavior of cervical cancer cells and the possible mechanism. Materials and methods: The expression of PRDX1 in human cervical cancer tissues and adjacent non-tumor tissues were detected by immunohistochemistry (IHC). Lentivirus containing PRDX1-cDNA or shRNA against PRDX1 was constructed to overexpress or knockdown PRDX1 in SiHa cervical cancer cells. Cell proliferation was tested by CCK-8 and BrdU incorporation assay and cell apoptosis was evaluated by AnnexinV-PE /7AAD assay. Scratch wound and transwell invasion assay were used to test migration and invasion activity after PRDX1 was overexpressed or suppressed. Furthermore, the effect of PRDX1 on cell proliferation and apoptosis was also studied using a xenograft model of nude mice. Results: The expression of PRDX1 protein was significantly up-regulated in the tumor tissues compared with the paired adjacent non-tumor tissues. Meanwhile, PRDX1 overexpression was associated with tumor stage, lymphatic metastasis and differentiation. Overexpression of PRDX1 significantly promoted proliferation and inhibited apoptosis by increasing the expression of Nanog, proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2) and downregulating the expression of Bcl2-associated X protein (BAX) in SiHa cervical cancer cells. Moreover, PRDX1 overexpression increased invasion and migration of SiHa cervical cancer cells via up-regulating the expression of Snail and matrix metalloprotein 9 (MMP-9) and down-regulating the expression of E-cadherin. Knockdown of PRDX1 resulted in the opposite results. The role of PRDX1 in promoting SiHa cervical cancer cell proliferation and inhibiting apoptosis has also been confirmed in vivo in a mouse xenograft model. Conclusions: PRDX1 promoted cell proliferation, migration, and invasion and suppressed apoptosis of cervical cancer possibly via regulating the expression of related protein.
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Affiliation(s)
| | | | | | | | | | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China
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Jin LJ, Chen WB, Zhang XY, Bai J, Zhao HC, Wang ZY. Analysis of factors potentially predicting prognosis of colorectal cancer. World J Gastrointest Oncol 2019; 11:1206-1217. [PMID: 31908725 PMCID: PMC6937433 DOI: 10.4251/wjgo.v11.i12.1206] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 08/05/2019] [Accepted: 08/26/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Accurate assessment of the prognosis after colorectal cancer surgery is of great significance in patients with colorectal cancer. However, there is no systematic analysis of factors affecting the prognosis of colorectal cancer currently.
AIM To systematically analyze the influence of clinical data and serological and histological indicators on the prognosis of patients with colorectal cancer, and to explore the indicators that can accurately assess the prognosis of patients with colorectal cancer.
METHODS A total of 374 patients with colorectal cancer were enrolled. The clinical data, tumor-node-metastasis (TNM) stage, and Dukes stage were recorded. All patients received examinations including carcinoembryonic antigen (CEA), carbohydrate antigen 199, C-reactive protein, albumin, D-dimer, and fibrinogen as well as routine blood tests one week before surgery. The tumor location, size, depth of invasion, lymph node metastasis, and distant metastasis were recorded during surgery. The pathological tissue typing and expression of proliferating cell nuclear antigen (PCNA) and p53 were observed. All patients were followed for 3 years, and patients with endpoint events were defined as a poor prognosis group, and the remaining patients were defined as a good prognosis group. The differences in clinical data, serology, and histology were analyzed between the two groups. Multivariate COX regression was used to analyze the independent influencing factors for the prognosis of colorectal cancer. The receiver operating characteristic curve was used to evaluate the predictive value of each of the independent influencing factors and their combination for the prognosis of colorectal cancer.
RESULTS The follow-up outcomes showed that 81 patients were in the good prognosis group and 274 patients in the poor prognosis group. The TNM stage, PCNA, Glasgow prognostic score (GPS), neutrophil-lymphocyte ratio (NLR), C-reactive protein/albumin ratio (CAR), D-dimer, and CEA were independent influencing factors for the prognosis of colorectal cancer (P = 0.000). NLR had the highest predictive power for colorectal cancer prognosis [area under the receiver operating characteristic curve (AUC) = 0.925], followed by D-dimer (AUC = 0.879) and GPS (AUC = 0.872). The accuracy of the combination of all indicators in predicting the prognosis of colorectal cancer was the highest (AUC = 0.973), which was significantly higher than that of any of the indicators alone (P < 0.05). The sensitivity and specificity of the combination were 92.59% and 90.51%, respectively.
CONCLUSION The independent influence factors for the prognosis of colorectal cancer include TNM stage, PCNA, GPS, NLR, CAR, D-dimer, and CEA. The combined assessment of the independent factors is the most accurate predictor of the prognosis after colorectal cancer surgery.
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Affiliation(s)
- Li-Jun Jin
- Department of Surgical Oncology (Division III), Cangzhou Central Hospital, Cangzhou 061001, Hebei Province, China
| | - Wei-Bin Chen
- Department of Radiology, North China University of Science and Technology Affiliated Hospital, Tangshan 063000, Hebei Province, China
| | - Xiao-Yu Zhang
- Department of Surgical Oncology (Division III), Cangzhou Central Hospital, Cangzhou 061001, Hebei Province, China
| | - Jie Bai
- Department of Surgical Oncology (Division III), Cangzhou Central Hospital, Cangzhou 061001, Hebei Province, China
| | - Hao-Chen Zhao
- Department of Anesthesiology (Division II), Cangzhou Central Hospital, Cangzhou 061001, Hebei Province, China
| | - Zun-Yi Wang
- Department of Surgical Oncology (Division III), Cangzhou Central Hospital, Cangzhou 061001, Hebei Province, China
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Jin LJ, Chen WB, Zhang XY, Bai J, Zhao HC, Wang ZY. Analysis of factors potentially predicting prognosis of colorectal cancer. World J Gastrointest Oncol 2019. [DOI: 10.4251/wjgo.v11.i11.1206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
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Renda I, Bianchi S, Vezzosi V, Nori J, Vanzi E, Tavella K, Susini T. Expression of FGD3 gene as prognostic factor in young breast cancer patients. Sci Rep 2019; 9:15204. [PMID: 31645624 PMCID: PMC6811624 DOI: 10.1038/s41598-019-51766-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 10/08/2019] [Indexed: 01/08/2023] Open
Abstract
The FGD3 gene works as a cell migration inhibitor and seems to be a promising indicator of outcome in some human cancers including breast. In this study, we analysed for the first time the prognostic role of FGD3 in young breast cancer patients. We studied the relationship between traditional prognostic factors, FGD3 expression and outcome in ≤40 years breast cancer patients. We found that lower FGD3 expression decreased the probability of disease-free survival (p = 0.042) and overall survival (p = 0.007). In a multivariate analysis for overall survival AJCC stage (p = 0.005) and FGD3 expression (p = 0.03) resulted independent prognostic factors. Low FGD3 expression increased the risk of death from disease (HR 5.73, p = 0.03). Moreover, low FGD3 expression was associated with more widespread lymph node involvement (p = 0.04) and a lower FGD3 staining intensity was found in positive-lymph-node patients vs negative (p = 0.003) and in patients with ≥10 involved lymph nodes vs <10 (p = 0.05). Our results suggest FGD3 to be a significant independent prognostic factor in young breast cancer patients in terms of disease-free survival and overall survival. A lower expression increased the risk of recurrence and death from disease and was associated with widespread lymph node metastases.
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Affiliation(s)
- Irene Renda
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, Florence, Italy
| | - Simonetta Bianchi
- Pathology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Vania Vezzosi
- Pathology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Jacopo Nori
- Diagnostic Senology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Ermanno Vanzi
- Diagnostic Senology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Ketty Tavella
- Medical Oncology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
| | - Tommaso Susini
- Breast Unit, Gynecology Section, Department of Health Sciences, University of Florence, Florence, Italy.
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Zhou L, Ye M, Xue F, Lu E, Sun LZ, Zhu X. Effects of dynein light chain Tctex-type 3 on the biological behavior of ovarian cancer. Cancer Manag Res 2019; 11:5925-5938. [PMID: 31308737 PMCID: PMC6612992 DOI: 10.2147/cmar.s205158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/27/2019] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE To investigate dynein light chain Tctex-type 3 (DYNLT3) protein expression in ovarian epithelial lesions and explore the effects and related mechanisms of DYNLT3 in terms of the biological behavior of ovarian cancer. MATERIALS AND METHODS Initially, expression of the DYNLT3 protein in ovarian epithelial lesions was detected by immunohistochemical staining, and the prognostic value of DYNLT3 mRNA expression in ovarian cancer patients was assessed using the Kaplan-Meier plotter database. Then, the mRNA and protein expression of DYNLT3 in IOSE80 normal ovarian epithelial cells and SKOV3 ovarian cancer cells was evaluated by quantitative real-time polymerase chain reaction and Western blotting respectively, and the proliferation, apoptosis, migration and invasion of SKOV3 cells after DYNLT3 over-expression and under-expression were investigated by CCK-8 assays and immunofluorescence staining, flow cytometry, wound healing assays and Transwell invasion assays, respectively. Furthermore, the expression of the proliferation-related proteins PCNA and Ki-67 and the invasion- and migration-related proteins Ezrin, Fascin, MMP2 and MMP9 in cells was examined by Western blotting. RESULTS The protein expression of DYNLT3 gradually increased during the progression of ovarian epithelial lesions, and was related to the development of ovarian cancer. High expression of DYNLT3 mRNA was related to poor overall survival and progression free survival, especially in serous ovarian cancer patients. In addition, overexpression of DYNLT3 promoted SKOV3 cell proliferation, invasion and migration. The corresponding results were also verified by a DYNLT3 knockdown assay. Moreover, DYNLT3 increased cell proliferation, which was related to Ki-67 expression. Besides, DYNLT3 enhanced cell invasion and migration through regulating Ezrin, but not Fascin, MMP2 or MMP9. CONCLUSION DYNLT3 exerts pro-tumoral effects on ovarian cancer through promoting cell proliferation, migration and invasion, possibly via regulating the protein expression of Ki-67 and Ezrin. DYNLT3 may be a potential prognostic predictor in ovarian cancer.
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Affiliation(s)
- Lulu Zhou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou325027, People’s Republic of China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou325027, People’s Republic of China
| | - Fang Xue
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou325027, People’s Republic of China
| | - Ermei Lu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou325027, People’s Republic of China
| | - Lu-Zhe Sun
- Departments of Cell Systems & Anatomy, School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou325027, People’s Republic of China
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Zhang W, Huang L, Lu X, Wang K, Ning X, Liu Z. Upregulated expression of MNX1-AS1 long noncoding RNA predicts poor prognosis in gastric cancer. Bosn J Basic Med Sci 2019; 19:164-171. [PMID: 30821221 DOI: 10.17305/bjbms.2019.3713] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 09/30/2018] [Indexed: 12/16/2022] Open
Abstract
As important regulators of gene expression long noncoding RNAs (lncRNAs) are implicated in various physiological and pathological processes, including cancer. An oncogenic role of MNX1 antisense RNA 1 (MNX1-AS1) lncRNA has been suggested in cervical cancer and glioblastoma. In this study, we investigated the clinicopathological significance and biological function of MNX1-AS1 in gastric cancer (GC). The expression of MNX1-AS1 was analyzed by qRT-PCR in 96 GC and adjacent non-tumor tissues in relation to clinicopathological features and overall survival (OS) of patients, and in five human GC cell lines compared to a normal gastric epithelial cell line. Loss-of-function experiments using small interfering RNA (siRNA) targeting MNX1-AS1 (si-MNX1-AS1) were carried out in AGS and MGC-803 GC cell lines. Cell proliferation (CCK-8 assay), migration (Transwell) and invasion (Transwell Matrigel), and protein expression of proliferating cell nuclear antigen (PCNA), E-cadherin, N-cadherin, vimentin and matrix metallopeptidase 9 (MMP-9) were analyzed in transfected GC cells. Expression of MNX1-AS1 was significantly higher in GC vs. adjacent non-tumor tissues. Higher MNX1-AS1 expression was significantly associated with tumor size, TNM stage and lymph node metastasis. Kaplan-Meier analysis showed that GC patients with higher MNX1-AS1 expression had worse OS compared to patients with lower MNX1-AS1 expression. Multivariate analysis showed that MNX1-AS1 is an independent poor prognostic factor in GC. Knockdown of MNX1-AS1 significantly inhibited proliferation, migration and invasion of AGS and MGC-803 cells, and resulted in increased E-cadherin and decreased PCNA, N-cadherin, vimentin and MMP-9 expression. Taken together, these results suggest that MNX1-AS1 has an oncogenic function in GC and potential as a molecular target in GC therapy.
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Affiliation(s)
- Wei Zhang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining, Shandong Province, China.
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Yuan Y, Wang Y, Liu Z, Sun Y, Yao Y, Yu W, Shen Z. MAT2B promotes proliferation and inhibits apoptosis in osteosarcoma by targeting epidermal growth factor receptor and proliferating cell nuclear antigen. Int J Oncol 2019; 54:2019-2029. [PMID: 30942439 PMCID: PMC6521932 DOI: 10.3892/ijo.2019.4764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 10/12/2018] [Indexed: 12/16/2022] Open
Abstract
Osteosarcoma (OS) is the most commonly diagnosed bone tumor in young people with poor prognosis. At present, the mechanisms underlying tumorigenesis in OS are not well understood. The methionine adnosyltransferase 2B (MAT2B) gene encodes the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies demonstrated that it is highly expressed in a number of human malignancies; however, is undefined in OS. In the present study, MAT2B expression was investigated in tumor samples and cell lines. In vivo and in vitro, lentivirus‑mediated small hairpin RNA was constructed to target the MAT2B gene and examine the role of MAT2B in OS proliferation. Microarray analysis was performed to examine the possible downstream molecular target of MAT2B in OS. MAT2B was markedly increased in OS specimens compared with the normal bone tissues, and it was additionally abundantly expressed in OS cell lines. Inhibition of MAT2B expression caused a marked decrease in proliferation and significant increase in apoptosis. In vivo, MAT2B silencing significantly inhibited OS cell growth. Microarray analysis suggested that epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) may function as downstream targets of MAT2B in OS, as confirmed by reverse transcription‑quantitative polymerase chain reaction assays and western blotting. Collectively, these results suggested that MAT2B serves a critical role in the proliferation of OS by regulating EGFR and PCNA and that it may be a potential therapeutic target and prognostic factor of OS.
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Affiliation(s)
- Yuan Yuan
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Yonggang Wang
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Zimei Liu
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Yong Sun
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Yang Yao
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Wenxi Yu
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Zan Shen
- Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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Tian H, Zhang Y, Zhang Q, Li S, Liu Y, Han X. Effects of BENC-511, a novel PI3K inhibitor, on the proliferation and apoptosis of A549 human lung adenocarcinoma cells. Biosci Trends 2019; 13:40-48. [DOI: 10.5582/bst.2019.01006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Huiqin Tian
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
- Department of Pharmacology, Shandong College of Traditional Chinese Medicine
| | - Yu Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
| | - Qianyun Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
| | - Shuixian Li
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
| | - Yang Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
| | - Xiuzhen Han
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University
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Sun S, Du G, Xue J, Ma J, Ge M, Wang H, Tian J. PCC0208009 enhances the anti-tumor effects of temozolomide through direct inhibition and transcriptional regulation of indoleamine 2,3-dioxygenase in glioma models. Int J Immunopathol Pharmacol 2018; 32:2058738418787991. [PMID: 29993291 PMCID: PMC6047256 DOI: 10.1177/2058738418787991] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in human
glioblastoma and involved in tumor immune escape and resistance to chemotherapy,
is clinically correlated with tumor progression and poor clinical outcomes, and
is a promising therapeutic target for glioblastoma. IDO inhibitors are
marginally efficacious as single-agents; therefore, combination with other
therapies holds promise for cancer therapy. The aim of this study was to
investigate the anti-tumor effects and mechanisms of the IDO inhibitor
PCC0208009 in combination with temozolomide. The effects of PCC0208009 on IDO
activity inhibition, and mRNA and protein expression in HeLa cells were
observed. In the mouse glioma GL261 heterotopic model, the effects of PCC0208009
on l-kynurenine/tryptophan (Kyn/Trp), tumor growth, flow cytometry for
T cells within tumors, and immunohistochemistry for IDO and Ki67 were examined.
In the rat glioma C6 orthotopic model, animal survival, flow cytometry for T
cells within tumors, and immunohistochemistry for proliferating cell nuclear
antigen (PCNA) and IDO were examined. The results show that PCC0208009 is a
highly effective IDO inhibitor, not only directly inhibiting IDO activity but
also participating in the gene regulation of IDO expression at the transcription
and translation levels. PCC0208009 significantly enhanced the anti-tumor effects
of temozolomide in GL261 and C6 models, by increasing the percentages of
CD3+, CD4+, and CD8+ T cells within tumors
and suppressing tumor proliferation. These findings indicate that PCC0208009 can
potentiate the anti-tumor efficacy of temozolomide and suggest that combination
of IDO inhibitor-based immunotherapy with chemotherapy is a potential strategy
for brain tumor treatment.
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Affiliation(s)
- Shanyue Sun
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Guangying Du
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Jiang Xue
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Jinbo Ma
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Minmin Ge
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Hongbo Wang
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
| | - Jingwei Tian
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, P.R. China
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Yang T, Zhang W, Wang L, Xiao C, Wang L, Gong Y, Huang D, Guo B, Li Q, Xiang Y, Nan Y. Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system. BMC Cancer 2018; 18:984. [PMID: 30326865 PMCID: PMC6192155 DOI: 10.1186/s12885-018-4871-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 09/28/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Application of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo. METHODS Human DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model. RESULTS We demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs. CONCLUSIONS The results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading.
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Affiliation(s)
- Tao Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Wenjun Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Li Wang
- Department of Oncology, Chongqing General Hospital, Chongqing, People's Republic of China
| | - Chunyan Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Li Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Yi Gong
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Dehong Huang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Bingling Guo
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Qiying Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Ying Xiang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China
| | - Yingyu Nan
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No.181 Hanyu Road, Chongqing, 400030, People's Republic of China.
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Tang X, Xu Y, Lu L, Jiao Y, Liu J, Wang L, Zhao H. Identification of key candidate genes and small molecule drugs in cervical cancer by bioinformatics strategy. Cancer Manag Res 2018; 10:3533-3549. [PMID: 30271202 PMCID: PMC6145638 DOI: 10.2147/cmar.s171661] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Purpose Cervical cancer (CC) is one of the most common malignant tumors among women. The present study aimed at integrating two expression profile datasets to identify critical genes and potential drugs in CC. Materials and methods Expression profiles, GSE7803 and GSE9750, were integrated using bioinformatics methods, including differentially expressed genes analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and protein–protein interaction (PPI) network construction. Subsequently, survival analysis was performed among the key genes using Gene Expression Profiling Interactive Analysis websites. Connectivity Map (CMap) was used to query potential drugs for CC. Results A total of 145 upregulated genes and 135 downregulated genes in CC were identified. The functional changes of these differentially expressed genes related to CC were mainly associated with cell cycle, DNA replication, p53 signaling pathway, and oocyte meiosis. A PPI network was identified by STRING with 220 nodes and 2,111 edges. Thirteen key genes were identified as the intersecting genes of the enrichment pathways and the top 20 nodes in PPI network. Survival analysis revealed that high mRNA expression of MCM2, PCNA, and RFC4 was significantly associated with longer overall survival, and the survival was significantly better in the low-expression RRM2 group. Moreover, CMap predicted nine small molecules as possible adjuvant drugs to treat CC. Conclusion Our study found key dysregulated genes involved in CC and potential drugs to combat it, which might provide insights into CC pathogenesis and might shed light on potential CC treatments.
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Affiliation(s)
- Xin Tang
- School of Rehabilitation, Kunming Medical University, Kunming, China
| | - Yicong Xu
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
| | - Lin Lu
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
| | - Yang Jiao
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
| | - Jianjun Liu
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
| | - Linlin Wang
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
| | - Hongbo Zhao
- Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China, .,Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Kunming, China,
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Xia Y, Yan Z, Wan Y, Wei S, Bi Y, Zhao J, Liu J, Liao DJ, Huang H. Knockdown of long noncoding RNA GHET1 inhibits cell‑cycle progression and invasion of gastric cancer cells. Mol Med Rep 2018; 18:3375-3381. [PMID: 30066922 PMCID: PMC6102745 DOI: 10.3892/mmr.2018.9332] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 07/19/2018] [Indexed: 12/17/2022] Open
Abstract
GHET1 is an oncogenic long noncoding RNA (lncRNA) that promotes the proliferation and invasion of many malignant cell types. However, the function and underlying mechanisms of lncRNA GHET1 in gastric cancer are not fully understood. In this study, the expression of GHET1 was investigated in gastric cancer and it was determined whether GHET1 may potentially be used as a biomarker for the disease. The gastric cancer cell lines MGC‑803 and AGS were transfected with GHET1‑directed small interfering RNA (siRNA) and the changes in phenotype and cell‑cycle‑related molecules were assessed. The downregulation of GHET1 induced G0/G1‑phase arrest in gastric cancer cells and inhibited their proliferation, migration, and invasion. DNA synthesis and the expression of proliferating cell nuclear antigen (PCNA) decreased, which was consistent with the results of the CCK‑8 assay. The levels of specific cell‑cycle regulators were determined and the expression and activities of positive cell‑cycle regulators (cyclin D, CDK4, CDK6, cyclin E, CDK2) were reduced, whereas those of a negative regulator (P21) were increased in GHET1‑knockdown cells. Taken together, the present findings show that the downregulation of GHET1 not only inhibits the migration and invasion of gastric cancer cells, but also inhibits their proliferation, at least in part by upregulating P21 expression and downregulating cyclin and CDK expression to inhibit the G0/G1 to S phase transition. The present findings may provide a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Ying Xia
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Zhiqiang Yan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Ying Wan
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Sixi Wei
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Ying Bi
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Juanjuan Zhao
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Juanjuan Liu
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Dezhong Joshua Liao
- Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Hai Huang
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
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Conti S, Vexler A, Hagoel L, Kalich-Philosoph L, Corn BW, Honig N, Shtraus N, Meir Y, Ron I, Eliaz I, Lev-Ari S. Modified Citrus Pectin as a Potential Sensitizer for Radiotherapy in Prostate Cancer. Integr Cancer Ther 2018; 17:1225-1234. [PMID: 30043669 PMCID: PMC6247563 DOI: 10.1177/1534735418790382] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: Radiotherapy is one of the primary therapies for
localized prostatic carcinoma. Therefore, there is an emerging need to sensitize
prostatic cancer cells to chemotherapy/radiotherapy. Modified citrus pectin
(MCP) is an effective inhibitor of galectin-3 (Gal-3), which is correlated with
tumor progression, proliferation, angiogenesis, and apoptosis.
Purpose: This study was directed to evaluate the efficacy of
combining ionizing radiation (IR) with MCP on PCa cells. Study
Design: Effects of treatments on PCa cells survival were evaluated
using XTT assay, flow cytometry, and clonogenic survival assay. Expression of
selected proteins was estimated using western blotting. Cell motility,
migration, and invasion were determined. Contribution of reactive oxygen species
production to treatment effects on cell viability was tested.
Results: Radiotherapy combined with MCP reduced viability and
enhanced radiosensitivity associated with a decrease in Gal-3, cleavage of the
precursor of caspase-3, increased expression of the pro-apoptotic protein Bax,
and downregulation of DNA repair pathways, poly-ADP-ribose polymerase, and
proliferating cell nuclear antigen. MCP significantly reduced the invasive and
migratory potential of PCa cells. Combining sodium pyruvate with MCP and IR
mitigated the effect on cell viability. Conclusion: Our findings
demonstrated that MCP sensitized PCa cells to IR by downregulating
anti-apoptotic Gal-3, modulating DNA repair pathways, and increasing ROS
production. For the first time the correlation between MCP, radiotherapy, and
Gal-3 for prostatic cancer treatment was found. In addition, MCP reduced the
metastatic properties of PCa cells. These findings provide MCP as a
radiosensitizing agent to enhance IR cytotoxicity, overcome radioresistance, and
reduce clinical IR dose.
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Affiliation(s)
- Sefora Conti
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
| | - Akiva Vexler
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
| | - Lior Hagoel
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
| | | | - Benjamin W. Corn
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Tel Aviv University, Tel Aviv,
Israel
| | - Nir Honig
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Tel Aviv University, Tel Aviv,
Israel
| | - Natan Shtraus
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Tel Aviv University, Tel Aviv,
Israel
| | - Yaron Meir
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Tel Aviv University, Tel Aviv,
Israel
| | - Ilan Ron
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Tel Aviv University, Tel Aviv,
Israel
| | - Isaac Eliaz
- Amitabha Medical Clinic and Healing
Center, Santa Rosa, CA, USA
| | - Shahar Lev-Ari
- Tel Aviv Sourasky Medical Center, Tel
Aviv, Israel
- Shahar Lev-Ari, Laboratory of Herbal
Medicine and Cancer Research, Institute of Oncology, Tel Aviv Sourasky Medical
Center, 6 Weizmann Street, Tel Aviv 64239, Israel.
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Wang L, Kong W, Liu B, Zhang X. Proliferating cell nuclear antigen promotes cell proliferation and tumorigenesis by up-regulating STAT3 in non-small cell lung cancer. Biomed Pharmacother 2018; 104:595-602. [PMID: 29803172 DOI: 10.1016/j.biopha.2018.05.071] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 05/15/2018] [Accepted: 05/15/2018] [Indexed: 01/10/2023] Open
Abstract
Proliferating cell nuclear antigen (PCNA) functions as a bridging molecule, which targets proteins that have distinct roles in cell growth. The expression of PCNA is dysregulated in some tumors and takes part in the progression of oncogenesis. However, the roles of PCNA in the progression of non-small cell lung cancer (NSCLC) remain unknown. The present study aimed to investigate the function of PCNA in the occurrence and development of NSCLC and its underlying molecular mechanisms. Western blotting, RT-PCR, and immunohistochemistry assays were used to detect the expression pattern of PCNA in NSCLC tissues and cells. A log rank test was performed to compare the overall survival (OS) of patients with high/low expression of PCNA. Besides, the relationship between PCNA and signal transducer and activator of transcription-3 (STAT3) proteins were evaluated. Then, MTT, flow cytometry, clonal formation, and in vivo xenograft assays were conducted to investigate the effects of PCNA/STAT3 on cell growth, clonal formation, apoptosis, and tumorigenesis. Results showed that PCNA expression was elevated in NSCLC tissues and cells and it could combine with STAT3 and increased its expression and phosphorylation. Moreover, the expression of PCNA showed a positive correlation with the TNM grade and occurrence rate of the lymphatic metastasis and poor prognosis of NSCLC patients. Overexpression of PCNA promoted cell proliferation, clonal formation, and tumorigenesis in lung cancer cells and inhibited cell apoptosis. In contrast, these effects were inhibited when knockdown of STAT3. In conclusion, this study demonstrates that PCNA functions as an oncogene in the progression of NSCLC through up-regulation of STAT3. These findings point to a potentially new therapeutic strategy for NSCLC.
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Affiliation(s)
- Liuxin Wang
- Department of Respiration, Jining First People's Hospital, Jining, Shandong, China
| | - Weixiang Kong
- Department of Respiration, Jining First People's Hospital, Jining, Shandong, China
| | - Bing Liu
- Department of Respiration, Jining First People's Hospital, Jining, Shandong, China
| | - Xueqing Zhang
- Department of Respiration, Jining First People's Hospital, Jining, Shandong, China.
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Wu K, Yi Y, Liu F, Wu W, Chen Y, Zhang W. Identification of key pathways and genes in the progression of cervical cancer using bioinformatics analysis. Oncol Lett 2018; 16:1003-1009. [PMID: 29963176 PMCID: PMC6019941 DOI: 10.3892/ol.2018.8768] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 05/15/2018] [Indexed: 12/22/2022] Open
Abstract
The aim of the present study was to investigate the key pathways and genes in the progression of cervical cancer. The gene expression profiles GSE7803 and GSE63514 were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using GEO2R and the limma package, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery. The hub genes were identified using Cytoscape and protein-protein interaction (PPI) networks were constructed using the STRING database. A total of 127 and 99 DEGs were identified in the pre-invasive and invasive stages of cervical cancer, respectively. GO enrichment analysis indicated that the DEGs in pre-invasive cervical cancer were primarily associated with the ‘protein binding’, ‘single-stranded DNA-dependent ATPase activity’, ‘DNA replication origin binding’ and ‘microtubule binding’ terms, whereas the DEGs in invasive cervical cancer were associated with the ‘extracellular matrix (ECM) structural constituent’, ‘heparin binding’ and ‘integrin binding’. KEGG enrichment analysis revealed that the pre-invasive DEGs were significantly enriched in the ‘cell cycle’, ‘DNA replication’ and ‘p53 signaling pathway’ terms, while the invasive DEGs were enriched in the ‘amoebiasis’, ‘focal adhesion’, ‘ECM-receptor interaction’ and ‘platelet activation’ terms. The PPI network identified 4 key genes (PCNA, CDK2, VEGFA and PIK3CA), which were hub genes for pre-invasive and invasive cervical cancer. In conclusion, bioinformatics analysis identified 4 key genes in cervical cancer progression (PCNA, CDK2, VEGFA and PIK3CA), which may be potential biomarkers for differentiating normal cervical epithelial tissue from cervical cancer.
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Affiliation(s)
- Kejia Wu
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yuexiong Yi
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Fulin Liu
- The First Department of Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wanrong Wu
- The First Department of Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yurou Chen
- The First Department of Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Zhang
- Department of Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
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49
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Willis S, Sun Y, Abramovitz M, Fei T, Young B, Lin X, Ni M, Achua J, Regan MM, Gray KP, Gray R, Wang V, Long B, Kammler R, Sparano JA, Williams C, Goldstein LJ, Salgado R, Loi S, Pruneri G, Viale G, Brown M, Leyland-Jones B. High Expression of FGD3, a Putative Regulator of Cell Morphology and Motility, Is Prognostic of Favorable Outcome in Multiple Cancers. JCO Precis Oncol 2017; 1:PO.17.00009. [PMID: 32913979 PMCID: PMC7446538 DOI: 10.1200/po.17.00009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. METHODS Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. RESULTS A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)-positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer-free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 (P = 3.8E-14) outperformed MKI67 (P = 1.06E-8) and AURKA (P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88E-5) outperformed MKI67 (P = .477) and AURKA (P = .820). CONCLUSION FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker.
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Affiliation(s)
- Scooter Willis
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Yuliang Sun
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Mark Abramovitz
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Teng Fei
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Brandon Young
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Xiaoqian Lin
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Min Ni
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Justin Achua
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Meredith M. Regan
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Kathryn P. Gray
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Robert Gray
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Victoria Wang
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Bradley Long
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Roswitha Kammler
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Joseph A. Sparano
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Casey Williams
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Lori J. Goldstein
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Roberto Salgado
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Sherene Loi
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Giancarlo Pruneri
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Giuseppe Viale
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Myles Brown
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
| | - Brian Leyland-Jones
- Scooter Willis, Yuliang Sun, Mark Abramovitz, Brandon Young, Xiaoqian Lin, Justin Achua, Casey Williams, and Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Teng Fei, Meredith M. Regan, Kathryn P. Gray, Robert Gray, Victoria Wang, and Myles Brown, Dana-Farber Cancer Institute, Boston, MA; Min Ni, Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX; Bradley Long, Molecular Core, Scripps Florida, Jupiter, FL; Roswitha Kammler, International Breast Cancer Study Group, Bern, Switzerland; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; Roberto Salgado, Breast Cancer Translational Research Laboratory/Institut Jules Bordet, Brussels, Belgium; Sherene Loi, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; and Giancarlo Pruneri and Giuseppe Viale, European Institute of Oncology, University of Milan, Milan, Italy
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Hu L, Li HL, Li WF, Chen JM, Yang JT, Gu JJ, Xin L. Clinical significance of expression of proliferating cell nuclear antigen and E-cadherin in gastric carcinoma. World J Gastroenterol 2017; 23:3721-3729. [PMID: 28611525 PMCID: PMC5449429 DOI: 10.3748/wjg.v23.i20.3721] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 03/27/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM to investigate the expression of proliferating cell nuclear antigen (PCNA) and E-cadherin in gastric carcinoma and to analyze their clinical significance.
METHODS A total of 146 patients were selected for this study, including 38 patients with intestinal metaplasia, 42 with dysplasia, and 66 with primary gastric cancer. In addition, 40 patients with normal gastric tissues were selected as controls. The expression of PCNA and E-cadherin was detected by immunohistochemistry. Differences in PCNA and the E-cadherin labeling indexes among normal gastric mucosa, intestinal metaplasia, dysplasia, and gastric carcinoma were compared. Subjects with normal gastric tissues were assigned to a normal group, while gastric cancer patients were assigned to a gastric cancer group. The difference in PCNA and E-cadherin expression between these two groups was compared. The relationship between expression of PCNA and E-cadherin and clinicopathological features was also explored in gastric cancer patients. Furthermore, prognosis-related factors, as well as the expression of PCNA and E-cadherin, were analyzed in patients with gastric cancer to determine the 3-year survival of these patients.
RESULTS The difference in PCNA and the E-cadherin labeling indexes among normal gastric mucosa, intestinal metaplasia, dysplasia, and gastric carcinoma was statistically significant (P < 0.05). During the transition of normal gastric mucosa to gastric cancer, the PCNA labeling index gradually increased, while the E-cadherin labeling index gradually decreased (P < 0.05). The PCNA labeling index was significantly higher and the E-cadherin labeling index was significantly lower in gastric cancer than in dysplasia (P < 0.05). The expression of PCNA was significantly higher in the gastric cancer group than in the normal group, but E-cadherin was weaker (P < 0.05). There was a negative correlation between the expression of PCNA and E-cadherin in gastric carcinoma (r = -0.741, P = 0.000). PCNA expression differed significantly between gastric cancer patients with and without lymph node metastasis and between patients at different T stages. E-cadherin expression also differed significantly between gastric cancer patients with and without lymph node metastasis (P < 0.05). High T stage and positive PCNA expression were risk factors for the prognosis of patients with gastric cancer (RR > 1), while the positive expression of E-cadherin was a protective factor (RR < 1). The sensitivity, specificity, and accuracy of PCNA positivity in predicting the 3-year survival of patients with gastric cancer were 93.33%, 38.89%, and 0.64, respectively; while these values for E-cadherin negativity were 80.0%, 41.67%, and 0.59, respectively. When PCNA positivity and E-cadherin negativity were combined, the sensitivity, specificity, and accuracy were 66.67%, 66.67%, and 0.67, respectively.
CONCLUSION Combined detection of PCNA and E-cadherin can improve the accuracy of assessing the prognosis of patients with gastric cancer.
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