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Zhang C, Zhang G, Xue L, Zhang Z, Zeng Q, Wu P, Wang L, Yang Z, Zheng B, Tan F, Xue Q, Gao S, Sun N, He J. Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8 + T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China. Int J Surg 2024; 110:4297-4309. [PMID: 36974732 PMCID: PMC11254267 DOI: 10.1097/js9.0000000000000064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 11/12/2022] [Indexed: 03/29/2023]
Abstract
BACKGROUND Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8 + T cell in SCCE for the first time. MATERIALS AND METHODS Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. RESULTS No patients had PD-L1 expressed in their tumor cells. PD-L1 + expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68 + monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression ( Ptrend <0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. CONCLUSION Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.
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Affiliation(s)
- Chaoqi Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhihui Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Qingpeng Zeng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Peng Wu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Lide Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Zhaoyang Yang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Zheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
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Liu H, Li X, Shi Y, Ye Z, Cheng X. Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling. Biomolecules 2024; 14:342. [PMID: 38540761 PMCID: PMC10967961 DOI: 10.3390/biom14030342] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/06/2024] [Accepted: 03/08/2024] [Indexed: 07/02/2024] Open
Abstract
Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3's intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its regulatory mechanisms, expression patterns, and multifaceted roles in cancer progression. PRL-3's involvement in proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance is discussed. Regulatory mechanisms encompass transcriptional control, alternative splicing, and post-translational modifications. PRL-3 exhibits selective expressions in specific cancer types, making it a potential target for therapy. Despite advances in small molecule inhibitors, further research is needed for clinical application. PRL-3-zumab, a humanized antibody, shows promise in preclinical studies and clinical trials. Our review summarizes the current understanding of the cancer-related cellular function of PRL-3, its prognostic value, and the research progress of therapeutic inhibitors.
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Affiliation(s)
- Haidong Liu
- Zhejiang Cancer Hospital, Hangzhou 310022, China;
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
| | - Xiao Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China;
| | - Yin Shi
- Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou 310058, China;
| | - Zu Ye
- Zhejiang Cancer Hospital, Hangzhou 310022, China;
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
| | - Xiangdong Cheng
- Zhejiang Cancer Hospital, Hangzhou 310022, China;
- Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310018, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China
- Zhejiang Provincial Research Center for Upper Gastrointestinal Tract Cancer, Zhejiang Cancer Hospital, Hangzhou 310022, China
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Deng Y, Li J, Zhang Y, Hu H, Wan F, Min H, Zhou H, Gu L, Liao X, Zhou J, Zhou J. NUF2 Promotes Breast Cancer Development as a New Tumor Stem Cell Indicator. Int J Mol Sci 2023; 24:ijms24044226. [PMID: 36835637 PMCID: PMC9965662 DOI: 10.3390/ijms24044226] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/31/2022] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Multiple new subtypes of breast cancer (BRCA) are identified in women each year, rendering BRCA the most common and rapidly expanding form of cancer in females globally. NUF2 has been identified as a prognostic factor in various human cancers, regulating cell apoptosis and proliferation. However, its role in BRCA prognosis has not been clarified. This study explored the role of NUF2 in breast cancer development and prognosis using informatic analysis combined with in vivo intracellular studies. Through the online website TIMER, we evaluated the transcription profile of NUF2 across a variety of different cancer types and found that NUF2 mRNA was highly expressed in BRCA patients. Its transcription level was found to be related to the subtype, pathological stage, and prognosis of BRCA. The R program analysis showed a correlation of NUF2 with cell proliferation and tumor stemness in the BRCA patient samples. Subsequently, the association between the NUF2 expression level and immune cell infiltration was analyzed using the XIANTAO and TIMER tools. The results revealed that NUF2 expression was correlated with the responses of multiple immune cells. Furthermore, we observed the effect of NUF2 expression on tumor stemness in BRCA cell lines in vivo. The experimental results illuminated that the overexpression of NUF2 statistically upregulated the proliferation and tumor stemness ability of the BRCA cell lines MCF-7 and Hs-578T. Meanwhile, the knockdown of NUF2 inhibited the abilities of both cell lines, a finding which was verified by analyzing the subcutaneous tumorigenic ability in nude mice. In summary, this study suggests that NUF2 may play a key role in the development and progression of BRCA by affecting tumor stemness. As a stemness indicator, it has the potential to be one of the markers for the diagnosis of BRCA.
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Oku Y, Madia F, Lau P, Paparella M, McGovern T, Luijten M, Jacobs MN. Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens. Int J Mol Sci 2022; 23:ijms232112718. [PMID: 36361516 PMCID: PMC9659232 DOI: 10.3390/ijms232112718] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/18/2022] [Accepted: 10/18/2022] [Indexed: 12/03/2022] Open
Abstract
With recent rapid advancement of methodological tools, mechanistic understanding of biological processes leading to carcinogenesis is expanding. New approach methodologies such as transcriptomics can inform on non-genotoxic mechanisms of chemical carcinogens and can be developed for regulatory applications. The Organisation for the Economic Cooperation and Development (OECD) expert group developing an Integrated Approach to the Testing and Assessment (IATA) of Non-Genotoxic Carcinogens (NGTxC) is reviewing the possible assays to be integrated therein. In this context, we review the application of transcriptomics approaches suitable for pre-screening gene expression changes associated with phenotypic alterations that underlie the carcinogenic processes for subsequent prioritisation of downstream test methods appropriate to specific key events of non-genotoxic carcinogenesis. Using case studies, we evaluate the potential of gene expression analyses especially in relation to breast cancer, to identify the most relevant approaches that could be utilised as (pre-) screening tools, for example Gene Set Enrichment Analysis (GSEA). We also consider how to address the challenges to integrate gene panels and transcriptomic assays into the IATA, highlighting the pivotal omics markers identified for assay measurement in the IATA key events of inflammation, immune response, mitogenic signalling and cell injury.
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Affiliation(s)
- Yusuke Oku
- The Organisation for Economic Cooperation and Development (OECD), 2 Rue Andre Pascal, 75016 Paris, France
- Correspondence: (Y.O.); (M.N.J.)
| | - Federica Madia
- European Commission, Joint Research Centre (JRC), Via Enrico Fermi, 2749, 21027 Ispra, Italy
| | - Pierre Lau
- Istituto Italiano di Tecnologia, 16163 Genova, Italy
| | - Martin Paparella
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innrain 80, 6020 Innbruck, Austria
| | - Timothy McGovern
- US Food and Drug Administration (FDA), 10903 New Hampshire Avenue, Silver Spring, MD 20901, USA
| | - Mirjam Luijten
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Antonie van Leeuwenhoeklaan 9, Bilthoven, 3721 MA Utrecht, The Netherlands
| | - Miriam N. Jacobs
- Centre for Radiation, Chemical and Environmental Hazard (CRCE), Public Health England (PHE), Chilton OX11 0RQ, Oxfordshire, UK
- Correspondence: (Y.O.); (M.N.J.)
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Marzano L, Darwich AS, Tendler S, Dan A, Lewensohn R, De Petris L, Raghothama J, Meijer S. A novel analytical framework for risk stratification of real-world data using machine learning: A small cell lung cancer study. Clin Transl Sci 2022; 15:2437-2447. [PMID: 35856401 PMCID: PMC9579402 DOI: 10.1111/cts.13371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 06/26/2022] [Accepted: 07/08/2022] [Indexed: 01/25/2023] Open
Abstract
In recent studies, small cell lung cancer (SCLC) treatment guidelines based on Veterans' Administration Lung Study Group limited/extensive disease staging and resulted in broad and inseparable prognostic subgroups. Evidence suggests that the eight versions of tumor, node, and metastasis (TNM) staging can play an important role to address this issue. The aim of the present study was to improve the detection of prognostic subgroups from a real-word data (RWD) cohort of patients and analyze their patterns using a development pipeline with thoracic oncologists and machine learning methods. The method detected subgroups of patients informing unsupervised learning (partition around medoids) including the impact of covariates on prognosis (Cox regression and random survival forest). An analysis was carried out using patients with SCLC (n = 636) with stage IIIA-IVB according to TNM classification. The analysis yielded k = 7 compacted and well-separated clusters of patients. Performance status (Eastern Cooperative Oncology Group-Performance Status), lactate dehydrogenase, spreading of metastasis, cancer stage, and CRP were the baselines that characterized the subgroups. The selected clustering method outperformed standard clustering techniques, which were not capable of detecting meaningful subgroups. From the analysis of cluster treatment decisions, we showed the potential of future RWD applications to understand disease, develop individualized therapies, and improve healthcare decision making.
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Affiliation(s)
- Luca Marzano
- Division of Health Informatics and LogisticsSchool of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of TechnologyHuddingeSweden
| | - Adam S. Darwich
- Division of Health Informatics and LogisticsSchool of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of TechnologyHuddingeSweden
| | - Salomon Tendler
- Department of Oncology‐PathologyKarolinska Institutet and the Thoracic Oncology Center, Karolinska University HospitalStockholmSweden
| | - Asaf Dan
- Department of Oncology‐PathologyKarolinska Institutet and the Thoracic Oncology Center, Karolinska University HospitalStockholmSweden
| | - Rolf Lewensohn
- Department of Oncology‐PathologyKarolinska Institutet and the Thoracic Oncology Center, Karolinska University HospitalStockholmSweden
| | - Luigi De Petris
- Department of Oncology‐PathologyKarolinska Institutet and the Thoracic Oncology Center, Karolinska University HospitalStockholmSweden
| | - Jayanth Raghothama
- Division of Health Informatics and LogisticsSchool of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of TechnologyHuddingeSweden
| | - Sebastiaan Meijer
- Division of Health Informatics and LogisticsSchool of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), KTH Royal Institute of TechnologyHuddingeSweden
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Tumor-Promoting ATAD2 and Its Preclinical Challenges. Biomolecules 2022; 12:biom12081040. [PMID: 36008934 PMCID: PMC9405547 DOI: 10.3390/biom12081040] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 02/06/2023] Open
Abstract
ATAD2 has received extensive attention in recent years as one prospective oncogene with tumor-promoting features in many malignancies. ATAD2 is a highly conserved bromodomain family protein that exerts its biological functions by mainly AAA ATPase and bromodomain. ATAD2 acts as an epigenetic decoder and transcription factor or co-activator, which is engaged in cellular activities, such as transcriptional regulation, DNA replication, and protein modification. ATAD2 has been reported to be highly expressed in a variety of human malignancies, including gastrointestinal malignancies, reproductive malignancies, urological malignancies, lung cancer, and other types of malignancies. ATAD2 is involved in the activation of multiple oncogenic signaling pathways and is closely associated with tumorigenesis, progression, chemoresistance, and poor prognosis, but the oncogenic mechanisms vary in different cancer types. Moreover, the direct targeting of ATAD2’s bromodomain may be a very challenging task. In this review, we summarized the role of ATAD2 in various types of malignancies and pointed out the pharmacological direction.
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Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, Yokozaki H, Sasaki H. Cell Cycle Regulation and DNA Damage Response Networks in Diffuse- and Intestinal-Type Gastric Cancer. Cancers (Basel) 2021; 13:5786. [PMID: 34830941 PMCID: PMC8616335 DOI: 10.3390/cancers13225786] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023] Open
Abstract
Dynamic regulation in molecular networks including cell cycle regulation and DNA damage response play an important role in cancer. To reveal the feature of cancer malignancy, gene expression and network regulation were profiled in diffuse- and intestinal-type gastric cancer (GC). The results of the network analysis with Ingenuity Pathway Analysis (IPA) showed that the activation states of several canonical pathways related to cell cycle regulation were altered. The G1/S checkpoint regulation pathway was activated in diffuse-type GC compared to intestinal-type GC, while canonical pathways of the cell cycle control of chromosomal replication, and the cyclin and cell cycle regulation, were activated in intestinal-type GC compared to diffuse-type GC. A canonical pathway on the role of BRCA1 in the DNA damage response was activated in intestinal-type GC compared to diffuse-type GC, where gene expression of BRCA1, which is related to G1/S phase transition, was upregulated in intestinal-type GC compared to diffuse-type GC. Several microRNAs (miRNAs), such as mir-10, mir-17, mir-19, mir-194, mir-224, mir-25, mir-34, mir-451 and mir-605, were identified to have direct relationships in the G1/S cell cycle checkpoint regulation pathway. Additionally, cell cycle regulation may be altered in epithelial-mesenchymal transition (EMT) conditions. The alterations in the activation states of the pathways related to cell cycle regulation in diffuse- and intestinal-type GC highlighted the significance of cell cycle regulation in EMT.
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Affiliation(s)
- Shihori Tanabe
- Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan;
| | - Sabina Quader
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki 210-0821, Japan;
| | - Ryuichi Ono
- Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan;
| | - Horacio Cabral
- Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Tokyo 113-0033, Japan;
| | - Kazuhiko Aoyagi
- Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan;
| | - Akihiko Hirose
- Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Kawasaki 210-9501, Japan;
| | - Hiroshi Yokozaki
- Department of Pathology, Kobe University of Graduate School of Medicine, Kobe 650-0017, Japan;
| | - Hiroki Sasaki
- Department of Translational Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan;
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Shan L, Zhu XL, Zhang Y, Gu GJ, Cheng X. Expression and clinical significance of NUF2 in kidney renal clear cell carcinoma. Transl Androl Urol 2021; 10:3628-3637. [PMID: 34733658 PMCID: PMC8511540 DOI: 10.21037/tau-21-620] [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: 06/25/2021] [Accepted: 08/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background To explore the expression and clinical significance of the cytokinesis-related gene NUF2 in kidney renal clear cell carcinoma (KIRC). Methods Gene expression profiles of KIRC patients were extracted from The Cancer Genome Atlas (TCGA) database. The differences in NUF2 mRNA expression between patients and controls, as well as the relationship between the clinical characteristics and overall survival of the patients, were analyzed. The expression of NUF2 protein in 83 cancer tissues and para-cancerous tissues was detected to analyze the relationship with clinical characteristics. Gene Set Enrichment Analysis (GSEA) was used to investigate the possible regulatory pathways of the NUF2 in the development of KIRC. Results NUF2 mRNA was significantly higher in patients with KIRC, and the prognosis of patients with high expression of NUF2 mRNA was significantly worse than those with low expression, and was related to the AJCC stage, T stage, lymph node metastases, and distant metastases. NUF2 mRNA was an independent prognostic risk factor for KIRC patients. The expression of NUF2 protein was significantly higher in KIRC patients than in paraneoplastic tissues and was markedly associated with the pathological grade. In addition, the high expression of NUF2 was associated with the upregulation of pathways such as homologous recombination and DNA replication. Conclusions NUF2 may act as an independent prognostic biomarker for predicting the survival of KIRC patients.
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Affiliation(s)
- Li Shan
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Xiao-Li Zhu
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Yuan Zhang
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Guo-Jian Gu
- Department of Pathology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
| | - Xu Cheng
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Suzhou, China
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A New Stemness-Related Prognostic Model for Predicting the Prognosis in Pancreatic Ductal Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6669570. [PMID: 34671679 PMCID: PMC8523240 DOI: 10.1155/2021/6669570] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 06/17/2021] [Accepted: 09/24/2021] [Indexed: 02/06/2023]
Abstract
Objective This study is aimed at identifying stemness-related genes in pancreatic ductal adenocarcinoma (PDAC). Methods The RNA-seq data of PADC patients were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The mRNA expression-based stemness index (mRNAsi) and epigenetically regulated mRNAsi (EREG-mRNAsi) of PADC patients were evaluated. The mRNAsi-related gene sets in PADC were identified by weighted gene coexpression network analysis (WGCNA). The key genes were further analyzed using functional enrichment analysis. The Kaplan-Meier survival analysis and the Cox proportional hazards model were used to evaluate the prognostic value of the key genes. Prognostic hub genes were used to establish nomograms. The receiver operating characteristic (ROC) curves, concordance index (C-index), and calibration curves were used to assess the discrimination and accuracy of the nomogram. Finally, these results were validated in the Gene Expression Omnibus (GEO) database. Results A total of 36 key genes related to mRNAsi were identified by WGCNA. A prognostic gene signature compromising seven genes (TPX2, ZWINT, UBE2C, CCNB2, CDK1, BUB1, and BIRC5) was established to predict the overall survival (OS) of PADC patients. The Cox regression analysis revealed that the risk score was an independent prognostic factor for PADC. Patients were then divided into the high-risk and low-risk groups. The ROC curves, C-index, and calibration curves indicated good performance of the prognostic signature in the TCGA and GEO datasets. Moreover, the nomogram incorporating clinical parameters showed better sensitivity and specificity for predicting the OS of PADC patients. Conclusion The stemness-related prognostic model successfully predicted the OS of PADC patients and could be used for the treatment of PADC.
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Liu D, Wen J, Chen J, Fan M, Zhang Z. Nomogram for the prediction of individualized overall survival of patients diagnosed with small cell esophageal carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1344. [PMID: 34532481 PMCID: PMC8422131 DOI: 10.21037/atm-21-3900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/16/2021] [Indexed: 11/06/2022]
Abstract
Background A nomogram was developed for the estimation of individualized overall survival (OS) of patients diagnosed with small cell esophageal carcinoma (SCEC). Methods From the SEER dataset, 427 patients diagnosed with SCEC during the period from 2004 to 2015 were selected as training sets. For the establishment of a nomogram capable of estimating the OS possibility of patients diagnosed with SCEC, a group of independent prognostic factors were identified and incorporated. The effectiveness of the nomogram was then both externally and internally verified among 159 patients from Fudan University Shanghai Cancer Center (FUSCC) who were diagnosed with SCEC between 2006 and 2015. The predictive accuracy and discriminative ability of the nomogram were measured by concordance index (C-index). Comparisons between nomogram and the AJCC staging systems (6th and 7th) were performed with calibration plots and area under the curves (AUC) values. Results We identified age, gender, primary site, SEER stage, surgery, radiotherapy, and chemotherapy as seven independent risk factors which were then used to set up the nomogram. Calibration curves indicated that the prediction of the nomogram was consistent with real observations for the possibilities of 1-, 3-, and 5-year OS, and applying the nomogram to the cohort for validation led to reproducible results. Moreover, the C-indices and AUC values were higher in the nomogram than those in the AJCC staging system AJCC which is also aimed at the prediction of OS. Conclusions This study resulted in the establishment of the first nomogram for the prediction of individualized OS of patients diagnosed with SCEC. The accuracy rate of prediction of this model may be higher than previously established staging systems.
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Affiliation(s)
- Di Liu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Junmiao Wen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Jiayan Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Min Fan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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Zhong W, Wang D, Yao B, Chen X, Wang Z, Qu H, Ma B, Ye L, Qiu J. Integrative analysis of prognostic long non-coding RNAs with copy number variation in bladder cancer. J Zhejiang Univ Sci B 2021; 22:664-681. [PMID: 34414701 DOI: 10.1631/jzus.b2000494] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Copy number variations (CNVs), which can affect the role of long non-coding RNAs (lncRNAs), are important genetic changes seen in some malignant tumors. We analyzed lncRNAs with CNV to explore the relationship between lncRNAs and prognosis in bladder cancer (BLCA). Messenger RNA (mRNA) expression levels, DNA methylation, and DNA copy number data of 408 BLCA patients were subjected to integrative bioinformatics analysis. Cluster analysis was performed to obtain different subtypes and differently expressed lncRNAs and coding genes. Weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression gene and lncRNA modules. CNV-associated lncRNA data and their influence on cancer prognosis were assessed with Kaplan-Meier survival curve. Multi-omics integration analysis revealed five prognostic lncRNAs with CNV, namely NR2F1-AS1, LINC01138, THUMPD3-AS1, LOC101928489,and TMEM147-AS1,and a risk-score signature related to overall survival in BLCA was identified. Moreover, validated results in another independent Gene Expression Omnibus (GEO) dataset, GSE31684, were consistent with these results. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the mitogen-activated protein kinase (MAPK) signaling pathway, focal adhesion pathway, and Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway were enriched in a high-risk score pattern, suggesting that imbalance in these pathways is closely related to tumor development. We revealed the prognosis-related lncRNAs by analyzing the expression profiles of lncRNAs and CNVs, which can be used as prognostic biomarkers for BLCA.
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Affiliation(s)
- Wenwen Zhong
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Dejuan Wang
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Bing Yao
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Xiaoxia Chen
- Department of Medical Record Management Section, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Zhongyang Wang
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Hu Qu
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Bo Ma
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Lei Ye
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Jianguang Qiu
- Department of Urology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China.
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12
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Wu YH, Zhang K, Chen HG, Wu WB, Li XJ, Zhang J. Primary small cell esophageal carcinoma, chemotherapy sequential immunotherapy: A case report. World J Clin Cases 2021; 9:6478-6484. [PMID: 34435015 PMCID: PMC8362569 DOI: 10.12998/wjcc.v9.i22.6478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/16/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Primary small cell esophageal carcinoma (PSCEC) is aggressive and rare, with a worse prognosis than other subtypes esophageal carcinoma. No definitive and optimum standard guidelines are established for treating it. Herein, we report a case of PSCEC, including a current literature review of PSCEC.
CASE SUMMARY A 79-year-old male was diagnosed PSCEC with multiple lymph node metastasis thorough computed tomography, positron emission tomography-computed tomography, endoscopy and pathology. Surgery was not suitable for this patient. He was treated with etoposide 100 mg/m2 and cisplatin 25 mg/m2 on days 1-3, every 3 wk for 4 cycles. The tumor and lymph nodes became smaller and dysphagia and vomiting symptoms improved. The patient could not tolerate subsequent chemotherapy (CT) because of hematological toxicity; therefore, we performed immunotherapy (durvalumab, 1500 mg) every 4 wk. At present the patient has received 12 cycles immunotherapy over about 1 year. He is still receiving treatment and follow-up.
CONCLUSION PSCEC with multiple lymph nodes metastasis does not always indicate surgery. CT may extend survival time and improve the quality of life in the absence of surgery. Immunotherapy or immunotherapy plus CT may also work as a treatment for PSCEC.
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Affiliation(s)
- Yong-Hui Wu
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Kai Zhang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Hui-Guo Chen
- Department of Thoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Wei-Bin Wu
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Jun Li
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Jian Zhang
- Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
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13
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Liu D, Wen J, Chen J, Wang B, Xu X, Zhang Z, Fan M. A Comparative Analysis of the Gene Expression Profiles of Small Cell Esophageal Carcinoma, Small Cell Lung Cancer, and Esophageal Adeno/Squamous Carcinoma. Front Surg 2021; 8:655159. [PMID: 34395507 PMCID: PMC8362887 DOI: 10.3389/fsurg.2021.655159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 06/08/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose/objectives: Primary small cell esophageal carcinoma (SCEC) is a rare malignancy without an established treatment strategy. This study investigated the gene expression profile of SCEC and compared it with the expression profiles of small cell lung cancer (SCLC) and esophageal adeno/squamous carcinoma (EAC/ESCC). Materials/methods: All patients with SCEC, SCLC, and EAC/ESCC in the Surveillance, Epidemiology, and End Results (SEER) database 1973-2014 were included. Overall survival (OS) and prognostic analysis were conducted. De novo expression array analysis was performed on three pairs of frozen primary SCEC tissues and the corresponding normal samples from the institutional tissue bank using the Affymetrix HG U133 plus 2.0 Array. These data were complemented with public domain expression data sets from the Gene Expression Omnibus (GEO) repository using the same working platforms, which included primary SCLC, EAC/ESCC, and normal lung/esophagus specimens (series GSE30219 and GSE26886). After individual normalization, the primary tumors were submitted to statistical analysis (GeneSpring GX 13.0) to identify the differentially expressed genes (DEGs) relative to their paired normal tissues. Enrichments of genes categorized by function and gene interactions were analyzed by DAVID 6.8 and STRING 11.0, respectively. Results: The clinical outcomes of the patients with SCEC were significantly more worse than those with EAC/ESCC and SCLC in the SEER database. SCEC had more DEGs in common with SCLC than EAC/ESCC [829 vs. 450; false discovery rate (FDR) < 0.01; and fold change ≥2], leading to a stronger correlation between SCEC and SCLC (Pearson's correlation coefficient was 0.60 for SCEC vs. SCLC, 0.51 or 0.45 for SCEC vs. ESCC or EAC, and the coefficient was 0.73 for ESCC vs. EAC). Similar findings were obtained by principal component analysis (PCA) using all DEGs retrieved from these four groups. Functional annotation showed that a higher proportion of pathways and biological processes were common between SCEC and SCLC and were associated with the cell cycle (mitosis), DNA replication, telomere maintenance, DNA repair, and P53 and RB pathways (Benjamini p < 0.05). Compared with EAC/ESCC, SCEC shared more co-upregulated DEGs coding for the aforementioned common pathways with SCLC (584 vs. 155). In addition, SCEC and SCLC were found to have possessed overlapping gene-interactive networks, with centromere protein F (CENPF), never in mitosis gene A-related kinase 2 ( NEK2), kinesin family member 11 (KIF11), thymopoietin (TMPO), and forkhead box protein M1 (FOXM1) as common skeletons centered by gene regulatory network (NUF2). Conclusions: This study is the first attempt to examine the genomic signatures of SCEC at the transcriptomic level and compare the expression profiles between SCEC, SCLC, and EAC/ESCC. Our preliminary data indicate that SCEC and SCLC display notably similar patterns of gene expression for mitosis and DNA repair. Further validation studies are warranted.
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Affiliation(s)
- Di Liu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Junmiao Wen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Jiayan Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Boyan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Xinyan Xu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
| | - Min Fan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Radiation Oncology, Shanghai, China
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14
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Xu Y, Zhu K, Chen J, Lin L, Huang Z, Zhang J, Chen Y. SASS6 promotes proliferation of esophageal squamous carcinoma cells by inhibiting the p53 signaling pathway. Carcinogenesis 2021; 42:254-262. [PMID: 32671379 DOI: 10.1093/carcin/bgaa067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 06/21/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
SASS6 encodes for the Homo sapiens SAS-6 centriolar assembly protein and is important for proper centrosome formation. Although centrosomes are amplified in a wide variety of tumor types, abnormally high SASS6 expression had previously only been identified in colon cancer. Moreover, the role of SASS6 in esophageal squamous cell carcinoma (ESCC) pathogenesis has not yet been elucidated. The aim of this study was to investigate the role and mechanisms of SASS6 in ESCC. In this study, we found that the mRNA and protein levels of SASS6 were increased in human ESCC samples. In addition, SASS6 protein expression was associated with the esophageal cancer stage and negatively affected survival of patients with ESCC. Furthermore, silencing of SASS6 inhibited cell growth and promoted apoptosis of ESCC cells in vitro and inhibited xenograft tumor formation in vivo. A genetic cluster and pathway analysis showed that SASS6 regulated the p53 signaling pathway. Western blot demonstrated that CCND2, GADD45A and EIF4EBP1 protein expression decreased and that TP53 protein expression increased after the knockdown of SASS6 in ESCC cells. Therefore, SASS6 promoted the proliferation of esophageal cancer by inhibiting the p53 signaling pathway. SASS6 has potential as a novel tumor marker and a therapeutic target for ESCC.
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Affiliation(s)
- Yuanji Xu
- Department of Radiation Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Kunshou Zhu
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Junqiang Chen
- Department of Radiation Oncology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Liyan Lin
- Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Zhengrong Huang
- Department of Integrative Traditional Chinese and Western Medicine, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Jiulong Zhang
- Department of Thoracic Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Yuanmei Chen
- Department of Thoracic Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China
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15
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Akabane S, Oue N, Sekino Y, Asai R, Thang PQ, Taniyama D, Sentani K, Yukawa M, Toda T, Kimura KI, Egi H, Shimizu W, Ohdan H, Yasui W. KIFC1 regulates ZWINT to promote tumor progression and spheroid formation in colorectal cancer. Pathol Int 2021; 71:441-452. [PMID: 33819373 DOI: 10.1111/pin.13098] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/12/2021] [Indexed: 02/02/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Kinesin Family Member C1 (KIFC1) has been proposed as a promising therapeutic target due to its pivotal role in centrosome clustering to mediate cancer cell progression. This study aimed to analyze the expression and biological function of KIFC1 in CRC. Immunohistochemically, 67 (52%) of 129 CRC cases were positive for KIFC1 and statistically associated with poorer overall survival. KIFC1 small interfering RNA (siRNA)-transfected cells demonstrated lower cell proliferation as compared to the negative control cells. A specific KIFC1 inhibitor, kolavenic acid analog (KAA) drastically inhibited CRC cell proliferation. Microarray analysis revealed that KAA-treated CRC cells presented reduced ZW10 interacting kinetochore protein (ZWINT) expression as compared to control cells. Immunohistochemical analysis demonstrated that 61 (47%) of 129 CRC cases were positive for ZWINT and ZWINT expression was significantly correlated with KIFC1 expression. ZWINT-positive cases exhibited significantly worse overall survival. KIFC1 siRNA-transfected cells showed reduced ZWINT expression while ZWINT siRNA-transfected cells decreased cell proliferation. Both KIFC1 and ZWINT knockdown cells attenuated spheroid formation ability. This study provides new insights into KIFC1 regulating ZWINT in CRC progression and its potential as a therapeutic target.
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Affiliation(s)
- Shintaro Akabane
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naohide Oue
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yohei Sekino
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryuichi Asai
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Pham Quoc Thang
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Taniyama
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuhiro Sentani
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masashi Yukawa
- Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Takashi Toda
- Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan
| | - Ken-Ichi Kimura
- Chemical Biology Laboratory, Graduate School of Arts and Sciences, Iwate University, Iwate, Japan
| | - Hiroyuki Egi
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Wataru Shimizu
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Wataru Yasui
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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16
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Ferreira WAS, Amorim CKN, Burbano RR, Villacis RAR, Marchi FA, Medina TS, Lima MMCD, Oliveira EHCD. Genomic and transcriptomic characterization of the human glioblastoma cell line AHOL1. ACTA ACUST UNITED AC 2021; 54:e9571. [PMID: 33470396 PMCID: PMC7812907 DOI: 10.1590/1414-431x20209571] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 10/26/2020] [Indexed: 01/08/2023]
Abstract
Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its karyotype, copy number alteration (CNA), and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2, and 15q11.1-q11.2 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y, and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.
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Affiliation(s)
- W A S Ferreira
- Laboratório de Cultura de Tecidos e Citogenética, SAMAM, Instituto Evandro Chagas, Ananindeua, PA, Brasil
| | - C K N Amorim
- Laboratório de Cultura de Tecidos e Citogenética, SAMAM, Instituto Evandro Chagas, Ananindeua, PA, Brasil
| | - R R Burbano
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brasil.,Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Belém, PA, Brasil.,Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém, PA, Brasil
| | - R A R Villacis
- Departamento de Genética e Morfologia, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, DF, Brasil
| | - F A Marchi
- Centro Internacional de Pesquisa, A.C. Camargo Cancer Center, São Paulo, SP, Brasil
| | - T S Medina
- Centro Internacional de Pesquisa, A.C. Camargo Cancer Center, São Paulo, SP, Brasil
| | - M M C de Lima
- Instituto de Ciências Biológicas, Faculdade de Biomedicina, Universidade Federal do Pará, Belém, PA, Brasil
| | - E H C de Oliveira
- Laboratório de Cultura de Tecidos e Citogenética, SAMAM, Instituto Evandro Chagas, Ananindeua, PA, Brasil.,Instituto de Ciências Exatas e Naturais, Faculdade de Ciências Naturais, Universidade Federal do Pará, Belém, PA, Brasil
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17
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Yu-jing T, Wen-jing T, Biao T. Integrated Analysis of Hub Genes and Pathways In Esophageal Carcinoma Based on NCBI's Gene Expression Omnibus (GEO) Database: A Bioinformatics Analysis. Med Sci Monit 2020; 26:e923934. [PMID: 32756534 PMCID: PMC7431388 DOI: 10.12659/msm.923934] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 05/21/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Esophageal carcinoma (ESCA) is a health challenge with poor prognosis and limited treatment options. Our aim is to screen for hub genes and pathways associated with ESCA pathology as diagnostic or therapeutic targets. MATERIAL AND METHODS We downloaded 2 ESCA-related datasets from the Gene Expression Omnibus (GEO) database. Subsequently, differentially expressed genes (DEGs) of ESCA were determined by statistical analysis. Both Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs were performed using online analytic tools. Network analysis was employed to construct a protein-protein interaction (PPI) network and to filter hub genes. We evaluated the expression level and impact of hub genes on survival of ESCA patients using the OncoLoc webserver. RESULTS A total of 210 DEGs were identified. The GO analysis showed that the DEGs were enriched in cell division. The KEGG pathway analysis showed DEGs that were enriched in cell cycle regulation, known cancer pathways, the PI3K-Akt signaling pathway, and the cGMP-PKG signaling pathway. The top 10 hub genes were markedly upregulated in ESCA tissue compared with normal esophageal tissue. Moreover, the expression level of the hub genes was different at different pathological stages of ESCA. Further prognostic analysis identified that the top 10 hub genes were related to late survival of ESCA patients, while exhibiting few associations with early survival time. CONCLUSIONS The signaling pathways involving the DEGs probably represent the pathological mechanism underlying ESCA. The hub genes were associated with survival of ESCA patients, and as such have the potential to serve as diagnostic indicators and therapeutic targets.
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18
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Wang N, Wang J, Meng X, Li T, Wang S, Bao Y. The Pharmacological Effects of Spatholobi Caulis Tannin in Cervical Cancer and Its Precise Therapeutic Effect on Related circRNA. Mol Ther Oncolytics 2019; 14:121-129. [PMID: 31194163 PMCID: PMC6551555 DOI: 10.1016/j.omto.2019.04.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 04/30/2019] [Indexed: 12/12/2022] Open
Abstract
The chemical components of Spatholobi Caulis tannin (SCT) have a modest therapeutic effect in patients with cervical cancer. However, the active components and the mechanism of action of SCT in HeLa cervical cancer cells need to be further studied. In this paper, 3D microfluidic chip technology was applied to simulate the effects of tannins in the human body, and the appropriate dose and time of administration were calculated. The cell cycle and apoptosis experiments demonstrated that SCT inhibits proliferation and stimulated apoptosis in HeLa cells. The differentially expressed genes were screened using The Cancer Genome Atlas (TCGA) and the GEO databases to identify common differentially expressed genes. A bioinformatic analysis of relevant genes, analysis using the molecular docking technique, and survival analysis were used to predict the target genes of SCT. Circular RNAs (circRNAs) associated with the SCT target genes and the regulatory effects of SCT on these circRNAs were determined. These studies showed that SCT mediates related circRNAs in HeLa cells to inhibit proliferation and promote apoptosis in HeLa cells. Thus, SCT may be an effective strategy for treating cervical cancer.
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Affiliation(s)
- Nijia Wang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, P.R. China
| | - Jiayi Wang
- Liaoning Institute for Drug Control, Shenyang 110036, P.R. China
| | - Xiansheng Meng
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, P.R. China
- Component Medicine Engineering Research Center of Liaoning Province, Dalian 116600, P.R. China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian 116600, P.R. China
- Liaoning University of Traditional Chinese Medicine-Agilent Technologies Modern TCM and Multi-omics Research Collaboration Laboratory, Dalian 116600, P.R. China
| | - Tianjiao Li
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, P.R. China
- Component Medicine Engineering Research Center of Liaoning Province, Dalian 116600, P.R. China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian 116600, P.R. China
- Liaoning University of Traditional Chinese Medicine-Agilent Technologies Modern TCM and Multi-omics Research Collaboration Laboratory, Dalian 116600, P.R. China
| | - Shuai Wang
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, P.R. China
- Component Medicine Engineering Research Center of Liaoning Province, Dalian 116600, P.R. China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian 116600, P.R. China
- Liaoning University of Traditional Chinese Medicine-Agilent Technologies Modern TCM and Multi-omics Research Collaboration Laboratory, Dalian 116600, P.R. China
| | - Yongrui Bao
- School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, P.R. China
- Component Medicine Engineering Research Center of Liaoning Province, Dalian 116600, P.R. China
- Liaoning Province Modern Chinese Medicine Research Engineering Laboratory, Dalian 116600, P.R. China
- Liaoning University of Traditional Chinese Medicine-Agilent Technologies Modern TCM and Multi-omics Research Collaboration Laboratory, Dalian 116600, P.R. China
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