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Chen D, Huang J, Yang A, Xiong Z. Prognostic and immunological implications of protein kinases in gastric cancer: a focus on hub gene ABL2 and its impact on the polarization of M2 macrophages. Biol Direct 2025; 20:35. [PMID: 40128818 PMCID: PMC11934801 DOI: 10.1186/s13062-025-00636-9] [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: 12/26/2024] [Accepted: 03/16/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Protein kinases are essential cellular signal modulators involved in tumorigenesis, metastasis, immune response, and drug resistance. However, the comprehensive features and clinical significance of protein kinases in gastric cancer (GC) remain inconclusive. METHODS We analyzed the transcriptional profiles of protein kinases in GC patients from the GEO and TCGA databases. Based on differentially expressed kinase genes (DE-KGs), a novel cluster was identified to assess its association with patient survival and the tumor microenvironment (TME) in GC. Subsequently, an optimal DE-KGs-based model (DE-KGsM) was determined using 101 machine-learning algorithm combinations. This model was evaluated using multi-omics data to investigate its associations with patient prognosis, clinical features, tumor microenvironment, tumor-infiltrating immune cells (TIICs), and immunotherapy response. Furthermore, scRNA-seq analysis and TIMER algorithm were applied to determine the correlation between the hub gene (ABL2) in the DE-KGsM and Macrophages. Finally, in vitro experiments were performed to explore the immune-related mechanisms of ABL2 in GC. RESULTS We identified two molecular subtypes of GC patients based on 64 DE-KGs expression. Significant differences were observed in overall survival and TIIC characteristics between Cluster 1 and Cluster 2. Among these 64 DE-KGs, we identified an optimal DE-KGsM that could be a prognostic indicator in GC. TIICs and TIDE analyses exhibited that GC patients in the high-DE-KGsM score group had a higher proportion of M2 macrophages and lower response rates to ICI treatment. scRNA-seq analysis indicated that ABL2 might play an indispensable role in tumor immunity. Furthermore, in vitro experiments demonstrated that ABL2 accelerated the proliferation, migration, and invasion of GC cells, as well as the polarization of M2 macrophages. CONCLUSIONS The DE-KGsM could be a powerful predictor of GC patients' survival and might facilitate the development of personalized therapy. Furthermore, as a hub gene in the DE-KGsM, ABL2 could be an immunological biomarker that modulates the polarization of M2 macrophages, thereby promoting GC progression. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Di Chen
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Ju Huang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
| | - Zhifan Xiong
- Department of Gastroenterology, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077, China.
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Wu YJ, Chiao CC, Chuang PK, Hsieh CB, Ko CY, Ko CC, Chang CF, Chen TY, Nguyen NUN, Hsu CC, Chu TH, Fang CC, Tsai HY, Tsai HC, Anuraga G, Ta HDK, Xuan DTM, Kumar S, Dey S, Wulandari FS, Manalu RT, Ly NP, Wang CY, Lee YK. Comprehensive analysis of bulk and single-cell RNA sequencing data reveals Schlafen-5 (SLFN5) as a novel prognosis and immunity. Int J Med Sci 2024; 21:2348-2364. [PMID: 39310264 PMCID: PMC11413889 DOI: 10.7150/ijms.97975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/13/2024] [Indexed: 09/25/2024] Open
Abstract
Recent advancements have elucidated the multifaceted roles of the Schlafen (SLFN) family, including SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14, which are implicated in immunological responses. However, little is known about the roles of this gene family in relation to malignancy development. The current study aimed to explore the diagnostic and prognostic potential of Schlafen family genes in colorectal adenocarcinoma (COAD) through bioinformatics analysis. Leveraging advanced bioinformatics tools of bulk RNA-sequencing and single-cell sequencing, we conducted in-depth analyses of gene expressions, functional enrichment, and survival patterns of patients with colorectal cancer compared to normal tissue. Among Schlafen family genes, the transcription levels of SLFN5 in COAD tissues were significantly elevated and correlated with poor survival outcomes. Furthermore, SLFN5 regulated the immune response via Janus kinase (JAK)/signal transduction and activator of transcription (STAT)/interferon (IFN)-alpha/beta signaling. These chemokines in inflammation are associated with diabetes and metabolism, suggesting their involvement in altered cellular energetics for COAD progress. In addition, an immune cell deconvolution analysis indicated a correlation between SLFN5 expression and immune-related cell populations, such as regulatory T cells (Tregs). These findings highlighted the potential clinical significance of SLFN5 in COAD and provided insights into its involvement in the tumor microenvironment and immune regulation. Meanwhile, the drug discovery data of SFLN5 with potential targeted small molecules suggested its therapeutic potential for COAD. Collectively, the current research demonstrated that SFLN5 play crucial roles in tumor development and serve as a prospective biomarker for COAD.
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Affiliation(s)
- Yueh-Jung Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Chung-Chieh Chiao
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Po-Kai Chuang
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Chung-Bao Hsieh
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, Taipei 114202, Taiwan
- Division of General Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Chou-Yuan Ko
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Ching-Chung Ko
- Department of Medical Imaging, Chi-Mei Medical Center, Tainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
- School of Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Chuan-Fa Chang
- Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Tung-Yuan Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Ngoc Uyen Nhi Nguyen
- Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas TX 75390, USA
| | - Ching-Cheng Hsu
- Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas TX 75390, USA
| | - Tian-Huei Chu
- Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Cheng-Chieh Fang
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
| | - Hsuan-Yen Tsai
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taiwan
| | - Hsien-Chun Tsai
- Department of Life Sciences, National University of Kaohsiung, Taiwan
| | - Gangga Anuraga
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, East Java, Surabaya 60234, Indonesia
| | - Hoang Dang Khoa Ta
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Do Thi Minh Xuan
- Faculty of Pharmacy, Van Lang University, 69/68 Dang Thuy Tram Street, Ward 13, Binh Thanh District, Ho Chi Minh City 70000, Vietnam
| | - Sachin Kumar
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Faculty of Biotechnology and Applied Sciences, Shoolini University of Biotechnology and Management Sciences, Himachal Pradesh, India
| | - Sanskriti Dey
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Fitria Sari Wulandari
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Rosario Trijuliamos Manalu
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Department of Pharmacy, Faculty of Pharmacy, National Institute of Science and Technology, Jakarta, 12640, Indonesia
| | - Ngoc Phung Ly
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea
| | - Chih-Yang Wang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Yung-Kuo Lee
- Institute of Medical Science and Technology, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan
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Zhang W, Wang S, Zhang H, Meng Y, Jiao S, An L, Zhou Z. Modeling human gastric cancers in immunocompetent mice. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0124. [PMID: 38940675 PMCID: PMC11271222 DOI: 10.20892/j.issn.2095-3941.2024.0124] [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: 04/04/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024] Open
Abstract
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. GC is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.
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Affiliation(s)
- Weihong Zhang
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shilong Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hui Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yan Meng
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liwei An
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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Wang N, Jiang Y, Li M, Wang H, Pan J, Tang Y, Xie S, Xu Y, Li X, Zhou X, Xu P, Lin W, Wang X. Protein Kinase STK24 Promotes Tumor Immune Evasion via the AKT-PD-L1 Axis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304342. [PMID: 38229183 PMCID: PMC10966517 DOI: 10.1002/advs.202304342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 12/27/2023] [Indexed: 01/18/2024]
Abstract
Immunotherapy targeting PD-L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine-threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD-L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN-γ-mediated PD-L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti-PD-1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD-L1/PD-1 signaling and is a promising target for combined immunotherapy.
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Affiliation(s)
- Ning Wang
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Yu Jiang
- Department of Clinical LaboratorySecond Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhouZhejiang310058China
| | - Mengjie Li
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Haofei Wang
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Jie Pan
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Yang Tang
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Shaofang Xie
- Westlake Laboratory of Life Sciences and BiomedicineSchool of Life SciencesWestlake UniversityHangzhouZhejiang310024China
| | - Yunyang Xu
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Xu Li
- Westlake Laboratory of Life Sciences and BiomedicineSchool of Life SciencesWestlake UniversityHangzhouZhejiang310024China
| | - Xuefei Zhou
- Department of PharmacologySchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Pinglong Xu
- Life Sciences InstituteZhejiang UniversityHangzhouZhejiang310058China
| | - Wenlong Lin
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
| | - Xiaojian Wang
- Institute of Immunology and Bone Marrow Transplantation CenterThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang310058China
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Palukuri MV, Patil RS, Marcotte EM. Molecular complex detection in protein interaction networks through reinforcement learning. BMC Bioinformatics 2023; 24:306. [PMID: 37532987 PMCID: PMC10394916 DOI: 10.1186/s12859-023-05425-7] [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: 02/05/2023] [Accepted: 07/20/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Proteins often assemble into higher-order complexes to perform their biological functions. Such protein-protein interactions (PPI) are often experimentally measured for pairs of proteins and summarized in a weighted PPI network, to which community detection algorithms can be applied to define the various higher-order protein complexes. Current methods include unsupervised and supervised approaches, often assuming that protein complexes manifest only as dense subgraphs. Utilizing supervised approaches, the focus is not on how to find them in a network, but only on learning which subgraphs correspond to complexes, currently solved using heuristics. However, learning to walk trajectories on a network to identify protein complexes leads naturally to a reinforcement learning (RL) approach, a strategy not extensively explored for community detection. Here, we develop and evaluate a reinforcement learning pipeline for community detection on weighted protein-protein interaction networks to detect new protein complexes. The algorithm is trained to calculate the value of different subgraphs encountered while walking on the network to reconstruct known complexes. A distributed prediction algorithm then scales the RL pipeline to search for novel protein complexes on large PPI networks. RESULTS The reinforcement learning pipeline is applied to a human PPI network consisting of 8k proteins and 60k PPI, which results in 1,157 protein complexes. The method demonstrated competitive accuracy with improved speed compared to previous algorithms. We highlight protein complexes such as C4orf19, C18orf21, and KIAA1522 which are currently minimally characterized. Additionally, the results suggest TMC04 be a putative additional subunit of the KICSTOR complex and confirm the involvement of C15orf41 in a higher-order complex with HIRA, CDAN1, ASF1A, and by 3D structural modeling. CONCLUSIONS Reinforcement learning offers several distinct advantages for community detection, including scalability and knowledge of the walk trajectories defining those communities. Applied to currently available human protein interaction networks, this method had comparable accuracy with other algorithms and notable savings in computational time, and in turn, led to clear predictions of protein function and interactions for several uncharacterized human proteins.
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Affiliation(s)
- Meghana V Palukuri
- Department of Molecular Biosciences, Center for Systems and Synthetic Biology, University of Texas, Austin, TX, 78712, USA.
- Oden Institute for Computational Engineering and Sciences, University of Texas, Austin, TX, 78712, USA.
| | - Ridhi S Patil
- Department of Biomedical Engineering, University of Texas, Austin, TX, 78712, USA.
| | - Edward M Marcotte
- Department of Molecular Biosciences, Center for Systems and Synthetic Biology, University of Texas, Austin, TX, 78712, USA.
- Oden Institute for Computational Engineering and Sciences, University of Texas, Austin, TX, 78712, USA.
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Mori Y, Nishikawa SG, Fratiloiu AR, Tsutsui M, Kataoka H, Joh T, Johnston RN. Modulation of Reoviral Cytolysis (I): Combination Therapeutics. Viruses 2023; 15:1472. [PMID: 37515160 PMCID: PMC10385176 DOI: 10.3390/v15071472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/30/2023] Open
Abstract
Patients with stage IV gastric cancer suffer from dismal outcomes, a challenge especially in many Asian populations and for which new therapeutic options are needed. To explore this issue, we used oncolytic reovirus in combination with currently used chemotherapeutic drugs (irinotecan, paclitaxel, and docetaxel) for the treatment of gastric and other gastrointestinal cancer cells in vitro and in a mouse model. Cell viability in vitro was quantified by WST-1 assays in human cancer cell lines treated with reovirus and/or chemotherapeutic agents. The expression of reovirus protein and caspase activity was determined by flow cytometry. For in vivo studies, athymic mice received intratumoral injections of reovirus in combination with irinotecan or paclitaxel, after which tumor size was monitored. In contrast to expectations, we found that reoviral oncolysis was only poorly correlated with Ras pathway activation. Even so, the combination of reovirus with chemotherapeutic agents showed synergistic cytopathic effects in vitro, plus enhanced reovirus replication and apoptosis. In vivo experiments showed that reovirus alone can reduce tumor size and that the combination of reovirus with chemotherapeutic agents enhances this effect. Thus, we find that oncolytic reovirus therapy is effective against gastric cancer. Moreover, the combination of reovirus and chemotherapeutic agents synergistically enhanced cytotoxicity in human gastric cancer cell lines in vitro and in vivo. Our data support the use of reovirus in combination with chemotherapy in further clinical trials, and highlight the need for better biomarkers for reoviral oncolytic responsiveness.
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Affiliation(s)
- Yoshinori Mori
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Sandra G Nishikawa
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Andreea R Fratiloiu
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Mio Tsutsui
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Hiromi Kataoka
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Takashi Joh
- Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
| | - Randal N Johnston
- Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
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Qiu J, Xiong J, Jiang L, Wang X, Zhang K, Yu H. Molecular mechanisms involved in regulating protein activity and biological function of MST3. Cell Div 2023; 18:8. [PMID: 37202821 DOI: 10.1186/s13008-023-00090-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/09/2023] [Indexed: 05/20/2023] Open
Abstract
Mammalian sterile 20-like (Ste20-like) protein kinase 3 (MST3) or serine/threonine-protein kinase 24 (STK24) is a serine/threonine protein kinase that belongs to the mammalian STE20-like protein kinase family. MST3 is a pleiotropic protein that plays a critical role in regulating a variety of events, including apoptosis, immune response, metabolism, hypertension, tumor progression, and development of the central nervous system. The MST3-mediated regulation is intricately related to protein activity, post-translational modification, and subcellular location. Here, we review the recent progress on the regulatory mechanisms against MST3 and its-mediated control of disease progression.
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Affiliation(s)
- Jing Qiu
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing, China
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Junzhi Xiong
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Lu Jiang
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xinmin Wang
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Kebin Zhang
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hua Yu
- Clinical Medical Research Center, Xinqiao Hospital, Army Medical University, Chongqing, China.
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Serine/threonine-protein kinase STK24 induces tumorigenesis by regulating the STAT3/VEGFA signaling pathway. J Biol Chem 2023; 299:102961. [PMID: 36720310 PMCID: PMC10011487 DOI: 10.1016/j.jbc.2023.102961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 01/19/2023] [Accepted: 01/23/2023] [Indexed: 01/30/2023] Open
Abstract
Lung cancer is the most common cause of cancer-related death. Although anti-angiogenesis therapy has been effective in the treatment of nonsmall cell lung cancer (NSCLC), drug-resistance is a common challenge. Therefore, there is a need to develop new therapeutic strategies for NSCLC. Serine/threonine-protein kinase 24 (STK24), also known as MST3, belongs to the germinal center kinase III subfamily, and the biological function of STK24 in NSCLC tumorigenesis and tumor angiogenesis is still unclear. In this study, we demonstrated that STK24 was overexpressed in lung cancer tissues compared with normal lung tissues, and lung cancer patients with higher STK24 expression levels had shorter overall survival time. In addition, our in vitro assays using A549 and H226 cell lines revealed that the STK24 expression level of cancer cells was positively correlated with cancer cells proliferation, migration, invasion, and tumor angiogenesis ability; in vivo assays also demonstrated that silencing of STK24 dramatically inhibited tumor progress and tumor angiogenesis. To investigate a mechanism, we revealed that STK24 positively regulated the signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor A (VEGFA) signaling pathway by inhibiting polyubiquitin-proteasomal-mediated degradation of STAT3. Furthermore, we performed in vivo assays in BALB/c nude mice and in vitro assays to show that STK24-regulated tumor angiogenesis depends on STAT3. These findings deepened our understanding of tumor angiogenesis, and the STK24/STAT3/VEGFA signaling pathway might be a novel therapeutic target for NSCLC treatment.
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Xuan DTM, Wu CC, Wang WJ, Hsu HP, Ta HDK, Anuraga G, Chiao CC, Wang CY. Glutamine synthetase regulates the immune microenvironment and cancer development through the inflammatory pathway. Int J Med Sci 2023; 20:35-49. [PMID: 36619229 PMCID: PMC9812810 DOI: 10.7150/ijms.75625] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/03/2022] [Indexed: 12/23/2022] Open
Abstract
Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER+) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER+ breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase (GLUL) might play essential roles in the recurrence of tamoxifen-resistant ER+ patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER+ breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL, which provide new targets for the treatment of tamoxifen-resistant breast cancer patients.
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Affiliation(s)
- Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Chung-Che Wu
- Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan.,Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Jan Wang
- Research Center for Cancer Biology, China Medical University, Taichung 40676, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Hoang Dang Khoa Ta
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, East Java, Surabaya 60234, Indonesia
| | - Chung-Chieh Chiao
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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10
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Lee D, Choi J, Oh HJ, Ham IH, Lee SH, Nomura S, Han SU, Hur H. Molecular and Immune Profiling of Syngeneic Mouse Models Predict Response to Immune Checkpoint Inhibitors in Gastric Cancer. Cancer Res Treat 2023; 55:167-178. [PMID: 35609622 PMCID: PMC9873335 DOI: 10.4143/crt.2022.094] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 05/20/2022] [Indexed: 02/04/2023] Open
Abstract
PURPOSE Appropriate preclinical mouse models are needed to evaluate the response to immunotherapeutic agents. Immunocompetent mouse models have rarely been reported for gastric cancer. Thus, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) in immunocompetent mouse models using various murine gastric cancer cell lines. MATERIALS AND METHODS We constructed subcutaneous syngeneic tumors with murine gastric cancer cell lines, YTN3 and YTN16, in C57BL/6J mice. Mice were intraperitoneally treated with IgG isotype control or an anti-programmed death-ligand 1 (PD-L1) neutralizing antibody. We used immunohistochemistry to evaluate the tumor-infiltrating immune cells of formalin-fixed paraffin-embedded mouse tumor tissues. We compared the protein and RNA expression between YTN3 and YTN16 cell lines using a mouse cytokine array and RNA sequencing. RESULTS The mouse tumors revealed distinct histological and molecular characteristics. YTN16 cells showed upregulation of genes and proteins related to immunosuppression, such as Ccl2 (CCL2) and Csf1 (M-CSF). Macrophages and exhausted T cells were more enriched in YTN16 tumors than in YTN3 tumors. Several YTN3 tumors were completely regressed by the PD-L1 inhibitor, whereas YTN16 tumors were unaffected. Although treatment with a PD-L1 inhibitor increased infiltration of T cells in both the tumors, the proportion of exhausted immune cells did not decrease in the non-responder group. CONCLUSION We confirmed the histological and molecular features of cancer cells with various responses to ICI. Our models can be used in preclinical research on ICI resistance mechanisms to enhance clinical efficacy.
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Affiliation(s)
- Dagyeong Lee
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
- Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, Suwon,
Korea
- Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon,
Korea
| | - Junyong Choi
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
- Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, Suwon,
Korea
- Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon,
Korea
| | - Hye Jeong Oh
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
| | - In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
- Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon,
Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan
| | - Sang-Uk Han
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon,
Korea
- Cancer Biology Graduate Program, Ajou University Graduate School of Medicine, Suwon,
Korea
- Inflamm-Aging Translational Research Center, Ajou University School of Medicine, Suwon,
Korea
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11
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Xuan DTM, Yeh IJ, Su CY, Liu HL, Ta HDK, Anuraga G, Chiao CC, Wang CY, Yen MC. Prognostic and Immune Infiltration Value of Proteasome Assembly Chaperone (PSMG) Family Genes in Lung Adenocarcinoma. Int J Med Sci 2023; 20:87-101. [PMID: 36619227 PMCID: PMC9812804 DOI: 10.7150/ijms.78590] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/19/2022] [Indexed: 12/23/2022] Open
Abstract
The complexity of lung adenocarcinoma (LUAD) including many interacting biological processes makes it difficult to find therapeutic biomarkers for treatment. Previous studies demonstrated that PSMG (proteasome assembly chaperone) family members regulate the degradation of abnormal proteins. However, transcript expressions of this gene family in LUAD still need to be more fully investigated. Therefore, we used a holistic bioinformatics approach to explore PSMG genes involved in LUAD patients by integrating several high-throughput databases and tools including The Cancer Genome Atlas (TCGA), and Kaplan-Meier plotter database. These data demonstrated that PSMG3 and PSMG4 were expressed at significantly higher levels in neoplastic cells than in normal lung tissues. Notably, increased expressions of these proteins were correlated with poor prognoses of lung cancer patients, which probably confirmed their fundamental roles in the staging of LUAD tumors. Meanwhile, it was also indicated that there were positive correlations between PSMG family genes and the immune response, metabolism of ubiquinone, cell cycle regulatory pathways, and heat shock protein 90 (HSP90)/phosphatidylinositol 3-kinase (PI3K)/Wnt signaling. Experimental data also confirmed that the knockdown of PSMG4 in LUAD cell lines decreased cell proliferation and influenced expressions of downstream molecules. Collectively, this study revealed that PSMG family members are novel prognostic biomarkers for LUAD progression, which also provide new therapeutic targets of LUAD patients.
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Affiliation(s)
- Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - I-Jeng Yeh
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Che-Yu Su
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Liang Liu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hoang Dang Khoa Ta
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, East Java, Surabaya 60234, Indonesia
| | - Chung-Chieh Chiao
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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12
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Wang J, Du L, Chen X. Oncolytic virus: A catalyst for the treatment of gastric cancer. Front Oncol 2022; 12:1017692. [PMID: 36505792 PMCID: PMC9731121 DOI: 10.3389/fonc.2022.1017692] [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: 08/12/2022] [Accepted: 11/02/2022] [Indexed: 11/25/2022] Open
Abstract
Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. According to the GLOBOCAN 2020 estimates of incidence and mortality for 36 cancers in 185 countries produced by the International Agency for Research on Cancer (IARC), GC ranks fifth and fourth, respectively, and seriously threatens the survival and health of people all over the world. Therefore, how to effectively treat GC has become an urgent problem for medical personnel and scientific workers at this stage. Due to the unobvious early symptoms and the influence of some adverse factors such as tumor heterogeneity and low immunogenicity, patients with advanced gastric cancer (AGC) cannot benefit significantly from treatments such as radical surgical resection, radiotherapy, chemotherapy, and targeted therapy. As an emerging cancer immunotherapy, oncolytic virotherapies (OVTs) can not only selectively lyse cancer cells, but also induce a systemic antitumor immune response. This unique ability to turn unresponsive 'cold' tumors into responsive 'hot' tumors gives them great potential in GC therapy. This review integrates most experimental studies and clinical trials of various oncolytic viruses (OVs) in the diagnosis and treatment of GC. It also exhaustively introduces the concrete mechanism of invading GC cells and the viral genome composition of adenovirus and herpes simplex virus type 1 (HSV-1). At the end of the article, some prospects are put forward to determine the developmental directions of OVTs for GC in the future.
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Affiliation(s)
- Junqing Wang
- School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Linyong Du
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Xiangjian Chen, ; Linyong Du,
| | - Xiangjian Chen
- School of the 1st Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China,*Correspondence: Xiangjian Chen, ; Linyong Du,
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13
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Ku SC, Liu HL, Su CY, Yeh IJ, Yen MC, Anuraga G, Ta HDK, Chiao CC, Xuan DTM, Prayugo FB, Wang WJ, Wang CY. Comprehensive analysis of prognostic significance of cadherin (CDH) gene family in breast cancer. Aging (Albany NY) 2022; 14:8498-8567. [PMID: 36315446 PMCID: PMC9648792 DOI: 10.18632/aging.204357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 09/23/2022] [Indexed: 11/07/2022]
Abstract
Breast cancer is one of the leading deaths in all kinds of malignancies; therefore, it is important for early detection. At the primary tumor site, tumor cells could take on mesenchymal properties, termed the epithelial-to-mesenchymal transition (EMT). This process is partly regulated by members of the cadherin (CDH) family of genes, and it is an essential step in the formation of metastases. There has been a lot of study of the roles of some of the CDH family genes in cancer; however, a holistic approach examining the roles of distinct CDH family genes in the development of breast cancer remains largely unexplored. In the present study, we used a bioinformatics approach to examine expression profiles of CDH family genes using the Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), cBioPortal, MetaCore, and Tumor IMmune Estimation Resource (TIMER) platforms. We revealed that CDH1/2/4/11/12/13 messenger (m)RNA levels are overexpressed in breast cancer cells compared to normal cells and were correlated with poor prognoses in breast cancer patients’ distant metastasis-free survival. An enrichment analysis showed that high expressions of CDH1/2/4/11/12/13 were significantly correlated with cell adhesion, the extracellular matrix remodeling process, the EMT, WNT/beta-catenin, and interleukin-mediated immune responses. Collectively, CDH1/2/4/11/12/13 are thought to be potential biomarkers for breast cancer progression and metastasis.
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Affiliation(s)
- Su-Chi Ku
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Department of General Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Hsin-Liang Liu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Che-Yu Su
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - I-Jeng Yeh
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Gangga Anuraga
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Department of Statistics, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya 60234, Indonesia
| | - Hoang Dang Khoa Ta
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Chung-Chieh Chiao
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Fidelia Berenice Prayugo
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Jan Wang
- Department of Biological Science and Technology, Research Center for Cancer Biology, China Medical University, Taichung 406040, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 40676, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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14
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Moradi MH, Mahmodi R, Farahani AHK, Karimi MO. Genome-wide evaluation of copy gain and loss variations in three Afghan sheep breeds. Sci Rep 2022; 12:14286. [PMID: 35996004 PMCID: PMC9395407 DOI: 10.1038/s41598-022-18571-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 08/16/2022] [Indexed: 11/23/2022] Open
Abstract
Copy number variation (CNV) is one of the main sources of variation between different individuals that has recently attracted much researcher interest as a major source for heritable variation in complex traits. The aim of this study was to identify CNVs in Afghan indigenous sheep consisting of three Arab, Baluchi, and Gadik breeds using genomic arrays containing 53,862 single nucleotide polymorphism (SNP) markers. Data were analyzed using the Hidden Markov Model (HMM) of PennCNV software. In this study, out of 45 sheep studied, 97.8% (44 animals) have shown CNVs. In total, 411 CNVs were observed for autosomal chromosomes and the entire sequence length of around 144 Mb was identified across the genome. The average number of CNVs per each sheep was 9.13. The identified CNVs for Arab, Baluchi, and Gadik breeds were 306, 62, and 43, respectively. After merging overlapped regions, a total of 376 copy number variation regions (CNVR) were identified, which are 286, 50, and 40 for Arab, Baluchi, and Gadik breeds, respectively. Bioinformatics analysis was performed to identify the genes and QTLs reported in these regions and the biochemical pathways involved by these genes. The results showed that many of these CNVRs overlapped with the genes or QTLs that are associated with various pathways such as immune system development, growth, reproduction, and environmental adaptions. Furthermore, to determine a genome-wide pattern of selection signatures in Afghan sheep breeds, the unbiased estimates of FST was calculated and the results indicated that 37 of the 376 CNVRs (~ 10%) have been also under selection signature, most of those overlapped with the genes influencing production, reproduction and immune system. Finally, the statistical methods used in this study was applied in an external dataset including 96 individuals of the Iranian sheep breed. The results indicated that 20 of the 114 CNVRs (18%) identified in Iranian sheep breed were also identified in our study, most of those overlapped with the genes influencing production, reproduction and immune system. Overall, this is the first attempts to develop the genomic map of loss and gain variation in the genome of Afghan indigenous sheep breeds, and may be important to shed some light on the genomic regions associated with some economically important traits in these breeds.
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Affiliation(s)
- Mohammad Hossein Moradi
- Department of Animal Science, Faculty of Agriculture and Natural Resources, Arak University, Arak, 38156-8-8349, Iran.
| | - Roqiah Mahmodi
- Department of Animal Science, Faculty of Agriculture and Natural Resources, Arak University, Arak, 38156-8-8349, Iran
| | | | - Mohammad Osman Karimi
- Department of Animal Science, Faculty of Agriculture and Natural Resources, Herat University, Herat, Afghanistan
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15
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Fang F, Zhang T, Li Q, Chen X, Jiang F, Shen X. The tumor immune-microenvironment in gastric cancer. TUMORI JOURNAL 2022; 108:541-551. [PMID: 35196917 DOI: 10.1177/03008916211070051] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AIMS AND BACKGROUND The tumor microenvironment significantly influences malignant behavior and progression. Many components are involved in the tumor microenvironment, including extracellular matrix, stromal cells, immune and inflammatory cells, as well as cytokines that promote tumor development with complex interactions through the exchange of molecular information. It is now known that tumor immune escape may be influenced by the tumor microenvironment. The aim of this work is to conduct a review of the tumor immune-microenvironment in gastric cancer. METHODS We review the current knowledge of several immune cells involved in the gastric tumor microenvironment. In addition, a brief description of immunotherapy strategies for gastric cancer is also reviewed. CONCLUSIONS Among immune cell populations, lymphocytes, macrophages, dendritic cells and myeloid-derived suppressor cells are revealed to make the difference in promoting or suppressing gastric tumorigenesis, either directly or indirectly, via regulating the immune responses. Understanding these interactions in detail within the tumor immune-microenvironment will contribute to unraveling new therapeutic targets.
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Affiliation(s)
- Fujin Fang
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Tiantian Zhang
- Department of Clinical Laboratory, The Third People's Hospital of Bengbu, Bengbu, China
| | - Qiong Li
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Xiaowei Chen
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Fei Jiang
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
| | - Xiaobing Shen
- Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, China.,Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, China
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16
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Ma ES, Wang ZX, Zhu MQ, Zhao J. Immune evasion mechanisms and therapeutic strategies in gastric cancer. World J Gastrointest Oncol 2022; 14:216-229. [PMID: 35116112 PMCID: PMC8790417 DOI: 10.4251/wjgo.v14.i1.216] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/22/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality. The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression. Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion. In this review, we systematically summarize the intricate crosstalk between GC cells and immune cells, including tumor-associated macrophages, neutrophils, myeloid-derived suppressor cells, natural killer cells, effector T cells, regulatory T cells, and B cells. We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack. We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies, both alone and in combination with conventional therapies. Anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment. However, the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients. This review provides a comprehensive understanding of the immune evasion mechanisms of GC, and highlights promising immunotherapeutic strategies.
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Affiliation(s)
- En-Si Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Zheng-Xin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Institute of Organ Transplantation, Fudan University, Shanghai 200040, China
| | - Meng-Qi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
- Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
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17
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Xuan DTM, Wu CC, Kao TJ, Ta HDK, Anuraga G, Andriani V, Athoillah M, Chiao CC, Wu YF, Lee KH, Wang CY, Chuang JY. Prognostic and immune infiltration signatures of proteasome 26S subunit, non-ATPase (PSMD) family genes in breast cancer patients. Aging (Albany NY) 2021; 13:24882-24913. [PMID: 34839279 PMCID: PMC8660617 DOI: 10.18632/aging.203722] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022]
Abstract
The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.
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Affiliation(s)
- Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Chung-Che Wu
- Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Division of Neurosurgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Tzu-Jen Kao
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Hoang Dang Khoa Ta
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, Surabaya 60234, East Java, Indonesia
| | - Vivin Andriani
- Department of Biological Science, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya 60234, East Java, Indonesia
| | - Muhammad Athoillah
- Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, Surabaya 60234, East Java, Indonesia
| | - Chung-Chieh Chiao
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Yung-Fu Wu
- Department of Medical Research, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
| | - Kuen-Haur Lee
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Jian-Ying Chuang
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan
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18
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Chen YL, Wang CY, Fang JH, Hsu HP. Serine/threonine-protein kinase 24 is an inhibitor of gastric cancer metastasis through suppressing CDH1 gene and enhancing stemness. Am J Cancer Res 2021; 11:4277-4293. [PMID: 34659887 PMCID: PMC8493374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 07/07/2021] [Indexed: 06/13/2023] Open
Abstract
Gastric cancer patients often present with distant metastasis and advanced stages. Suppressing serine/threonine-protein kinase 24 (STK24, also known as MST3) is known to promote gastric tumorigenesis. Here, we investigated the effects from STK24 on the metastasis of gastric cancer. We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology for genetic knockout of STK24 at the genomic DNA level in human MKN45 and mouse M12 gastric cancer cells. To assess the consequences of STK24 knockdown, western blot, cell migration, and wound healing assays were conducted in vitro. An in vivo mouse model of liver metastasis was established and tested, and bioinformatics analyses were performed. The knockdown of the STK24 gene enhanced cell migration and increased liver metastasis in the mouse model of gastric cancer. STK24-silenced tumors suppressed CD4+ T cells and enhanced the expansion of CD11b+Ly6C+ myeloid-derived suppressor cells (MDSCs) and F4/80+ macrophages in the spleen of the mice. In MKN45 cells, STK24 silencing resulted in downregulation of E-cadherin (gene CDH1, Cadherin-1, or epithelial cadherin). In 38 paired specimens of gastric adenocarcinomas and normal tissues, we examined STK24 and CDH1 expression levels via western blot; a positive correlation between the expression levels of STK24 and CDH1 was found (R2 = 0.5507, P = 9.72 × 10-8). Furthermore, in Oncomine database and Kaplan-Meier plotter analysis, the loss of CDH1, increase in CCL2, and upregulation of CD44 were correlated with poor prognosis of gastric cancer patients. Our results demonstrate that knockdown of STK24 increases cell migration through suppressing CDH1 and enhancing CD44. In experimental model of metastatic gastric cancer in syngeneic inbred mice, STK24 is important for immune suppression through expansion of CD11b+Ly6C+ MDSCs and F4/80+ macrophages. We confirmed that STK24 is an inhibitor of gastric cancer metastasis.
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Affiliation(s)
- Yi-Ling Chen
- Department of Senior Citizen Service Management, Chia Nan University of Pharmacy and ScienceTainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and ScienceTainan, Taiwan
| | - Chih-Yang Wang
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityTaipei, Taiwan
| | - Jung-Hua Fang
- Laboratory Animal Center, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainan, Taiwan
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19
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Kao TJ, Wu CC, Phan NN, Liu YH, Ta HDK, Anuraga G, Wu YF, Lee KH, Chuang JY, Wang CY. Prognoses and genomic analyses of proteasome 26S subunit, ATPase (PSMC) family genes in clinical breast cancer. Aging (Albany NY) 2021; 13:17970. [PMID: 34329194 PMCID: PMC8351721 DOI: 10.18632/aging.203345] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/08/2021] [Indexed: 12/11/2022]
Abstract
Breast cancer is a complex disease, and several processes are involved in its development. Therefore, potential therapeutic targets need to be discovered for these patients. Proteasome 26S subunit, ATPase gene (PSMC) family members are well reported to be involved in protein degradation. However, their roles in breast cancer are still unknown and need to be comprehensively researched. Leveraging publicly available databases, such as cBioPortal and Oncomine, for high-throughput transcriptomic profiling to provide evidence-based targets for breast cancer is a rapid and robust approach. By integrating the aforementioned databases with the Kaplan–Meier plotter database, we investigated potential roles of six PSMC family members in breast cancer at the messenger RNA level and their correlations with patient survival. The present findings showed significantly higher expression profiles of PSMC2, PSMC3, PSMC4, PSMC5, and PSMC6 in breast cancer compared to normal breast tissues. Besides, positive correlations were also revealed between PSMC family genes and ubiquinone metabolism, cell cycle, and cytoskeletal remodeling. Meanwhile, we discovered that high levels of PSMC1, PSMC3, PSMC4, PSMC5, and PSMC6 transcripts were positively correlated with poor survival, which likely shows their importance in breast cancer development. Collectively, PSMC family members have the potential to be novel and essential prognostic biomarkers for breast cancer development.
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Affiliation(s)
- Tzu-Jen Kao
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Chung-Che Wu
- Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Division of Neurosurgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh 700000, Vietnam
| | - Yen-Hsi Liu
- School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
| | - Hoang Dang Khoa Ta
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Gangga Anuraga
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Department of Statistics, Faculty of Science and Technology, PGRI Adi Buana University, Surabaya, East Java 60234, Indonesia
| | - Yung-Fu Wu
- Department of Medical Research, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei 11490, Taiwan
| | - Kuen-Haur Lee
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Jian-Ying Chuang
- The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan.,Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.,Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chih-Yang Wang
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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20
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Identification of Dipeptidyl Peptidase (DPP) Family Genes in Clinical Breast Cancer Patients via an Integrated Bioinformatics Approach. Diagnostics (Basel) 2021; 11:diagnostics11071204. [PMID: 34359286 PMCID: PMC8304478 DOI: 10.3390/diagnostics11071204] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 12/17/2022] Open
Abstract
Breast cancer is a heterogeneous disease involving complex interactions of biological processes; thus, it is important to develop therapeutic biomarkers for treatment. Members of the dipeptidyl peptidase (DPP) family are metalloproteases that specifically cleave dipeptides. This family comprises seven members, including DPP3, DPP4, DPP6, DPP7, DPP8, DPP9, and DPP10; however, information on the involvement of DPPs in breast cancer is lacking in the literature. As such, we aimed to study their roles in this cancerous disease using publicly available databases such as cBioportal, Oncomine, and Kaplan–Meier Plotter. These databases comprise comprehensive high-throughput transcriptomic profiles of breast cancer across multiple datasets. Furthermore, together with investigating the messenger RNA expression levels of these genes, we also aimed to correlate these expression levels with breast cancer patient survival. The results showed that DPP3 and DPP9 had significantly high expression profiles in breast cancer tissues relative to normal breast tissues. High expression levels of DPP3 and DPP4 were associated with poor survival of breast cancer patients, whereas high expression levels of DPP6, DPP7, DPP8, and DPP9 were associated with good prognoses. Additionally, positive correlations were also revealed of DPP family genes with the cell cycle, transforming growth factor (TGF)-beta, kappa-type opioid receptor, and immune response signaling, such as interleukin (IL)-4, IL6, IL-17, tumor necrosis factor (TNF), and interferon (IFN)-alpha/beta. Collectively, DPP family members, especially DPP3, may serve as essential prognostic biomarkers in breast cancer.
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21
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Chen PS, Hsu HP, Phan NN, Yen MC, Chen FW, Liu YW, Lin FP, Feng SY, Cheng TL, Yeh PH, Omar HA, Sun Z, Jiang JZ, Chan YS, Lai MD, Wang CY, Hung JH. CCDC167 as a potential therapeutic target and regulator of cell cycle-related networks in breast cancer. Aging (Albany NY) 2021; 13:4157-4181. [PMID: 33461170 PMCID: PMC7906182 DOI: 10.18632/aging.202382] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
According to cancer statistics reported in 2020, breast cancer constitutes 30% of new cancer cases diagnosed in American women. Histological markers of breast cancer are expressions of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2. Up to 80% of breast cancers are grouped as ER-positive, which implies a crucial role for estrogen in breast cancer development. Therefore, identifying potential therapeutic targets and investigating their downstream pathways and networks are extremely important for drug development in these patients. Through high-throughput technology and bioinformatics screening, we revealed that coiled-coil domain-containing protein 167 (CCDC167) was upregulated in different types of tumors; however, the role of CCDC167 in the development of breast cancer still remains unclear. Integrating many kinds of databases including ONCOMINE, MetaCore, IPA, and Kaplan-Meier Plotter, we found that high expression levels of CCDC167 predicted poor prognoses of breast cancer patients. Knockdown of CCDC167 attenuated aggressive breast cancer growth and proliferation. We also demonstrated that treatment with fluorouracil, carboplatin, paclitaxel, and doxorubicin resulted in decreased expression of CCDC167 and suppressed growth of MCF-7 cells. Collectively, these findings suggest that CCDC167 has high potential as a therapeutic target for breast cancer.
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Affiliation(s)
- Pin-Shern Chen
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh 700000, Vietnam
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China
| | - Feng-Wei Chen
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China
| | - Yu-Wei Liu
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China
| | - Fang-Ping Lin
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China
| | - Sheng-Yao Feng
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China
| | - Tsung-Lin Cheng
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China.,Orthopedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China
| | - Pei-Hsiang Yeh
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China
| | - Hany A Omar
- Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates.,Department of Clinical Sciences, College of Pharmacy, Ajman University, Ajman 23000, United Arab Emirates.,Department of Pharmacology, Faculty of Pharmacy, BeniSuef University, Beni-Suef 62511, Egypt
| | - Zhengda Sun
- Kaiser Permanente, Northern California Regional Laboratories, The Permanente Medical Group, Berkeley, CA 94710, USA
| | - Jia-Zhen Jiang
- Emergency Department, Huashan Hospital North, Fudan University, Shanghai 201508, People's Republic of China
| | - Yi-Shin Chan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, Republic of China
| | - Ming-Derg Lai
- Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, Republic of China
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, Republic of China.,PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan, Republic of China
| | - Jui-Hsiang Hung
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 70101, Taiwan, Republic of China.,Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China
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22
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Wu YH, Yeh IJ, Phan NN, Yen MC, Liu HL, Wang CY, Hsu HP. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection induces dysregulation of immunity: in silico gene expression analysis. Int J Med Sci 2021; 18:1143-1152. [PMID: 33526974 PMCID: PMC7847623 DOI: 10.7150/ijms.52256] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Highly pathogenic coronaviruses (CoVs) induce acute respiratory distress syndrome, and the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused a pandemic since late 2019. The diversity of clinical manifestations after SARS-CoV-2 infection results in great challenges to diagnose CoV disease 2019 (COVID-19). There is a growing body of published research on this topic; however, effective medications are still undergoing a long process of being assessed. In the search for potential genetic targets for this infection, we applied a holistic bioinformatics approach to study alterations of gene signatures between SARS-CoV-2-infected cells and mock-infected controls. Two different kinds of lung epithelial cells, A549 with angiotensin-converting enzyme 2 (ACE2) overexpression and normal human bronchial epithelial (NHBE) cells, were infected with SARS-CoV-2. We performed bioinformatics analyses of RNA-sequencing in this study. Through a Venn diagram, Database for Annotation, Visualization and Integrated Discovery, Gene Ontology, Ingenuity Pathway Analysis, and Gene Set Enrichment Analysis, the pathways and networks were constructed from commonly upregulated genes in SARS-CoV-2-infected lung epithelial cells. Genes associated with immune-related pathways, responses of host cells after intracellular infection, steroid hormone biosynthesis, receptor signaling, and the complement system were enriched. Dysregulation of the immune system and malfunction of interferon contribute to a failure to kill SARS-CoV-2 and exacerbate respiratory distress in severely ill patients. Current findings from this study provide a comprehensive investigation of SARS-CoV-2 infection using high-throughput technology.
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Affiliation(s)
- Yen-Hung Wu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - I-Jeng Yeh
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Liang Liu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chih-Yang Wang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- ✉ Corresponding authors: Chih-Yang Wang (), and Hui-Ping Hsu (). Tel: +886- 2-26972035 ext. 117 (to Chih-Yang Wang), and +886-6-2353535 ext. 5272 (to Hui-Ping Hsu)
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- ✉ Corresponding authors: Chih-Yang Wang (), and Hui-Ping Hsu (). Tel: +886- 2-26972035 ext. 117 (to Chih-Yang Wang), and +886-6-2353535 ext. 5272 (to Hui-Ping Hsu)
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23
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Wang CY, Chao YJ, Chen YL, Wang TW, Phan NN, Hsu HP, Shan YS, Lai MD. Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer. Int J Med Sci 2021; 18:256-269. [PMID: 33390794 PMCID: PMC7738964 DOI: 10.7150/ijms.48123] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 10/28/2020] [Indexed: 02/07/2023] Open
Abstract
Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha (PPARA) and retinoid X receptor (RXR)-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that PPARA and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of PPARA messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of PPARA and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.
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Affiliation(s)
- Chih-Yang Wang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Ying-Jui Chao
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yi-Ling Chen
- Senior Citizen Service Management, Chia-Nan University of Pharmacy and Science, Tainan 71710, Taiwan
| | - Tzu-Wen Wang
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam
| | - Hui-Ping Hsu
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.,Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan
| | - Ming-Derg Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.,Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 70101, Taiwan.,Center for Infectious Diseases and Signaling Research, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
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24
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Wu CC, Ekanem TI, Phan NN, Loan DTT, Hou SY, Lee KH, Wang CY. Gene signatures and prognostic analyses of the Tob/BTG pituitary tumor-transforming gene (PTTG) family in clinical breast cancer patients. Int J Med Sci 2020; 17:3112-3124. [PMID: 33173433 PMCID: PMC7646110 DOI: 10.7150/ijms.49652] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown. Meanwhile, a holistic genetic analysis exploring whether PTTG family members regulate breast cancer progression via the cell cycle as well as the energy metabolism-related network is lacking. To comprehensively understand the messenger RNA expression profiles of PTTG proteins in breast cancer, we herein conducted a high-throughput screening approach by integrating information from various databases such as Oncomine, Kaplan-Meier Plotter, Metacore, ClueGo, and CluePedia. These useful databases and tools provide expression profiles and functional analyses. The present findings revealed that PTTG1 and PTTG3 are two important genes with high expressions in breast cancer relative to normal breast cells, implying their unique roles in breast cancer progression. Results of our coexpression analysis demonstrated that PTTG family genes were positively correlated with thiamine triphosphate (TTP), deoxycytidine triphosphate (dCTP) metabolic, glycolysis, gluconeogenesis, and cell-cycle related pathways. Meanwhile, through Cytoscape analyzed indicated that in addition to the metastasis markers AURKA, AURKB, and NDC80, many of the kinesin superfamily (KIF) members including KIFC1, KIF2C, KIF4A, KIF14, KIF20A, KIF23, were also correlated with PTTG family transcript expression. Finally, we revealed that high levels of PTTG1 and PTTG3 transcription predicted poor survival, which provided useful insights into prospective research of cancer associated with the PTTG family. Therefore, these members of the PTTG family would serve as distinct and essential prognostic biomarkers in breast cancer.
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Affiliation(s)
- Chung-Che Wu
- Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Titus Ime Ekanem
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Department of Hematology, University of Uyo, Uyo 520221, Nigeria
| | - Nam Nhut Phan
- NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam
| | - Do Thi Thuy Loan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Sz-Ying Hou
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Kuen-Haur Lee
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.,Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei 11031, Taiwan
| | - Chih-Yang Wang
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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