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Wang X, Zeng J, Liu S, Qi F, Xin C, Li X, Gao Y, Fan D, Qu Y, Ren Z, Liu J, Xue R, Chen H, Zhang Y, Ha J, Su X, Wang J. Targeted degradation of DDR1 by proteolytic targeting chimera reverses immune exclusion for tumor immunotherapy. Eur J Med Chem 2025; 294:117750. [PMID: 40382838 DOI: 10.1016/j.ejmech.2025.117750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 05/07/2025] [Accepted: 05/08/2025] [Indexed: 05/20/2025]
Abstract
The formation of immune exclusion microenvironment restricts the infiltration of immune cells into the core of tumors. The extracellular domain of the discoidin domain receptor tyrosine kinase 1 (DDR1) protein plays a pivotal role in this process by aligning collagen fibers to remodel the extracellular matrix (ECM), thereby excluding immune cells. Targeted degradation of DDR1 represents a promising approach to suppress the catalytic functions of the protein and remodel the extracellular matrix of DDR1-related tumors. Here, we report the discovery of a selective DDR1 degrader (DP 1), using the proteolysis targeting chimera (PROTAC) approach. Compound DP 1 exhibited potent DDR1 degradation ability with DC50 values reaching nanomolar range across various cell lines. The degradation of DDR1 effectively blocked the downstream signaling pathways, leading to further inhibition of tumor cell migration and invasion. More importantly, the in vivo studies highlighted the therapeutic potential of DDR1 degradation, indicated by the administration of DP 1 could facilitate the infiltration of immune cells into the tumor core which was associated with enhanced tumor apoptosis. In summary, we report a novel DDR1-targeting degrader with efficacious anti-tumor activity and excellent safety profile. Our studies offer a new perspective for cancer immunotherapy by targeting the immune-exclusion microenvironment.
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Affiliation(s)
- Xiaoyu Wang
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Jiangmeng Zeng
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Shilin Liu
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Fei Qi
- TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China
| | - Chao Xin
- TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China
| | - Xinyu Li
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Yan Gao
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Dan Fan
- TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China
| | - Yuxuan Qu
- TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China
| | - Zhiyi Ren
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Jinzhi Liu
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Ruoyu Xue
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Hongwei Chen
- The First Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Yong Zhang
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Jing Ha
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Xiangdong Su
- TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China.
| | - Jinxu Wang
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China; TPD Pharmaceutical Technology (SJZ) Co., Ltd., Shijiazhuang, 050035, China.
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Maharati A, Rajabloo Y, Moghbeli M. Molecular mechanisms of mTOR-mediated cisplatin response in tumor cells. Heliyon 2025; 11:e41483. [PMID: 39834411 PMCID: PMC11743095 DOI: 10.1016/j.heliyon.2024.e41483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/22/2025] Open
Abstract
Cisplatin (CDDP) is one of the main chemotherapeutic drugs that is widely used in many cancers. However, CDDP resistance is a frequent therapeutic challenge that reduces prognosis in cancer patients. Since, CDDP has noticeable side effects in normal tissues and organs, it is necessary to assess the molecular mechanisms associated with CDDP resistance to improve the therapeutic methods in cancer patients. Drug efflux, detoxifying systems, DNA repair mechanisms, and drug-induced apoptosis are involved in multidrug resistance in CDDP-resistant tumor cells. Mammalian target of rapamycin (mTOR), as a serine/threonine kinase has a pivotal role in various cellular mechanisms such as autophagy, metabolism, drug efflux, and cell proliferation. Although, mTOR is mainly activated by PI3K/AKT pathway, it can also be regulated by many other signaling pathways. PI3K/Akt/mTOR axis functions as a key modulator of drug resistance and unfavorable prognosis in different cancers. Regarding, the pivotal role of mTOR in CDDP response, in the present review we discussed the molecular mechanisms that regulate mTOR mediated CDDP response in tumor cells.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yasamin Rajabloo
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Zhang F, Li W, Zheng X, Ren Y, Li L, Yin H. The novel immune landscape of immune-checkpoint blockade in EBV-associated malignancies. FASEB J 2024; 38:e70139. [PMID: 39520274 DOI: 10.1096/fj.202301980rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 09/15/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
The Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus and a class 1 carcinogen that is closely associated with a series of malignant lymphomas and epithelial cell carcinomas. Although these EBV-related cancers may exhibit different features in clinical symptoms and anatomical sites, they all have a characteristic immune-suppressed tumor immune microenvironment (TIME) that is tightly correlated with an abundance of tumor-infiltrating lymphocytes (TILs) that primarily result from the EBV infection. Overwhelming evidence indicates that an upregulation of immune-checkpoint molecules is a powerful strategy employed by the EBV to escape immune surveillance. While previous studies have mainly focused on the therapeutic effects of PD-1 and CTLA-4 blockades in treating EBV-associated tumors, several novel inhibitory receptors (e.g., CD47, LAG-3, TIM-3, VISTA, and DDR1) have recently been identified as potential targets for treating EBV-associated malignancies (EBVaMs). This review retrospectively summarizes the biological mechanisms used for immune checkpoint evasion in EBV-associated tumors. Its purpose is to update our current knowledge concerning the underlying mechanisms by which an immune checkpoint blockade triggers host antitumor immunity against EBVaMs. Additionally, this review may help investigators to more fully understand the correlation between EBV infection and tumor development and subsequently develop novel therapeutic strategies.
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Affiliation(s)
- Feng Zhang
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Wenjing Li
- The First Class Ward 2 of the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xinglong Zheng
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yinlong Ren
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Lijun Li
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Haiyan Yin
- Department of Intensive Care Unit, the First Affiliated Hospital of Jinan University, Guangzhou, China
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Bezrookove V, Khan I, Bhattacharjee A, Fan J, Jones R, Sharma A, Nosrati M, Desprez PY, Salomonis N, Shi Y, Dar A, Kashani-Sabet M. miR-876-3p is a tumor suppressor on 9p21 that is inactivated in melanoma and targets ERK. J Transl Med 2024; 22:758. [PMID: 39138582 PMCID: PMC11321151 DOI: 10.1186/s12967-024-05527-7] [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: 06/04/2024] [Accepted: 07/20/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND While melanomas commonly harbor losses of 9p21, on which CDKN2A resides, the presence of additional tumor suppressor elements at this locus is incompletely characterized. Here we assess the expression levels and functional role of microRNA-876-3p (miR-876), whose gene also maps to 9p21. METHODS Expression of miR-876 was assessed in human tissues and cell lines using quantitative miRNA reverse transcriptase polymerase chain reaction (qRT-PCR). MIR876 copy number was determined in The Cancer Genome Atlas (TCGA) melanoma cohort. The consequences of regulation of miR-876 expression were assessed on melanoma cell colony formation, migration, invasion, apoptosis, cell cycle progression, and drug sensitivity in culture, and on in vivo tumor growth in a xenograft model. Genome-wide transcriptomic changes induced by miR-876 overexpression were determined using RNA sequencing (RNA-Seq). RESULTS miR-876 expression was significantly decreased in primary melanoma samples when compared with nevi, and in human melanoma cell lines when compared with human melanocytes. Analysis of the TCGA cohort revealed deletions in MIR876 in > 50% of melanomas. miR-876 overexpression resulted in decreased melanoma cell colony formation, migration, and invasion, which was accompanied by cell cycle arrest and increased apoptosis. Intra-tumoral injections of miR-876 significantly suppressed melanoma growth in vivo. RNA-Seq analysis of miR-876-treated tumors revealed downregulation of several growth-promoting genes, along with upregulation of tumor suppressor genes, which was confirmed by qRT-PCR analysis. Computational analyses identified MAPK1 (or ERK2) as a possible target of miR-876 action. Overexpression of miR-876 significantly suppressed luciferase expression driven by the MAPK1/ERK2 3' UTR, and resulted in decreased ERK protein expression in melanoma cells. MAPK1/ERK2 cDNA overexpression rescued the effects of miR-876 on melanoma colony formation. miR-876 overexpression sensitized melanoma cells to treatment with the BRAF inhibitor vemurafenib. CONCLUSIONS These studies identify miR-876 as a distinct tumor suppressor on 9p21 that is inactivated in melanoma and suggest miR-876 loss as an additional mechanism to activate ERK and the mitogen activated protein kinase (MAPK) pathway in melanoma. In addition, they suggest the therapeutic potential of combining miR-876 overexpression with BRAF inhibition as a rational therapeutic strategy for melanoma.
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Affiliation(s)
- Vladimir Bezrookove
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
- Center for Melanoma Research and Treatment, CPMC, San Francisco, CA, USA
| | - Imran Khan
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
- Center for Melanoma Research and Treatment, CPMC, San Francisco, CA, USA
| | - Anukana Bhattacharjee
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Juifang Fan
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Robyn Jones
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Anima Sharma
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Mehdi Nosrati
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
- Center for Melanoma Research and Treatment, CPMC, San Francisco, CA, USA
| | - Pierre-Yves Desprez
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Nathan Salomonis
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Yihui Shi
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Altaf Dar
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA
| | - Mohammed Kashani-Sabet
- California Pacific Medical Center (CPMC) Research Institute, 475 Brannan St., Suite 130, San Francisco, CA, 94107, USA.
- Center for Melanoma Research and Treatment, CPMC, San Francisco, CA, USA.
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Lai W, Wang Y, Huang C, Xu H, Zheng X, Li K, Wang J, Lou Z. DIREN mitigates DSS-induced colitis in mice and attenuates collagen deposition via inhibiting the Wnt/β-catenin and focal adhesion pathways. Biomed Pharmacother 2024; 175:116671. [PMID: 38678963 DOI: 10.1016/j.biopha.2024.116671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/01/2024] Open
Abstract
BACKGROUND DIREN is a SHE ethnic medicine with stasis-resolving, hemostasis, clearing heat, and removing toxin effects. It is clinically used in the treatment of gastrointestinal bleeding, such as ulcerative colitis (UC). AIM OF THE STUDY Fibrosis is one of the pathological changes in the progression of UC, which can make it challenging to respond to a treatment. We aimed to illuminate the role of DIREN in DSS-induced UC and tried to unveil its related mechanisms from two perspectives: intestinal inflammation and collagen deposition. MATERIALS AND METHODS A 2.5 % dextran sulfate sodium (DSS) water solution was used to induce colitis in mice. The therapeutic effect of DIREN was assessed using the disease activity index, histopathological score, and colon length. Masson and Sirius Red staining was used to observe the fibrosis in the colon. Apoptosis of colonic epithelial cells was observed by TUNEL immunofluorescence staining. RNA-seq observed differential genes and enrichment pathways. Immunohistochemistry and RT-qPCR were used to detect the expression of molecules related to fibrosis and focal adhesion signaling in colon tissue. RESULTS The administration of DIREN resulted in a reduction of disease activity index (DAI) in mice with UC while simultaneously promoting an increase in colon length. DIREN mitigated the loss of goblet cells in the colon of UC mice and maintained the integrity of the intestinal mucosa barrier. Masson staining revealed a reduction in colonic fibrosis with DIREN treatment, while Sirius red staining demonstrated a decrease in collagen Ⅰ deposition. DIREN reduced apoptosis of colonic epithelial cells and the expression of genes, such as CDH2, ITGA1, and TGF-β2. Additionally, the results of GSEA analysis of colon tissue transcriptome showed that the differentially expressed genes were enriched in the focal adhesion pathway. DIREN was found to downregulate the protein expression of BAX, N-cadherin, β-catenin, Integrin A1, and Vinculin while upregulating the protein expression of BCL2. Additionally, it led to the co-expression of N-cadherin and α-SMA. CONCLUSION DIREN exerts a protective effect against DSS-induced UC by ameliorating colonic fibrosis via regulation of focal adhesion and the WNT/β-catenin signaling pathway, thereby inhibiting fibroblast migration and reducing collagen secretion.
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Affiliation(s)
- Weizhi Lai
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yingying Wang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Chen Huang
- The First School of Clinical Medical, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Hao Xu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Xunjie Zheng
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Ke Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Jue Wang
- Department of Oncology, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, China
| | - Zhaohuan Lou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Songyang Institute of Zhejiang Chinese Medical University, Lishui, Zhejiang 323400, China.
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Liu M, Zhang J, Li X, Wang Y. Research progress of DDR1 inhibitors in the treatment of multiple human diseases. Eur J Med Chem 2024; 268:116291. [PMID: 38452728 DOI: 10.1016/j.ejmech.2024.116291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 02/25/2024] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.
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Affiliation(s)
- Mengying Liu
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Neuro-system and Multimorbidity Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China
| | - Jifa Zhang
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Neuro-system and Multimorbidity Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China
| | - Xiaoxue Li
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yuxi Wang
- Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, Neuro-system and Multimorbidity Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, Sichuan, China.
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Aranda S, Muntané G, Vilella E. Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder. Transl Psychiatry 2024; 14:112. [PMID: 38395959 PMCID: PMC10891045 DOI: 10.1038/s41398-024-02823-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/08/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.
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Affiliation(s)
- Selena Aranda
- Institut d'Investigació Sanitària Pere Virgili-CERCA, Reus, Spain
- Hospital Universitari Institut Pere Mata, Reus, Spain
- Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM)-Instituto de Salud Carlos III, Madrid, Spain
| | - Gerard Muntané
- Institut d'Investigació Sanitària Pere Virgili-CERCA, Reus, Spain
- Hospital Universitari Institut Pere Mata, Reus, Spain
- Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM)-Instituto de Salud Carlos III, Madrid, Spain
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
| | - Elisabet Vilella
- Institut d'Investigació Sanitària Pere Virgili-CERCA, Reus, Spain.
- Hospital Universitari Institut Pere Mata, Reus, Spain.
- Universitat Rovira i Virgili, Reus, Spain.
- Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM)-Instituto de Salud Carlos III, Madrid, Spain.
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Maitz K, Valadez-Cosmes P, Raftopoulou S, Kindler O, Kienzl M, Bolouri H, Houghton AM, Schicho R, Heinemann A, Kargl J. Altered Treg Infiltration after Discoidin Domain Receptor 1 (DDR1) Inhibition and Knockout Promotes Tumor Growth in Lung Adenocarcinoma. Cancers (Basel) 2023; 15:5767. [PMID: 38136314 PMCID: PMC10742023 DOI: 10.3390/cancers15245767] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/20/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, has been associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). However, its role in tumorigenesis remains poorly understood. This work aimed to explore the impact of DDR1 expression on immune cell infiltration in lung adenocarcinoma. Pharmacological inhibition and knockout of DDR1 were used in an immunocompetent mouse model of KRAS/p53-driven lung adenocarcinoma (LUAD). Tumor cells were engrafted subcutaneously, after which tumors were harvested for investigation of immune cell composition via flow cytometry. The Cancer Genome Atlas (TCGA) cohort was used to perform gene expression analysis of 509 patients with LUAD. Pharmacological inhibition and knockout of DDR1 increased the tumor burden, with DDR1 knockout tumors showing a decrease in CD8+ cytotoxic T cells and an increase in CD4+ helper T cells and regulatory T cells. TCGA analysis revealed that low-DDR1-expressing tumors showed higher FoxP3 (regulatory T-cell marker) expression than high-DDR1-expressing tumors. Our study showed that under certain conditions, the inhibition of DDR1, a potential therapeutic target in cancer treatment, might have negative effects, such as inducing a pro-tumorigenic tumor microenvironment. As such, further investigations are necessary.
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Affiliation(s)
- Kathrin Maitz
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Paulina Valadez-Cosmes
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Sofia Raftopoulou
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Oliver Kindler
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Melanie Kienzl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
| | - Hamid Bolouri
- Center for Systems Immunology, Benaroya Research Center, Seattle, WA 98101, USA
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - A. McGarry Houghton
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98195, USA
| | - Rudolf Schicho
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
- BioTechMed, 8010 Graz, Austria
| | - Akos Heinemann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
- BioTechMed, 8010 Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, 8010 Graz, Austria
- BioTechMed, 8010 Graz, Austria
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Mariadoss AVA, Wang CZ. Exploring the Cellular and Molecular Mechanism of Discoidin Domain Receptors (DDR1 and DDR2) in Bone Formation, Regeneration, and Its Associated Disease Conditions. Int J Mol Sci 2023; 24:14895. [PMID: 37834343 PMCID: PMC10573612 DOI: 10.3390/ijms241914895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/01/2023] [Accepted: 10/02/2023] [Indexed: 10/15/2023] Open
Abstract
The tyrosine kinase family receptor of discoidin domain receptors (DDR1 and DDR2) is known to be activated by extracellular matrix collagen catalytic binding protein receptors. They play a remarkable role in cell proliferation, differentiation, migration, and cell survival. DDR1 of the DDR family regulates matrix-metalloproteinase, which causes extracellular matrix (ECM) remodeling and reconstruction during unbalanced homeostasis. Collagenous-rich DDR1 triggers the ECM of cartilage to regenerate the cartilage tissue in osteoarthritis (OA) and temporomandibular disorder (TMD). Moreover, DDR2 is prominently present in the fibroblasts, smooth muscle cells, myofibroblasts, and chondrocytes. It is crucial in generating and breaking collagen vital cellular activities like proliferation, differentiation, and adhesion mechanisms. However, the deficiency of DDR1 rather than DDR2 was detrimental in cases of OA and TMDs. DDR1 stimulated the ECM cartilage and improved bone regeneration. Based on the above information, we made an effort to outline the advancement of the utmost promising DDR1 and DDR2 regulation in bone and cartilage, also summarizing their structural, biological activity, and selectivity.
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Affiliation(s)
| | - Chau-Zen Wang
- Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Regeneration Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 912301, Taiwan
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10
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Yang L, Zhang Y, Tang Y, Wang Y, Jiang P, Liu F, Feng N. A pan-cancer analysis of DDR1 in prognostic signature and tumor immunity, drug resistance. Sci Rep 2023; 13:5779. [PMID: 37031216 PMCID: PMC10082773 DOI: 10.1038/s41598-023-27975-9] [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: 11/04/2022] [Accepted: 01/11/2023] [Indexed: 04/10/2023] Open
Abstract
Disk-like domain receptor 1 (DDR1) is a crucial regulator of pro-inflammatory mediators and matrix-degrading enzymes. Although mounting evidence supports a vital role for DDR1 in the tumorigenesis of some cancers, no pan-cancer analysis of DDR1 has been reported. Therefore, we aimed to explore the prognostic value of DDR1 in 33 cancer types and investigate its potential immune function. We used a range of bioinformatics approaches to explore the potential carcinogenic role of DDR1 in multiple cancers. We found that DDR1 was expressed at high levels in most cancers. DDR1 expression was positively or negatively associated with prognosis in different cancers. DDR1 expression was significantly associated with DNA methylation in 8 cancers, while there was a correlation between DDR1 expression and RNA methylation-related genes and mismatch repair gene in most cancers. Furthermore, DDR1 expression was significantly associated with microsatellite instability in 6 cancers and tumor mutation burden in 11 cancers. In addition, DDR1 expression was also significantly correlated with immune cell infiltration, tumor microenvironment, immune-related genes, and drug resistance in various cancers. In conclusion, DDR1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.
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Affiliation(s)
- Longfei Yang
- Medical School of Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China
| | - Yuwei Zhang
- Medical School of Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China
| | - Yifan Tang
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China
| | - Yang Wang
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China
| | - Peng Jiang
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China
| | - Fengping Liu
- Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214028, Jiangsu, China.
| | - Ninghan Feng
- Medical School of Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China.
- Department of Urology, Affiliated Wuxi No. 2 Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu, China.
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Rahim NS, Wu YS, Sim MS, Velaga A, Bonam SR, Gopinath SCB, Subramaniyan V, Choy KW, Teow SY, Fareez IM, Samudi C, Sekaran SD, Sekar M, Guad RM. Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance. Pharmaceuticals (Basel) 2023; 16:110. [PMID: 36678607 PMCID: PMC9867095 DOI: 10.3390/ph16010110] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/15/2022] [Accepted: 01/03/2023] [Indexed: 01/13/2023] Open
Abstract
There are six members of the transmembrane 4 superfamily (TM4SF) that have similar topology and sequence homology. Physiologically, they regulate tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis. Accumulating evidence has demonstrated, among six TM4SF members, the regulatory roles of transmembrane 4 L6 domain family members, particularly TM4SF1, TM4SF4, and TM4SF5, in cancer angiogenesis, progression, and chemoresistance. Hence, targeting derailed TM4SF for cancer therapy has become an emerging research area. As compared to others, this review aimed to present a focused insight and update on the biological roles of TM4SF1, TM4SF4, and TM4SF5 in the progression, metastasis, and chemoresistance of various cancers. Additionally, the mechanistic pathways, diagnostic and prognostic values, and the potential and efficacy of current anti-TM4SF antibody treatment were also deciphered. It also recommended the exploration of other interactive molecules to be implicated in cancer progression and chemoresistance, as well as potential therapeutic agents targeting TM4SF as future perspectives. Generally, these three TM4SF members interact with different integrins and receptors to significantly induce intracellular signaling and regulate the proliferation, migration, and invasion of cancer cells. Intriguingly, gene silencing or anti-TM4SF antibody could reverse their regulatory roles deciphered in different preclinical models. They also have prognostic and diagnostic value as their high expression was detected in clinical tissues and cells of various cancers. Hence, TM4SF1, TM4SF4, and TM4SF5 are promising therapeutic targets for different cancer types preclinically and deserve further investigation.
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Affiliation(s)
- Nur Syafiqah Rahim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
- Department of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, Perlis Branch, Arau Campus, Arau 02600, Malaysia
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Selangor Branch, Puncak Alam Campus, Bandar Puncak Alam 42300, Malaysia
| | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Petaling Jaya 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Petaling Jaya 47500, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Appalaraju Velaga
- Department of Medicinal Chemistry, Faculty of Pharmacy, MAHSA University, Jenjarom 42610, Malaysia
| | - Srinivasa Reddy Bonam
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA
| | - Subash C. B. Gopinath
- Faculty of Chemical Engineering & Technology, Universiti Malaysia Perlis (UniMAP), Arau 02600, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis (UniMAP), Kangar 01000, Malaysia
- Micro System Technology, Centre of Excellence (CoE), Universiti Malaysia Perlis (UniMAP), Pauh Campus, Arau 02600, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Jenjarom 42610, Malaysia
| | - Ker Woon Choy
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh 47000, Malaysia
| | - Sin-Yeang Teow
- Department of Biology, College of Science and Technology, Wenzhou-Kean University, 88 Daxue Road, Quhai, Wenzhou 325060, China
| | - Ismail M. Fareez
- Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM), Selangor Branch, Puncak Alam Campus, Bandar Puncak Alam 42300, Malaysia
- School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, Selangor Branch, Shah Alam Campus, 40450 Shah Alam, Malaysia
| | - Chandramathi Samudi
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Shamala Devi Sekaran
- Faculty of Medical and Health Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia
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12
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Wang J, Xie SA, Li N, Zhang T, Yao W, Zhao H, Pang W, Han L, Liu J, Zhou J. Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis. Bioact Mater 2022; 17:406-424. [PMID: 35386458 PMCID: PMC8964982 DOI: 10.1016/j.bioactmat.2022.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/16/2021] [Accepted: 01/06/2022] [Indexed: 11/16/2022] Open
Abstract
Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.
DDR1 is a mechanosensor in vSMC to perceive ECM stiffness in a collagen binding-independent way. Activation of DDR1 leads to repression of DNMT1 expression via the ERK-p53 pathway. The DDR1-DNMT1 axis mediates ECM stiffening-induced vascular inflammation.
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Affiliation(s)
- Jin Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, PR China
| | - Si-an Xie
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, PR China
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, PR China
| | - Ning Li
- Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory), And Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, PR China
- School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing, PR China
| | - Tao Zhang
- Department of Vascular Surgery, Peking University People's Hospital, Beijing, PR China
| | - Weijuan Yao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
| | - Hucheng Zhao
- Institute of Biomechanics and Medical Engineering, School of Aerospace Engineering, Tsinghua University, Beijing, PR China
| | - Wei Pang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
| | - Lili Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
| | - Jiayu Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, PR China
| | - Jing Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
- National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, PR China
- Corresponding author. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Hemorheology Center, School of Basic Medical Sciences, Peking University, Beijing, PR China.
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13
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Borza CM, Bolas G, Pozzi A. Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease. Front Pharmacol 2022; 13:1001122. [PMID: 36249782 PMCID: PMC9554349 DOI: 10.3389/fphar.2022.1001122] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Following injury the kidney undergoes a repair process, which results in replacement of the injured tissue with little evidence of damage. However, repetitive injuries or inability of the kidney to stop the repair process result in abnormal deposition of extracellular matrix (ECM) components leading to fibrosis and organ dysfunction. The synthesis/degradation of ECM components is finely regulated by several factors, including discoidin domain receptors (DDRs). These are receptor tyrosine kinases that are activated by collagens. Upon activation, DDRs control several cell functions that, when exacerbated, contribute to kidney injury and fibrosis. DDRs are undetectable in healthy kidney, but become rapidly upregulated in several kidney fibrotic conditions, thus making them attractive anti-fibrotic targets. DDRs contribute to kidney injury and fibrosis by promoting apoptosis of injured kidney cells, stimulating the production of pro-inflammatory cytokines, and regulating the production of ECM components. They achieve these effects by activating canonical intracellular molecules or by directly interacting with nuclear chromatin and promoting the transcription of pro-fibrotic genes. The goal of this review is to highlight canonical and non-canonical mechanisms whereby DDRs contribute to kidney injury/fibrosis. This review will summarize key findings obtained using cells and mice lacking DDRs and it will discuss the discovery and development of targeted DDR small molecule- and antisense-based inhibitors. Understanding the molecular mechanisms whereby DDRs control kidney injury and fibrosis might enable us to not only develop more selective and potent inhibitors, but to also determine when DDR inhibition needs to be achieved to prevent and/or halt the development of kidney fibrosis.
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Affiliation(s)
- Corina M. Borza
- Department of Medicine (Division of Nephrology), Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Gema Bolas
- Department of Medicine (Division of Nephrology), Vanderbilt University School of Medicine, Nashville, TN, United States
| | - Ambra Pozzi
- Department of Medicine (Division of Nephrology), Vanderbilt University School of Medicine, Nashville, TN, United States
- Veterans Affairs Hospitals, Nashville, TN, United States
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14
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Ko S, Jung KH, Yoon YC, Han BS, Park MS, Lee YJ, Kim SE, Cho YJ, Lee P, Lim JH, Ryu JK, Kim K, Kim TY, Hong S, Lee SH, Hong SS. A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer. Am J Cancer Res 2022; 12:4326-4342. [PMID: 36225647 PMCID: PMC9548003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/04/2022] [Indexed: 06/16/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity. In this study, we developed a novel DDR1 inhibitor, KI-301690 and investigated whether it could improve the anticancer activity of gemcitabine, a cytotoxic agent widely used for the treatment of pancreatic cancer. KI-301690 synergized with gemcitabine to suppress the growth of pancreatic cancer cells. Importantly, its combination significantly attenuated the expression of major tumor ECM components including collagen, fibronectin, and vimentin compared to gemcitabine alone. Additionally, this combination effectively decreased mitochondrial membrane potential (MMP), thereby inducing apoptosis. Further, the combination synergistically inhibited cell migration and invasion. The enhanced anticancer efficacy of the co-treatment could be explained by the inhibition of DDR1/PYK2/FAK signaling, which significantly reduced tumor growth in a pancreatic xenograft model. Our results demonstrate that KI-301690 can inhibit aberrant ECM expression by DDR1/PYK2/FAK signaling pathway blockade and attenuation of ECM-induced chemoresistance observed in desmoplastic pancreatic tumors, resulting in enhanced antitumor effect through effective induction of gemcitabine apoptosis.
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Affiliation(s)
- Soyeon Ko
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Kyung Hee Jung
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Young-Chan Yoon
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Beom Seok Han
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Min Seok Park
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Yun Ji Lee
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Sang Eun Kim
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Ye Jin Cho
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Pureunchowon Lee
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Joo Han Lim
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Ji-Kan Ryu
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
| | - Kewon Kim
- Center for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST)Daejeon 34141, Korea
| | - Tae Young Kim
- Chemical Kinomics Research Center, Korea Institute of Science and TechnologySeoul 02792, Korea
| | - Sungwoo Hong
- Center for Catalytic Hydrocarbon Functionalization, Institute of Basic Science (IBS) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST)Daejeon 34141, Korea
| | - So Ha Lee
- Chemical Kinomics Research Center, Korea Institute of Science and TechnologySeoul 02792, Korea
| | - Soon-Sun Hong
- Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University3-ga, Sinheung-dong, Jung-gu, Incheon 22332, Korea
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15
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Li X, Li Q, Xiong B, Chen H, Wang X, Zhang D. Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis. Pharmacol Res 2022; 183:106368. [PMID: 35905891 DOI: 10.1016/j.phrs.2022.106368] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/12/2022] [Accepted: 07/22/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Discoidin domain receptor 1 (DDR1) encodes a receptor tyrosine kinase involved in multiple physiological and pathological processes. DDR1 is expressed in the intestinal epithelium, but its role in Ulcerative Colitis (UC) is poorly understand. This study aimed to identify the function of DDR1 in maintaining the homeostasis of UC. METHODS The DDR1 expression level in non-inflamed and inflamed colon samples from IBD patients were assessed. DDR1 knock-out (DDR1-/-) and wild-type (WT) mice were administered dextran sulfate sodium (DSS) to induce colitis and assessed based on colitis symptoms. In addition, intestinal epithelial barrier injury was induced by TNF-α and IFN-γ incubation to cell monolayers transfected with PCDH-DDR1 or pLKO.1-sh-DDR1-1 plasmids. The effect of DDR1 in regulating barrier integrity, tight junctions (TJ) protein status, and cell apoptosis was investigated in vivo and in vitro. Furthermore, the activation of the NF-κB p65-MLCK-p-MLC2 pathway was also investigated. RESULTS Decreased DDR1 expression levels were observed at the inflamed sites compared with the non-inflamed. DDR1-/- mice had alleviated intestinal mucosal barrier injuries, upregulated TJ proteins, decreased epithelium apoptosis from DSS-induced colitis, and reduced proinflammatory cytokines production in the colon. These findings were further confirmed in vitro. DDR1 over-expression aggravated the TNF-α/IFN-γ-induced TJ disruption, while DDR1 shRNA prevented TJ damage even in the presence of JSH-23. DDR1 dependently destroyed the intestinal barrier via the NF-κB p65-MLCK-p-MLC2 pathway. CONCLUSION Our findings revealed that DDR1 regulated the intestinal barrier in colitis by modulating TJ proteins expression and epithelium apoptosis, making it a potential target of UC.
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Affiliation(s)
- Xiaoli Li
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Qianqian Li
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Bin Xiong
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Huiling Chen
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Xiaochun Wang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China
| | - Dekui Zhang
- Department of Gastroenterology, The Second Clinical Medical College of Lanzhou University, LanZhou University Second Hospital, Lanzhou, China; Key Laboratory of Digestive Diseases, LanZhou University Second Hospital, Lanzhou, China.
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16
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Wang S, Fu Y, Kuerban K, Liu J, Huang X, Pan D, Chen H, Zhu Y, Ye L. Discoidin domain receptor 1 is a potential target correlated with tumor invasion and immune infiltration in gastric cancer. Front Immunol 2022; 13:933165. [PMID: 35935941 PMCID: PMC9353406 DOI: 10.3389/fimmu.2022.933165] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Discoidin domain receptor 1 (DDR1) has been demonstrated to be able to promote tumor invasion and metastasis and being closely related to tumor immune infiltration. However, DDR1 has rarely been studied in gastric cancer. Here, we primarily evaluated DDR1 expression in gastric cancer and its cell lines using multiple databases. Subsequently, the cancer prognosis was investigated in relation to DDR1 expression. After analysis, we discovered that DDR1 was highly expressed and significantly connected with poor prognosis in gastric cancer. To comprehensively understand the molecular mechanism of DDR1, we explored genes and proteins interacting with DDR1 in gastric cancer using databases. Additionally, we found that the expression level of DDR1 was inversely correlated with immune infiltration and significantly relative to various immune cell markers. Overall, DDR1 was implicated in invasion, metastasis, and immune infiltration of gastric cancer. Inhibition of DDR1 may have the potential to alleviate the strong invasiveness and metastasis of advanced gastric cancer. Meanwhile, immune exclusion by DDR1 may also provide a new strategy for improving the efficacy of immune checkpoints inhibitors (ICIs), such as programmed cell death protein 1 (PD-1) antibody.
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Affiliation(s)
- Songna Wang
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Yuan Fu
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
| | - Kudelaidi Kuerban
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Jiayang Liu
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Xuan Huang
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Danjie Pan
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Huaning Chen
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
| | - Yizhun Zhu
- School of Pharmacy, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Li Ye
- Minhang Hospital and Department of Biological Medicines at School of Pharmacy, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China
- School of Pharmacy, Macau University of Science and Technology, Macao, Macao SAR, China
- *Correspondence: Li Ye,
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17
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Hong FU, Castro M, Linse K. Tumor specifically internalizing peptide ‘HN-1’: Targeting the putative receptor retinoblastoma-regulated discoidin domain receptor 1 involved in metastasis. World J Clin Oncol 2022; 13:323-338. [PMID: 35662982 PMCID: PMC9153073 DOI: 10.5306/wjco.v13.i5.323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/06/2021] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Less than 0.5% of intravenously injected drugs reach tumors, contributing to side effects. To limit damage to healthy cells, various delivery vectors have been formulated; yet, previously developed vectors suffer from poor penetration into solid tumors. This issue was resolved by the discovery of HN-1 peptide isolated via biopanning a phage-display library. HN-1 targets human head and neck squamous cell carcinoma (HNSCC) (breast, thyroid; potentially lung, cervix, uterine, colon cancer), translocates across the cell membrane, and efficiently infiltrates solid tumors. HN-1 peptide has been conjugated to various anticancer drugs and imaging agents though the identity of its receptor remained enigmatic.
AIM To decipher the clues that pointed to retinoblastoma (Rb)-regulated discoidin-domain receptor 1 as the putative receptor for HN-1 is described.
METHODS HN-1 peptide was synthesized and purified using reverse-phase high-performance liquid chromatography and gel electrophoresis. The predicted mass was confirmed by mass spectroscopy. To image the 3-dimensional structure of HN-1 peptide, PyMOL was used. Molecular modeling was also performed with PEP-FOLD3 software via RPBS bioinformatics web portal (INSERM, France). The immunohistochemistry results of discoidin domain receptor 1 (DDR1) protein were obtained from the publicly accessible database in the Human Protein Atlas portal, which contained the images of immunohistochemically labeled human cancers and the corresponding normal tissues.
RESULTS The clues that led to DDR1 involved in metastasis as the putative receptor mediating HN-1 endocytosis are the following: (1) HN-1 is internalized in phosphate-buffered saline and its uptake is competitively inhibited; (2) HN-1 (TSPLNIHNGQKL) exhibits similarity with a stretch of amino acids in alpha5 beta3 integrin (KLLITIHDRKEF). Aside from two identical residues (Ile-His) in the middle, the overall distribution of polar and nonpolar residues throughout the sequences is nearly identical. As HN-1 sequence lacks the Arg-Gly-Asp motif recognized by integrins, HN-1 may interact with an "integrin-like" molecule. The tertiary structure of both peptides showed similarity at the 3-dimensional level; (3) HN-1 is internalized by attached cells but not by suspended cells. As culture plates are typically coated with collagen, collagen-binding receptor (expressed by adherent but not suspended cells) may represent the receptor for HN-1; (4) DDR1 is highly expressed in head and neck cancer (or breast cancer) targeted by HN-1; (5) Upon activation by collagen, DDR1 becomes internalized and compartmentalized in endosomes consistent with the determination of ’energy-dependent clathrin-mediated endocytosis’ as the HN-1 entry route and the identification of HN-1 entrapped vesicles as endosomes; and (6) DDR1 is essential for the development of mammary glands consistent with the common embryonic lineage rationale used to identify breast cancer as an additional target of HN-1. In summary, collagen-activated tyrosine kinase receptor DDR1 overexpressed in HNSCC assumes a critical role in metastasis. Further studies are warranted to assess HN-1 peptide’s interaction with DDR1 and the therapeutic potential of treating metastatic cancer. Additionally, advances in delivery (conformation, endocytic mechanism, repertoire of targeted cancers of HN-1 peptide), tracking (HN-1 conjugated imaging agents), and activity (HN-1 conjugated therapeutic agents) are described.
CONCLUSION The discovery of DDR1 as HN-1 peptide’s putative receptor represents a significant advance as it enables identification of metastatic cancers or clinical application of previously developed therapeutics to block metastasis.
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Affiliation(s)
- Frank-Un Hong
- Research & Development, Bio-Synthesis, Inc., Lewisville, TX 75057, United States
| | - Miguel Castro
- Research & Development, Bio-Synthesis, Inc., Lewisville, TX 75057, United States
| | - Klaus Linse
- Research & Development, Bio-Synthesis, Inc., Lewisville, TX 75057, United States
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18
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Ngai D, Mohabeer AL, Mao A, Lino M, Bendeck MP. Stiffness-Responsive Feedback Autoregulation of DDR1 Expression is Mediated by a DDR1-YAP/TAZ Axis. Matrix Biol 2022; 110:129-140. [PMID: 35562016 DOI: 10.1016/j.matbio.2022.05.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 05/02/2022] [Accepted: 05/05/2022] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Increased matrix stiffness is sensed by the collagen-binding receptor tyrosine kinase discoidin domain receptor 1 (DDR1). We have previously shown that DDR1 stimulates a positive feedback loop to increase its own expression in vascular smooth muscle cells (VSMCs). The transcriptional co-factors YAP/TAZ are stiffness sensing molecules that have not previously been investigated in DDR1 signaling. Here, we test the hypothesis that DDR1 signals through YAP/TAZ to auto-regulate its own expression. APPROACH AND RESULTS We used vascular smooth muscle cells (VSMCs) from wild-type and DDR1 knockout mice stimulated with collagen and/or substrates of different stiffness. We show that DDR1 controls YAP/TAZ nuclear localization and activity, whereas knockdown of YAP/TAZ attenuates DDR1 expression. In response to increased substrate stiffness, collagen stimulation, or RhoA activation, YAP/TAZ translocate to the nucleus and bind to chromatin. Finally, collagen stimulation promotes increased YAP/TAZ association with the Ddr1 promoter. CONCLUSIONS These findings reveal the mechanism by which DDR1 regulates YAP/TAZ activity which can then mediate positive feedback regulation of DDR1 expression by promoting transcription of the DDR1 gene.
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Affiliation(s)
- David Ngai
- Department of Laboratory Medicine and Pathobiology, University of Toronto; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto
| | - Amanda L Mohabeer
- Department of Laboratory Medicine and Pathobiology, University of Toronto; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto
| | - Amanda Mao
- Department of Laboratory Medicine and Pathobiology, University of Toronto; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto
| | - Marsel Lino
- Department of Laboratory Medicine and Pathobiology, University of Toronto; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto
| | - Michelle P Bendeck
- Department of Laboratory Medicine and Pathobiology, University of Toronto; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto.
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19
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Angre T, Kumar A, Singh AK, Thareja S, Kumar P. Role of collagen regulators in cancer treatment: A comprehensive review. Anticancer Agents Med Chem 2022; 22:2956-2984. [DOI: 10.2174/1871520622666220501162351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/13/2022] [Accepted: 03/25/2022] [Indexed: 12/24/2022]
Abstract
Abstract:
Collagen is the most important structural protein and also a main component of extra-cellular matrix (ECM). It plays a role in tumor progression. Collagen can be regulated by altering it’s biosynthesis pathway through various signaling pathways, receptors and genes. Activity of cancer cells can also be regulated by other ECM components like metalloproteinases, hyaluronic acid, fibronectin and so on. Hypoxia is also one of the condition which leads to cancer progression by stimulating the expression of procollagen lysine as a collagen crosslinker, which increases the size of collagen fibres promoting cancer spread. The collagen content in cancerous cells leads to resistance in chemotherapy. So, to reduce this resistance, some of the collagen regulating therapies are introduced, which include inhibiting its biosynthesis, disturbing cancer cell signaling pathway, mediating ECM components and directly utilizing collagenase. This study is an effort to compile the strategies reported to control the collagen level and different collagen inhibitors reported so far. More research is needed in this area, growing understandings of collagen’s structural features and its role in cancer progression will aid in the advancement of newer chemotherapies.
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Affiliation(s)
- Tanuja Angre
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, India
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20
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Xiong B, Song FX, Chen HL, Wang XJ, Jin ZX, Han TY, Li Y, Zhang DK. Discoidin domain receptor 1a (DDR1a) confers 5-fluorouracil cytotoxicity in LoVo cell via PI3K/AKT/Bcl-2 pathway. Bioengineered 2022; 13:9805-9814. [PMID: 35416117 PMCID: PMC9161994 DOI: 10.1080/21655979.2022.2060782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
5-Fluorouracil (5-FU) is a common chemotherapy drug for patients with advanced colorectal cancer; however, many patients develop resistance to 5-FU and suffer from treatment failure. Discoidin domain receptor 1 (DDR1) is upregulated in multiple cancers and positively associated with chemoresistance. We explored the effect of DDR1a on the cytotoxicity induced by 5-FU in LoVo cells and the underlying mechanism. Therefore, DDR1a overexpression (DDR1ahigh) and knockdown in LoVo cell lines (shDDR1a) were constructed to detect cell viability and cytotoxicity induced by 5-FU. The results showed that cell viability of DDR1ahigh cells was higher in comparison with that of the control group. When 5-FU (5 µM) was administered, the percentage of apoptotic cells, cytochrome C release and caspase-3 activity was found to be higher in the shDDR1a group than that in the control group. Both of PI3K and MDM2 proteins level decreased in DDR1ahigh and shDDR1a, but the BAX/Bcl-2 level in the shDDR1a group increased compared to that in the control. Therefore, DDR1a might be a potential therapeutic target for 5-FU chemoresistance in colorectal cancer.
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Affiliation(s)
- Bin Xiong
- Department of Oncology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Fei-Xue Song
- Department of Oncology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Hui-Ling Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Xiao-Juan Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Zheng-Xu Jin
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Ti-Yun Han
- Laboratory of Digestive Disease, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yi Li
- School/Hospital of Stomatology Lanzhou University, Lanzhou, Gansu, China
| | - De-Kui Zhang
- Department of Gastroenterology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, China
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21
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Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation. Oncogene 2022; 41:2571-2586. [PMID: 35322197 DOI: 10.1038/s41388-022-02266-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 02/08/2022] [Accepted: 03/01/2022] [Indexed: 11/09/2022]
Abstract
Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
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22
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Zhang X, Hu Y, Pan Y, Xiong Y, Zhang Y, Han M, Dong K, Song J, Liang H, Ding Z, Zhang X, Zhu H, Liu Q, Lu X, Feng Y, Chen X, Zhang Z, Zhang B. DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6. Oncogene 2022; 41:1821-1834. [PMID: 35140331 PMCID: PMC8933278 DOI: 10.1038/s41388-022-02212-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 01/06/2022] [Accepted: 01/26/2022] [Indexed: 12/11/2022]
Abstract
Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family, and its ligand is collagen. Previous studies demonstrated that DDR1 is highly expressed in many tumors. However, its role in hepatocellular carcinoma (HCC) remains obscure. In this study, we found that DDR1 was upregulated in HCC tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues, and high DDR1 expression was associated with poor prognosis. Gene expression analysis showed that DDR1 target genes were functionally involved in HCC metastasis. DDR1 positively regulated the migration and invasion of HCC cells and promoted lung metastasis. Human Phospho-Kinase Array showed that DDR1 activated ERK/MAPK signaling pathway. Mechanically, DDR1 interacted with ARF6 and activated ARF6 through recruiting PSD4. The kinase activity of DDR1 was required for ARF6 activation and its role in metastasis. High expression of PSD4 was associated with poor prognosis in HCC. In summary, our findings indicate that DDR1 promotes HCC metastasis through collagen induced DDR1 signaling mediated PSD4/ARF6 signaling, suggesting that DDR1 and ARF6 may serve as novel prognostic biomarkers and therapeutic targets for metastatic HCC.
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Affiliation(s)
- Xiaochao Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
- Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yabing Hu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yonglong Pan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yixiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yuxin Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Mengzhen Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Keshuai Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xuewu Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - He Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xun Lu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Yongdong Feng
- Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, P. R. China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, P. R. China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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23
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Pan Y, Han M, Zhang X, He Y, Yuan C, Xiong Y, Li X, Zeng C, Lu K, Zhu H, Lu X, Liu Q, Liang H, Liao Z, Ding Z, Zhang Z, Chen X, Zhang W, Zhang B. Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of SLC1A5 and the mTORC1 signaling pathway. Cell Oncol (Dordr) 2022; 45:163-178. [PMID: 35089546 DOI: 10.1007/s13402-022-00659-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2022] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers in the world with a high mortality rate. Receptor tyrosine kinases play important roles in the occurrence and development of various cancers. Discoid protein domain receptor 1 (DDR1) is a special type of transmembrane receptor tyrosine kinase. Here, we show that the expression of DDR1 is significantly increased in HCC and is related to a poor clinical prognosis. METHODS The expression of DDR1 in HCC cell lines and primary HCC specimens was evaluated using Western blotting and immunohistochemistry. A correlation between DDR1 and SLC1A5 expression was also investigated in primary HCC specimens. Cell proliferation was evaluated using in vitro CCK8 and colony formation assays. Gene knock-down and overexpression assays, CHX, NH4CL and Mg132 interference tests and immunoprecipitation, as well as nude mouse xenograft models were used to assess the mechanism by which DDR1 promotes tumorigenesis in vitro and in vivo. RESULTS We found that DDR1 promotes the proliferation of HCC cells and accelerates the growth of HCC tumor xenografts, while DDR1 downregulation had the opposite effect. We also found that loss or gain of DDR1 expression affected HCC cell cycle progression. Mechanistically, we found that DDR1 interacts with SLC1A5, which belongs to the solute carrier (SLC) family of transporters, and regulates its stability, thereby affecting the mTORC1 signaling pathway. In addition, we found that SLC1A5 regulation by DDR1 can be restored by lysosome inhibitors. We also found that DDR1 is highly expressed in HCC tissues and that increased DDR1 expression predicts a shorter overall survival (OS) time. We additionally found that the expression of SLC1A5 was positively correlated with that of DDR1. Together, our data indicate that DDR1 acts as a tumor-promoting factor that can control HCC cell proliferation and cell cycle progression by stabilizing SLC1A5 in a lysosome-dependent way. CONCLUSIONS Our study reveals a new mechanism by which DDR1 plays a liver cancer-promoting role. We also found that DDR1 expression serves as an independent prognostic marker, and that DDR1 and SLC1A5 expression levels are positively correlated in clinical samples. Our findings provide a new perspective for understanding HCC development and offers new targets for the treatment and management of HCC.
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Affiliation(s)
- Yonglong Pan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Mengzhen Han
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xiaochao Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Yi He
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Chaoyi Yuan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Yixiao Xiong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xinxin Li
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Chenglong Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Kan Lu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - He Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Xun Lu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China
| | - Zeyang Ding
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China.
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan, China.
- Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, China.
- Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, China.
- Key Laboratory of Organ Transplantation, Chinese Academy of Medical Science, Wuhan, China.
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Chen L, Kong X, Fang Y, Paunikar S, Wang X, Brown JAL, Bourke E, Li X, Wang J. Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer. Front Cell Dev Biol 2021; 9:747314. [PMID: 34805157 PMCID: PMC8595330 DOI: 10.3389/fcell.2021.747314] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.
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Affiliation(s)
- Li Chen
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Xiangyi Kong
- Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yi Fang
- Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Shishir Paunikar
- Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Xiangyu Wang
- Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - James A. L. Brown
- Department of Biological Sciences, University of Limerick, Limerick, Ireland
- Health Research Institute, University of Limerick, Limerick, Ireland
| | - Emer Bourke
- Discipline of Pathology, School of Medicine, Lambe Institute for Translational Research, National University of Ireland Galway, Galway, Ireland
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Wang
- Department of Breast Surgical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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25
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Yan L, Xie X, Niu BX, Wu MT, Tong WQ, He SY, Huang CY, Zhao WC, Li G, Li NS, Jiang JL. Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes. Eur J Pharmacol 2021; 908:174317. [PMID: 34270989 DOI: 10.1016/j.ejphar.2021.174317] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/21/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
Endothelial cell dysfunction is a prominent feature of diabetic cardiovascular complications, and endothelial cell senescence is considered to be an important contributor to endothelial dysfunction. Discoidin domain receptor 1 (DDR1) has been reported to be involved in atherogenesis and cerebral ischemia/reperfusion injury. In this study, we aimed to explore the role of DDR1 in endothelial cell senescence under diabetic conditions and elucidate the underlying mechanisms. A diabetic rat model was established by a single intraperitoneal injection of streptozocin (STZ) (60 mg/kg), which showed an increase in senescence-associated β-galactosidase (SA-β-gal) staining signal of thoracic aortic endothelium, impaired vascular structure and function, accompanied by an up-regulation of DDR1. Next, we verified the role of DDR1 in endothelial senescence and the underlying mechanisms in high glucose-treated human umbilical vein endothelial cells (HUVECs). Consistent with the in vivo findings, high glucose induced endothelial senescence, impaired endothelial function and elevated DDR1 expression, accompanied by the elevation of senescence-related genes p53 and p21 expression, and these effects were reversed by DDR1 siRNA. DDR1 has been documented to be a potential target of miR-199a-3p. Here, we found that miR-199a-3p was down-regulated by high glucose in the aorta tissue and HUVECs, while miR-199a-3p mimic significantly suppressed increased endothelial senescence and elevated DDR1 induced by high glucose. In conclusion, our data demonstrated that miR-199a-3p/DDR1/p53/p21 signaling pathway was involved in endothelial senescence under diabetic conditions, and therapeutic targeting DDR1 would be exploited to inhibit endothelial senescence owing to high glucose exposure.
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Affiliation(s)
- Li Yan
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Departments of Pharmacy, Wuhan Asia General Hospital, Wuhan, 430056, China
| | - Xu Xie
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Bing-Xuan Niu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Mei-Ting Wu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Wei-Qiang Tong
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Shuang-Yi He
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Chu-Yi Huang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Wei-Chen Zhao
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Ge Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Nian-Sheng Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Jun-Lin Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, China.
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26
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Yuzhalin AE. Parallels between the extracellular matrix roles in developmental biology and cancer biology. Semin Cell Dev Biol 2021; 128:90-102. [PMID: 34556419 DOI: 10.1016/j.semcdb.2021.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/07/2021] [Accepted: 09/12/2021] [Indexed: 12/28/2022]
Abstract
Interaction of a tumor with its microenvironment is an emerging field of investigation, and the crosstalk between cancer cells and the extracellular matrix is of particular interest, since cancer patients with abundant and stiff extracellular matrices display a poorer prognosis. At the post-juvenile stage, the extracellular matrix plays predominantly a structural role by providing support to cells and tissues; however, during development, matrix proteins exert a plethora of diverse signals to guide the movement and determine the fate of pluripotent cells. Taking a closer look at the communication between the extracellular matrix and cells of a developing body may bring new insights into cancer biology and identify cancer weaknesses. This review discusses parallels between the extracellular matrix roles during development and tumor growth.
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Affiliation(s)
- Arseniy E Yuzhalin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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27
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Baek YY, Sung B, Choi JS, Go HK, Kim DH, Hyon JY, You JC. In Vivo Efficacy of Imatinib Mesylate, a Tyrosine Kinase Inhibitor, in the Treatment of Chemically Induced Dry Eye in Animal Models. Transl Vis Sci Technol 2021; 10:14. [PMID: 34520512 PMCID: PMC8444463 DOI: 10.1167/tvst.10.11.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Purpose Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface accompanied by ocular discomfort, visual disturbance, tear film instability, and ocular surface inflammation. In the present study, we evaluated the efficacy of the tyrosine kinase inhibitor imatinib mesylate for the treatment of DED. Methods Experimental models of DED were generated in Sprague Dawley rats using a combination of benzalkonium chloride (BAC) with atropine sulfate and in New Zealand White rabbits using BAC. The animals were treated twice daily with eye drops of vehicle, imatinib (0.01%-0.3%), or a positive control (Restasis). The improvement in DED due to imatinib was assessed by staining with fluorescein, lissamine green, impression cytology, and histological analysis. In addition, immunofluorescence staining was performed at the end of the study to evaluate the inflammatory response in the ocular surface. Results Topical application of imatinib significantly reduced ocular surface damage compared with vehicle-treated animals. Imatinib restored the morphology and structure of the conjunctival epithelium and reduced the recruitment of immune cells in the corneal epithelium. Furthermore, imatinib significantly reduced the impression cytology score, thus demonstrating that imatinib prevents the loss of goblet cells in DED animal models. The therapeutic efficacy of imatinib was similar to or better than that of cyclosporine treatment. Conclusions In this study, we provide an animal in vivo proof of concept of the therapeutic potential of imatinib for the treatment of DED. Translational Relevance With this study we show the possibility of developing imatinib as a new ophthalmic drop to treat DED.
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Affiliation(s)
| | | | | | | | | | - Joon Young Hyon
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ji Chang You
- Avixgen Inc., Seoul, Republic of Korea.,National Research Laboratory for Molecular Virology, Department of Pathology, School of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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28
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Fujii Y, Ono A, Hayes CN, Aikata H, Yamauchi M, Uchikawa S, Kodama K, Teraoka Y, Fujino H, Nakahara T, Murakami E, Miki D, Okamoto W, Kawaoka T, Tsuge M, Imamura M, Chayama K. Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:215. [PMID: 34174931 PMCID: PMC8235843 DOI: 10.1186/s13046-021-02016-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02016-3.
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Affiliation(s)
- Yasutoshi Fujii
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Shinsuke Uchikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kenichiro Kodama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Wataru Okamoto
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan. .,RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
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DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System. Biomolecules 2021; 11:biom11070926. [PMID: 34206590 PMCID: PMC8301864 DOI: 10.3390/biom11070926] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/18/2022] Open
Abstract
The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR/IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.
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30
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The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development. Cancers (Basel) 2021; 13:cancers13071725. [PMID: 33917302 PMCID: PMC8038660 DOI: 10.3390/cancers13071725] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The tumor microenvironment plays an important role in tumor development and metastasis. Collagens are major components of the extracellular matrix and can influence tumor development and metastasis by activating discoidin domain receptors (DDRs). This work shows the different roles of DDRs in various cancers and highlights the complexity of anti-DDR therapies in cancer treatment. Abstract The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.
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31
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Gao Y, Zhou J, Li J. Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies. Cancer Sci 2021; 112:962-969. [PMID: 33377205 PMCID: PMC7935774 DOI: 10.1111/cas.14789] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/23/2020] [Accepted: 12/26/2020] [Indexed: 12/18/2022] Open
Abstract
Discoidin domain receptors (DDR), including DDR1 and DDR2, are special types of the transmembrane receptor tyrosine kinase superfamily. DDR are activated by binding to the triple-helical collagen and, in turn, DDR can activate signal transduction pathways that regulate cell-collagen interactions involved in multiple physiological and pathological processes such as cell proliferation, migration, apoptosis, and cytokine secretion. Recently, DDR have been found to contribute to various diseases, including cancer. In addition, aberrant expressions of DDR have been reported in various human cancers, which indicates that DDR1 and DDR2 could be new targets for cancer treatment. Considerable effort has been made to design DDR inhibitors and several molecules have shown therapeutic effects in pre-clinical models. In this article, we review the recent literature on the role of DDR in cancer progression, the development status of DDR inhibitors, and the clinical potential of targeting DDR in cancer therapies.
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Affiliation(s)
- Yuan Gao
- Tongji University School of Medicine, Shanghai, China
| | - Jiuli Zhou
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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32
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DDR1 and DDR2: a review on signaling pathway and small molecule inhibitors as an anticancer agent. Med Chem Res 2021. [DOI: 10.1007/s00044-020-02694-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Nokin MJ, Darbo E, Travert C, Drogat B, Lacouture A, San José S, Cabrera N, Turcq B, Prouzet-Mauleon V, Falcone M, Villanueva A, Wang H, Herfs M, Mosteiro M, Jänne PA, Pujol JL, Maraver A, Barbacid M, Nadal E, Santamaría D, Ambrogio C. Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma. JCI Insight 2020; 5:137869. [PMID: 32759499 DOI: 10.1172/jci.insight.137869] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022] Open
Abstract
Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.
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Affiliation(s)
- Marie-Julie Nokin
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Elodie Darbo
- University of Bordeaux, INSERM U1218, ACTION Laboratory, Bordeaux INP, CNRS, LaBRI, UMR5800, Talence, France
| | - Camille Travert
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Benjamin Drogat
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Aurélie Lacouture
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Sonia San José
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Nuria Cabrera
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Béatrice Turcq
- University of Bordeaux, INSERM U1218, ACTION Laboratory, Laboratory of Mammary and Leukaemic Oncogenesis, Bordeaux, France
| | - Valérie Prouzet-Mauleon
- University of Bordeaux, INSERM U1218, ACTION Laboratory, Laboratory of Mammary and Leukaemic Oncogenesis, Bordeaux, France
| | - Mattia Falcone
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Alberto Villanueva
- Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Haiyun Wang
- School of Life Science and Technology, Tongji University, Shanghai, China
| | - Michael Herfs
- Laboratory of Experimental Pathology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Miguel Mosteiro
- Department of Medical Oncology, Catalan Institute of Oncology, Clinical Research in Solid Tumors (CReST) Group, Oncobell Program, IDIBELL, L'Hospitalet, Barcelona, Spain
| | - Pasi A Jänne
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Jean-Louis Pujol
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.,Montpellier Academic Hospital, Hôpital Arnaud de Villeneuve, Montpellier, France
| | - Antonio Maraver
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Mariano Barbacid
- Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Ernest Nadal
- Department of Medical Oncology, Catalan Institute of Oncology, Clinical Research in Solid Tumors (CReST) Group, Oncobell Program, IDIBELL, L'Hospitalet, Barcelona, Spain
| | - David Santamaría
- University of Bordeaux, INSERM U1218, ACTION Laboratory, IECB, Pessac, France
| | - Chiara Ambrogio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
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Lorusso G, Rüegg C, Kuonen F. Targeting the Extra-Cellular Matrix-Tumor Cell Crosstalk for Anti-Cancer Therapy: Emerging Alternatives to Integrin Inhibitors. Front Oncol 2020; 10:1231. [PMID: 32793493 PMCID: PMC7387567 DOI: 10.3389/fonc.2020.01231] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/16/2020] [Indexed: 12/11/2022] Open
Abstract
The extracellular matrix (ECM) is a complex network composed of a multitude of different macromolecules. ECM components typically provide a supportive structure to the tissue and engender positional information and crosstalk with neighboring cells in a dynamic reciprocal manner, thereby regulating tissue development and homeostasis. During tumor progression, tumor cells commonly modify and hijack the surrounding ECM to sustain anchorage-dependent growth and survival, guide migration, store pro-tumorigenic cell-derived molecules and present them to enhance receptor activation. Thereby, ECM potentially supports tumor progression at various steps from initiation, to local growth, invasion, and systemic dissemination and ECM-tumor cells interactions have long been considered promising targets for cancer therapy. Integrins represent key surface receptors for the tumor cell to sense and interact with the ECM. Yet, attempts to therapeutically impinge on these interactions using integrin inhibitors have failed to deliver anticipated results, and integrin inhibitors are still missing in the emerging arsenal of drugs for targeted therapies. This paradox situation should urge the field to reconsider the role of integrins in cancer and their targeting, but also to envisage alternative strategies. Here, we review the therapeutic targets implicated in tumor cell adhesion to the ECM, whose inhibitors are currently in clinical trials and may offer alternatives to integrin inhibition.
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Affiliation(s)
- Girieca Lorusso
- Experimental and Translational Oncology, Department of Oncology Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Curzio Rüegg
- Experimental and Translational Oncology, Department of Oncology Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - François Kuonen
- Department of Dermatology and Venereology, Hôpital de Beaumont, Lausanne University Hospital Center, Lausanne, Switzerland
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35
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Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β 1-integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding. Int J Mol Sci 2020; 21:ijms21144956. [PMID: 32668815 PMCID: PMC7404217 DOI: 10.3390/ijms21144956] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/02/2020] [Accepted: 07/09/2020] [Indexed: 12/23/2022] Open
Abstract
Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.
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36
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Veeroju S, Mamazhakypov A, Rai N, Kojonazarov B, Nadeau V, Breuils-Bonnet S, Li L, Weissmann N, Rohrbach S, Provencher S, Bonnet S, Seeger W, Schermuly R, Novoyatleva T. Effect of p53 activation on experimental right ventricular hypertrophy. PLoS One 2020; 15:e0234872. [PMID: 32559203 PMCID: PMC7304610 DOI: 10.1371/journal.pone.0234872] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 06/03/2020] [Indexed: 11/19/2022] Open
Abstract
The leading cause of death in Pulmonary Arterial Hypertension (PAH) is right ventricular (RV) failure. The tumor suppressor p53 has been associated with left ventricular hypertrophy (LVH) and remodeling but its role in RV hypertrophy (RVH) is unclear. The purpose of this study was to determine whether pharmacological activation of p53 by Quinacrine affects RV remodeling and function in the pulmonary artery banding (PAB) model of compensated RVH in mice. The effects of p53 activation on cellular functions were studied in isolated cardiomyocytes, cardiac fibroblasts and endothelial cells (ECs). The expression of p53 was examined both on human RV tissues from patients with compensated and decompensated RVH and in mouse RV tissues early and late after the PAB. As compared to control human RVs, there was no change in p53 expression in compensated RVH, while a marked upregulation was found in decompensated RVH. Similarly, in comparison to SHAM-operated mice, unaltered RV p53 expression 7 days after PAB, was markedly induced 21 days after the PAB. Quinacrine induced p53 accumulation did not further deteriorate RV function at day 7 after PAB. Quinacrine administration did not increase EC death, neither diminished EC number and capillary density in RV tissues. No major impact on the expression of markers of sarcomere organization, fatty acid and mitochondrial metabolism and respiration was noted in Quinacrine-treated PAB mice. p53 accumulation modulated the expression of Heme Oxygenase 1 (HO-1) and Glucose Transporter (Glut1) in mouse RVs and in adult cardiomyocytes. We conclude that early p53 activation in PAB-induced RVH does not cause substantial detrimental effects on right ventricular remodeling and function.
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Affiliation(s)
- Swathi Veeroju
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
| | - Argen Mamazhakypov
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
| | - Nabham Rai
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
| | - Baktybek Kojonazarov
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
- Institute for Lung Health, Giessen, Germany
| | - Valerie Nadeau
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada
| | - Sandra Breuils-Bonnet
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada
| | - Ling Li
- Institute of Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Norbert Weissmann
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
| | - Susanne Rohrbach
- Institute of Physiology, Justus-Liebig University Giessen, Giessen, Germany
| | - Steve Provencher
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada
| | - Sébastien Bonnet
- Pulmonary Hypertension and Vascular Biology Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Department of Medicine, Québec, Canada
| | - Werner Seeger
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Ralph Schermuly
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
- * E-mail: (RTS); (TN)
| | - Tatyana Novoyatleva
- Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany
- * E-mail: (RTS); (TN)
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Le CC, Bennasroune A, Collin G, Hachet C, Lehrter V, Rioult D, Dedieu S, Morjani H, Appert-Collin A. LRP-1 Promotes Colon Cancer Cell Proliferation in 3D Collagen Matrices by Mediating DDR1 Endocytosis. Front Cell Dev Biol 2020; 8:412. [PMID: 32582700 PMCID: PMC7283560 DOI: 10.3389/fcell.2020.00412] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 05/04/2020] [Indexed: 12/19/2022] Open
Abstract
Low density lipoprotein receptor related protein-1 (LRP-1) is a large ubiquitous endocytic receptor mediating the clearance of various molecules from the extracellular matrix. Several studies have shown that LRP-1 plays crucial roles during tumorigenesis functioning as a main signal pathway regulator, especially by interacting with other cell-surface receptors. Discoïdin Domain Receptors (DDRs), type I collagen receptors with tyrosine kinase activity, have previously been associated with tumor invasion and aggressiveness in diverse tumor environments. Here, we addressed whether it could exist functional interplays between LRP-1 and DDR1 to control colon carcinoma cell behavior in three-dimensional (3D) collagen matrices. We found that LRP-1 established tight molecular connections with DDR1 at the plasma membrane in colon cancer cells. In this tumor context, we provide evidence that LRP-1 regulates by endocytosis the cell surface levels of DDR1 expression. The LRP-1 mediated endocytosis of DDR1 increased cell proliferation by promoting cell cycle progression into S phase and decreasing apoptosis. In this study, we identified a new molecular way that controls the cell-surface expression of DDR1 and consequently the colon carcinoma cell proliferation and apoptosis and highlighted an additional mechanism by which LRP-1 carries out its sensor activity of the tumor microenvironment.
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Affiliation(s)
- Cao Cuong Le
- Université de Reims Champagne-Ardenne, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France.,Unité BioSpecT, EA7506, Reims, France
| | - Amar Bennasroune
- Université de Reims Champagne-Ardenne, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France
| | - Guillaume Collin
- Université de Reims Champagne-Ardenne, Reims, France.,Unité BioSpecT, EA7506, Reims, France
| | - Cathy Hachet
- Université de Reims Champagne-Ardenne, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France
| | - Véronique Lehrter
- Université de Reims Champagne-Ardenne, Reims, France.,Unité BioSpecT, EA7506, Reims, France
| | - Damien Rioult
- Plateau Technique Mobile de Cytométrie Environnementale MOBICYTE, URCA/INERIS, Reims Champagne-Ardenne University (URCA), Reims, France
| | - Stéphane Dedieu
- Université de Reims Champagne-Ardenne, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France
| | - Hamid Morjani
- Université de Reims Champagne-Ardenne, Reims, France.,Unité BioSpecT, EA7506, Reims, France
| | - Aline Appert-Collin
- Université de Reims Champagne-Ardenne, Reims, France.,CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire, MEDyC, Reims, France
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38
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Chappell WH, Candido S, Abrams SL, Akula SM, Steelman LS, Martelli AM, Ratti S, Cocco L, Cervello M, Montalto G, Nicoletti F, Libra M, McCubrey JA. Influences of TP53 and the anti-aging DDR1 receptor in controlling Raf/MEK/ERK and PI3K/Akt expression and chemotherapeutic drug sensitivity in prostate cancer cell lines. Aging (Albany NY) 2020; 12:10194-10210. [PMID: 32492656 PMCID: PMC7346063 DOI: 10.18632/aging.103377] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 05/20/2020] [Indexed: 12/20/2022]
Abstract
Background: TP53 plays critical roles in sensitivity to chemotherapy, and aging. Collagen is very important in aging. The molecular structure and biochemical properties of collagen changes during aging. The discoidin domain receptor (DDR1) is regulated in part by collagen. Elucidating the links between TP53 and DDR1 in chemosensitivity and aging could improve therapies against cancer and aging. Results: Restoration of WT-TP53 activity resulted in increased sensitivity to chemotherapeutic drugs and elevated expression of key components of the Raf/MEK/ERK, PI3K/Akt and DDR1 pathways. DDR1 could modulate the levels of Raf/MEK/ERK and PI3K/Akt pathways as well as sensitize the cells to chemotherapeutic drugs. In contrast, suppression of WT TP53 with a dominant negative (DN) TP53 gene, suppressed DDR1 protein levels and increased their chemoresistance. Conclusion: Restoration of WT TP53 activity or increased expression of the anti-aging DDR1 collagen receptor can result in enhanced sensitivity to chemotherapeutic drugs. Our innovative studies indicate the important links between WT TP53 and DDR1 which can modulate Raf/MEK/ERK and PI3K/Akt signaling as well as chemosensitivity and aging. Methods: We investigated the roles of wild type (WT) and mutant TP53 on drug sensitivity of prostate cancer cells and the induction of Raf/MEK/ERK, PI3K/Akt and DDR1 expression and chemosensitivity.
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Affiliation(s)
- William H Chappell
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.,Current Address: Becton, Dickinson and Company (BD), BD Diagnostics, Franklin Lakes, NJ 07417, USA
| | - Saverio Candido
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania, Italy.,Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Shaw M Akula
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Alberto M Martelli
- Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy
| | - Lucio Cocco
- Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy
| | - Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy.,Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Massimo Libra
- Research Center for Prevention, Diagnosis and Treatment of Cancer (PreDiCT), University of Catania, Catania, Italy.,Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
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Lazare C, Zhi W, Dai J, Cao C, Sookha RR, Wang L, Meng Y, Gao P, Wu P, Wei J, Hu J, Wu P. A pilot study comparing the genetic molecular biology of gestational and non-gestational choriocarcinoma. Am J Transl Res 2019; 11:7049-7062. [PMID: 31814908 PMCID: PMC6895522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 10/30/2019] [Indexed: 06/10/2023]
Abstract
Non-gestational choriocarcinoma (NGC) is a rare subtype of choriocarcinoma differing in origin and phenotypic characteristics compared to gestational choriocarcinoma (GC). This study aimed to analyze the molecular biology of GC and NGC and evaluate genetic anomalies of choriocarcinoma subtypes. DNA was extracted and paired from tumor-normal tissue of one NGC and one GC (control) patient for whole-exome sequencing. To further understand the role of DNAJB9, a p53 regulator mutated in the NGC tumor, on p53 upregulation in choriocarcinoma, CRISPR/Cas9 was used to induce DNAJB9 site-specific mutations in choriocarcinoma cells JEG-3. We hypothesized that DNAJB9 dysfunction would result in p53 overexpression. Sequencing revealed the GC tumor contained > 7 times more somatic mutations than the NGC tumor. Missense (98.86% vs. 94.97%), stop-gain (0.57% vs. 0.93%), and frameshift mutations (0.57% vs. 4.10%) were observed in the GC and NGC samples, respectively (x 2 = 24.63, P < 0.00001). The transition substitution rate was 67.54% and 55.71% in the GC and NGC samples, while the transversion substitution rate was 32.46% and 44.29% in the GC and NGC samples, respectively (x 2 = 11.56, P < 0.000673). Pathway enrichment analysis revealed ECM-receptor interaction and graft-versus-host disease were most enriched in the GC and NGC tumors, respectively. In vitro investigations showed that DNAJB9 mRNA and protein levels were downregulated in Cas9-DNAJB9-sgRNA transfected cells compared to the control (P < 0.001), while p53 protein levels were upregulated. Our findings display the genetic distinctness of choriocarcinoma subtypes, especially NGC, and further highlight the relationship between p53 and DNAJB9 in choriocarcinoma cells, laying the foundation for further investigations.
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Affiliation(s)
- Cordelle Lazare
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Wenhua Zhi
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Jun Dai
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Canhui Cao
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Rajiv Rai Sookha
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Ling Wang
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Yifan Meng
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Peipei Gao
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Ping Wu
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Juncheng Wei
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Junbo Hu
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
| | - Peng Wu
- The Key Laboratory of Cancer Invasion and Metastasis of The Ministry of Education of China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
- Department of Gynecologic Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhan, Hubei Province, China
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40
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Golonko A, Lewandowska H, Świsłocka R, Jasińska U, Priebe W, Lewandowski W. Curcumin as tyrosine kinase inhibitor in cancer treatment. Eur J Med Chem 2019; 181:111512. [DOI: 10.1016/j.ejmech.2019.07.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 07/03/2019] [Accepted: 07/04/2019] [Indexed: 12/12/2022]
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Villalba M, Redin E, Exposito F, Pajares MJ, Sainz C, Hervas D, Guruceaga E, Diaz-Lagares A, Cirauqui C, Redrado M, Valencia K, de Andrea C, Jantus-Lewintre E, Camps C, Lopez-Lopez R, Lahoz A, Montuenga L, Pio R, Sandoval J, Calvo A. Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1. Sci Rep 2019; 9:15400. [PMID: 31659178 PMCID: PMC6817908 DOI: 10.1038/s41598-019-51066-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 07/29/2019] [Indexed: 12/23/2022] Open
Abstract
Finding novel targets in non-small cell lung cancer (NSCLC) is highly needed and identification of synthetic lethality between two genes is a new approach to target NSCLC. We previously found that TMPRSS4 promotes NSCLC growth and constitutes a prognostic biomarker. Here, through large-scale analyses across 5 public databases we identified consistent co-expression between TMPRSS4 and DDR1. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down (KD) cells, but not single KD cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and a larger number of cells in apoptosis. Moreover, double KD cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in double KD-injected mice. In conclusion, we have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4.
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Affiliation(s)
- Maria Villalba
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain
| | - Esther Redin
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Francisco Exposito
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain
| | - Maria Jose Pajares
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain
| | - Cristina Sainz
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - David Hervas
- Data Science, Bioestatistics and Bioinformatics, Health Research Institute La Fe, Valencia, Spain
| | - Elizabeth Guruceaga
- Bioinformatics Platform, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Angel Diaz-Lagares
- CIBERONC, ISC-III, Madrid, Spain.,Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, Spain
| | - Cristina Cirauqui
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Miriam Redrado
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - Karmele Valencia
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain.,Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain
| | - Carlos de Andrea
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain
| | - Eloisa Jantus-Lewintre
- CIBERONC, ISC-III, Madrid, Spain.,Molecular Oncology Laboratory, General University Hospital Research Foundation, Valencia, Spain.,Department of Biotechnology, Universitat Politecnica de Valencia, Valencia, Spain
| | - Carlos Camps
- CIBERONC, ISC-III, Madrid, Spain.,Molecular Oncology Laboratory, General University Hospital Research Foundation, Valencia, Spain.,Department of Medicine Universitat de Valencia, Valencia, Spain
| | - Rafael Lopez-Lopez
- CIBERONC, ISC-III, Madrid, Spain.,Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS), Santiago de Compostela, Spain
| | - Agustin Lahoz
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, Valencia, Spain
| | - Luis Montuenga
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain
| | - Ruben Pio
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,CIBERONC, ISC-III, Madrid, Spain.,Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain
| | - Juan Sandoval
- Biomarkers and Precision Medicine Unit, Health Research Institute la Fe, Valencia, Spain.
| | - Alfonso Calvo
- IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. .,Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, Pamplona, Spain. .,CIBERONC, ISC-III, Madrid, Spain.
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Chou ST, Peng HY, Mo KC, Hsu YM, Wu GH, Hsiao JR, Lin SF, Wang HD, Shiah SG. MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1. J Exp Clin Cancer Res 2019; 38:281. [PMID: 31253192 PMCID: PMC6599238 DOI: 10.1186/s13046-019-1283-z] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 06/17/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Discoidin domain receptor-1 (DDR1) tyrosine kinase is highly expressed in a variety of human cancers and involved in various steps of tumorigenesis. However, the precise mechanisms underlying the abnormal expression of DDR1 in oral squamous cell carcinoma (OSCC) has not been well investigated. METHODS The expression of DDR1 on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-486-3p and DDR1 were accessed by MTT and Annexin V analyses using gain- and loss-of-function approaches. Chromatin immunoprecipitation (ChIP) and methylation specific PCR (MSP) were performed to explore the molecular mechanisms by arecoline treatment. RESULTS Here, we reported that DDR1 was significantly upregulated in OSCC tissues and its levels were inversely correlated with miR-486-3p expression. The experimental results in vitro confirmed that miR-486-3p decreased DDR1 expression by targeting the 3'-UTR of DDR1 mRNA. Overexpression of miR-486-3p led to growth inhibition and apoptosis induction with a similar function by knockdown of DDR1. Aberrant methylation of ANK1 promoter was a highly prevalent in OSCC and contributes to oral carcinogenesis by epigenetic silencing of ANK1 and miR-486-3p. We found that miR-486-3p can be transcriptionally co-regulated with its host gene ANK1 through epigenetic repression. DNA methylation inhibitor treatment re-expressed ANK1 and miR-486-3p. Importantly, arecoline, a major betel nut alkaloid, recruited DNMT3B binding to ANK1 promoter for DNA methylation and then attenuated the expression of miR-486-3p in OSCC. CONCLUSION This study was the first to demonstrate that betel nut alkaloid may recruit DNMT3B to regulate miR-486-3p/DDR1 axis in oral cancer andmiR-486-3p and DDR1 may serve as potential therapeutic targets of oral cancer.
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Affiliation(s)
- Sung-Tau Chou
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Hsuan-Yu Peng
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
| | - Kuan-Chi Mo
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
| | - Yuan-Ming Hsu
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
| | - Guan-Hsun Wu
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
| | - Jenn-Ren Hsiao
- Department of Otolaryngology, Head and Neck Collaborative Oncology Group, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Su-Fang Lin
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
| | - Horng-Dar Wang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
| | - Shine-Gwo Shiah
- National Institute of Cancer Research, National Health Research Institutes, No. 35 Keyan Road, Zhunan Town, Miaoli County 35053 Taiwan
- Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Ye L, Pu C, Tang J, Wang Y, Wang C, Qiu Z, Xiang T, Zhang Y, Peng W. Transmembrane-4 L-six family member-1 (TM4SF1) promotes non-small cell lung cancer proliferation, invasion and chemo-resistance through regulating the DDR1/Akt/ERK-mTOR axis. Respir Res 2019; 20:106. [PMID: 31142317 PMCID: PMC6542073 DOI: 10.1186/s12931-019-1071-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 05/13/2019] [Indexed: 02/06/2023] Open
Abstract
Background Tumor chemo-resistance is a hallmark of malignant tumors as well as the major cause of poor survival rates in lung cancer. Transmembrane-4 L-six family member-1 (TM4SF1), an antigen that serves as an oncogene, mainly affects tumor invasion and metastasis. We investigated the roles of TM4SF1 in non-small-cell lung cancer progression, particularly in the regulation of chemo-sensitivity. Methods TM4SF1 was silenced by small interfering RNA transfection.TM4SF1 expression in cell lines and tissues were determined by Quantitative Real-time PCR. MTS, clonogenic, Transwell assay, Flow cytometry verified cell function. By RT-PCR, Western blot, the mechanisms were studied. Results TM4SF1 was upregulated in both lung cancer cell lines and tissues, compared with 293 T epithelial cells. Analysis of online databases revealed that high expression of TM4SF1 is associated with the older patient age, smoking habits, and poor patient survival and outcome. Knockdown of TM4SF1 substantially inhibited tumor cell growth, migration, and invasion, and enhanced the chemo-sensitivity of the lung cancer cell lines A549 and H1299 to cisplatin and paclitaxel. Furthermore, the silencing of TM4SF1 induced lung cancer cell apoptosis and arrested cells at the G2/M phase. These results suggest that TM4SF1 is associated with lung cancer progression and appears to be required for tumor cell growth, maintenance of chemo-resistance and metastasis. We further found that TM4SF1 exerts these effects in part by regulating the expression of the discoidin domain receptor DDR1 and its downstream target, the Akt/ERK/mTOR pathway, and consequently alters cell sensitivity to chemo-reagents and contributes to invasion and metastasis. Conclusions These findings demonstrate that TM4SF1 may serve as a prognostic factor for lung cancer chemo-response and patient outcome.
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Affiliation(s)
- Lin Ye
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chunyun Pu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Tang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Wang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Can Wang
- Department of Oncology, Chongqing University Cancer Hospital& Chongqing Cancer Institute, Chongqing, China
| | - Zhu Qiu
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Tingxiu Xiang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunmei Zhang
- Nursing College, Chongqing Medical University, Chongqing, China.
| | - Weiyan Peng
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Saby C, Collin G, Sinane M, Buache E, Van Gulick L, Saltel F, Maquoi E, Morjani H. DDR1 and MT1-MMP Expression Levels Are Determinant for Triggering BIK-Mediated Apoptosis by 3D Type I Collagen Matrix in Invasive Basal-Like Breast Carcinoma Cells. Front Pharmacol 2019; 10:462. [PMID: 31130862 PMCID: PMC6509437 DOI: 10.3389/fphar.2019.00462] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 04/11/2019] [Indexed: 12/29/2022] Open
Abstract
Type I collagen is the major adhesive component in breast interstitial stroma, which represents the first barrier against tumor cell invasion after basement-membrane degradation. Among cellular receptors, type I collagen is able to activate discoidin domain receptors DDR1 and DDR2. We have previously shown that in 3D collagen matrix, DDR1 plays a key role as it promotes cell growth suppression and apoptosis through the upregulation of the pro-apoptotic mediator BIK in noninvasive luminal-like breast carcinoma cells. We have also shown that MT1-MMP is able to rescue these cells and protect them against the effects induced by collagen/DDR1/BIK axis. Our data suggested that the protective effect of MT1-MMP might be mediated through the degradation of type I collagen and/or DDR1 cleavage. Decreased DDR1 expression has been associated with the epithelial to mesenchymal transition process in breast cancer, and its overexpression in aggressive basal-like breast cancer cells reduces their invasiveness in 3D cultures and in vivo. In the present work, we propose to study the role of MT1-MMP in the resistance against collagen-induced apoptosis in basal-like breast carcinoma MDA-MB-231 cells. We aimed to investigate whether MT1-MMP depletion is able to restore apoptosis mediated by collagen/DDR1/BIK axis and to verify if such depletion is able to restore full-length DDR1 expression and phosphorylation. ShRNA strategy against MT1-MMP mRNA was able to partially restore full length DDR1 expression and phosphorylation. This was accompanied by a decrease in cell growth and an upregulation of BIK expression. This suggested that MT1-MMP expression in basal-like breast carcinoma cells, in addition to a low basal level of DDR1 expression, protects these cells against collagen-induced apoptosis via DDR1 cleavage. Since DDR1 was moderately expressed in MDA-MB-231 cells, we then investigated whether overexpression of DDR1 could be able to increase its ability to suppress cell growth and to induce apoptosis. Data showed that overexpression of DDR1 induced a decrease in cell growth and an increase in BIK expression, suggesting that moderate expression level of full length DDR1 in basal-like breast carcinoma provides them with a capacity to resist to collagen-induced cell growth suppression and apoptosis. Finally, the combined overexpression of DDR1 and depletion of MT1-MMP in MDA-MB-231 cells synergistically increased collagen-induced cell growth suppression and apoptosis to a level similar to that observed in luminal breast carcinoma. Taken together, our data suggest that during the acquisition of mesenchymal features, the low level of DDR1 expression should be considered as an important biomarker in the prognosis of basal-like breast carcinoma, conferring them a high rate of cell growth and resistance to BIK-mediated apoptosis induced by the stromal collagen.
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Affiliation(s)
- Charles Saby
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
| | - Guillaume Collin
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
| | - Maha Sinane
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
| | - Emilie Buache
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
| | - Laurence Van Gulick
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
| | - Frédéric Saltel
- INSERM, UMR1053, BaRITOn Bordeaux Research in Translational Oncology, Bordeaux, France
| | - Erik Maquoi
- Unit of Cancer, Laboratory of Tumour and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué (GIGA), University of Liège, Liège, Belgium
| | - Hamid Morjani
- Unité BioSpecT, EA7506, SFR CAP-Santé, UFR de Pharmacie, Université de Reims Champagne-Ardenne, Reims, France
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Yeh YC, Lin HH, Tang MJ. Dichotomy of the function of DDR1 in cells and disease progression. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:118473. [PMID: 30954568 DOI: 10.1016/j.bbamcr.2019.04.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 12/20/2018] [Accepted: 01/06/2019] [Indexed: 12/18/2022]
Abstract
Discoidin domain receptors DDR1 and DDR2 are collagen receptor tyrosine kinases that have many roles in tissue development and disease progression. Under physiological conditions, DDR1 is predominantly expressed in epithelial cells and functions to maintain cell differentiation and tissue homeostasis. A switch in expression from DDR1 to DDR2 occurs during epithelial-to-mesenchymal transition. However, opposite effects of DDR1 are reported to be involved in the progression of cancer and fibrotic diseases. Accumulating evidence suggests that DDR1 is involved in pro-metastasis and pro-survival signals. This review summarizes the roles of DDR1 in epithelial cell differentiation, cell migration, cancer progression and tissues fibrosis and highlights how the dichotomous functions of DDR1 may relevant to different cell types and statues. Elucidation of the underlying mechanism of the dichotomous functions of DDR1 will help to develop DDR1 as a therapeutic target.
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Affiliation(s)
- Yi-Chun Yeh
- International Center for Wound Repair and Regeneration, Tainan, Taiwan
| | - Hsi-Hui Lin
- International Center for Wound Repair and Regeneration, Tainan, Taiwan; Department of Physiology, National Cheng Kung University, Tainan, Taiwan
| | - Ming-Jer Tang
- International Center for Wound Repair and Regeneration, Tainan, Taiwan; Department of Physiology, National Cheng Kung University, Tainan, Taiwan.
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Moll S, Desmoulière A, Moeller MJ, Pache JC, Badi L, Arcadu F, Richter H, Satz A, Uhles S, Cavalli A, Drawnel F, Scapozza L, Prunotto M. DDR1 role in fibrosis and its pharmacological targeting. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:118474. [PMID: 30954571 DOI: 10.1016/j.bbamcr.2019.04.004] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 12/20/2018] [Accepted: 01/06/2019] [Indexed: 01/28/2023]
Abstract
Discoidin domain receptor1 (DDR1) is a collagen activated receptor tyrosine kinase and an attractive anti-fibrotic target. Its expression is mainly limited to epithelial cells located in several organs including skin, kidney, liver and lung. DDR1's biology is elusive, with unknown downstream activation pathways; however, it may act as a mediator of the stromal-epithelial interaction, potentially controlling the activation state of the resident quiescent fibroblasts. Increased expression of DDR1 has been documented in several types of cancer and fibrotic conditions including skin hypertrophic scars, idiopathic pulmonary fibrosis, cirrhotic liver and renal fibrosis. The present review article focuses on: a) detailing the evidence for a role of DDR1 as an anti-fibrotic target in different organs, b) clarifying DDR1 tissue distribution in healthy and diseased tissues as well as c) exploring DDR1 protective mode of action based on literature evidence and co-authors experience; d) detailing pharmacological efforts attempted to drug this subtle anti-fibrotic target to date.
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Affiliation(s)
- Solange Moll
- Department of Pathology, University Hospital of Geneva, Switzerland; Department of Pathology, Lausanne University Hospital, Switzerland
| | - Alexis Desmoulière
- Department of Physiology, Faculty of Pharmacy, University of Limoges, Limoges, France
| | - Marcus J Moeller
- Department of Nephrology and Clinical Immunology, RWTH University Hospital, Aachen, Germany
| | | | - Laura Badi
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Filippo Arcadu
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Hans Richter
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Alexander Satz
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Sabine Uhles
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Andrea Cavalli
- Institute for Research in Biomedicine, Università della Svizzera Italiana, CH-6500, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Faye Drawnel
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | - Leonardo Scapozza
- School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland
| | - Marco Prunotto
- Roche Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
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Argun-Kurum G, Kaya-Dagistanli F, Ozturk M. DPP4 inhibitor induces beta cell regeneration and DDR-1 protein expression as an endocrine progenitor cell marker in neonatal STZ-diabetic rats. Pharmacol Rep 2019; 71:721-731. [PMID: 31207434 DOI: 10.1016/j.pharep.2019.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 02/25/2019] [Accepted: 03/14/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND We aim to investigate the effects of dipeptidyl-peptidase-4 inhibitor (Vildagliptin-VG) on DDR-1 as a marker for endocrine progenitor cells, β-cell regeneration, and apoptosis in neonatal streptozotocin (n2-STZ) diabetics. METHODS Neonatal rats were divided into two main groups as short- and long-term treatment, each consisted of four groups; (1) Control, (2) n2-STZ diabetic (single dose of 100 mg/kg STZ at 2nd day of birth), (3) n2-STZ + VG (60 mg/kg/day VG orally; for 8 and 28 days), (4) VG (60 mg/kg/day orally; for 8 and 28 days). Blood glucose levels and body weights were measured, and the tissue sections were immunostained using insulin, glucagon, somatostatin, PCNA, Pdx-1 and DDR-1 antibodies. The TUNEL method was used for apoptosis. RESULTS The number of β cells in islets of the n2-STZ + VG group increased compared to the n2-STZ group; insulin (+) cells were observed individually or as small clusters in exocrine tissue, between pancreatic duct epithelial cells, and around the ducts. The number of Pdx-1 and DDR-1 positive cells in islet and extra-islet pancreas tissue was elevated as a result of VG application compared to the STZ diabetic group; the number of double positive cells for DDR-1 and insulin increased in n2-STZ + VG rats. CONCLUSION We showed that vildagliptin promotes β cell neogenesis and regeneration, stimulates DDR-1 expression as an endocrine cell progenitor marker, suppresses apoptosis, induces islet cell proliferation and rearranges islet morphology in the n2-STZ diabetes model.
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Affiliation(s)
- Gamze Argun-Kurum
- Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Medical Biology, Istanbul, Turkey
| | - Fatma Kaya-Dagistanli
- Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Medical Biology, Istanbul, Turkey
| | - Melek Ozturk
- Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty, Department of Medical Biology, Istanbul, Turkey.
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Vehlow A, Klapproth E, Jin S, Hannen R, Hauswald M, Bartsch JW, Nimsky C, Temme A, Leitinger B, Cordes N. Interaction of Discoidin Domain Receptor 1 with a 14-3-3-Beclin-1-Akt1 Complex Modulates Glioblastoma Therapy Sensitivity. Cell Rep 2019; 26:3672-3683.e7. [DOI: 10.1016/j.celrep.2019.02.096] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 12/13/2018] [Accepted: 02/22/2019] [Indexed: 12/20/2022] Open
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Gupta K, Burns TC. Radiation-Induced Alterations in the Recurrent Glioblastoma Microenvironment: Therapeutic Implications. Front Oncol 2018; 8:503. [PMID: 30467536 PMCID: PMC6236021 DOI: 10.3389/fonc.2018.00503] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/15/2018] [Indexed: 01/19/2023] Open
Abstract
Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year, despite best available treatment including radiotherapy (RT). Impacts of prior brain RT on recurrent tumors are poorly understood, though increasing evidence suggests RT-induced changes in the brain microenvironment contribute to recurrent GBM aggressiveness. The tumor microenvironment impacts malignant cells directly and indirectly through stromal cells that support tumor growth. Changes in extracellular matrix (ECM), abnormal vasculature, hypoxia, and inflammation have been reported to promote tumor aggressiveness that could be exacerbated by prior RT. Prior radiation may have long-term impacts on microglia and brain-infiltrating monocytes, leading to lasting alterations in cytokine signaling and ECM. Tumor-promoting CNS injury responses are recapitulated in the tumor microenvironment and augmented following prior radiation, impacting cell phenotype, proliferation, and infiltration in the CNS. Since RT is vital to GBM management, but substantially alters the tumor microenvironment, we here review challenges, knowledge gaps, and therapeutic opportunities relevant to targeting pro-tumorigenic features of the GBM microenvironment. We suggest that insights from RT-induced changes in the tumor microenvironment may provide opportunities to target mechanisms, such as cellular senescence, that may promote GBM aggressiveness amplified in previously radiated microenvironment.
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Affiliation(s)
- Kshama Gupta
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
| | - Terry C Burns
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, United States
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Gadiya M, Chakraborty G. Signaling by discoidin domain receptor 1 in cancer metastasis. Cell Adh Migr 2018; 12:315-323. [PMID: 30187813 PMCID: PMC6363035 DOI: 10.1080/19336918.2018.1520556] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 08/20/2018] [Accepted: 08/27/2018] [Indexed: 12/16/2022] Open
Abstract
Collagen is the most abundant component of tumor extracellular matrix (ECM). ECM collagens are known to directly interact with the tumor cells via cell surface receptor and play crucial role in tumor cell survival and promote tumor progression. Collagen receptor DDR1 is a member of receptor tyrosine kinase (RTK) family with a unique motif in the extracellular domain resembling Dictyostelium discoideum protein discoidin-I. DDR1 displays delayed and sustained activation upon interaction with collagen and recent findings have demonstrated that DDR1-collagen signaling play important role in cancer progression. In this review, we discuss the current knowledge on the role of DDR1 in cancer metastasis and possibility of a potential therapeutic approach of DDR1 targeted therapy in cancer.
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Affiliation(s)
- Mayur Gadiya
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA
| | - Goutam Chakraborty
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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