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Vegni F, De Stefano IS, Policardo F, Tralongo P, Feraco A, Carlino A, Ferraro G, Zhang Q, Scaglione G, D'Alessandris N, Navarra E, Zannoni G, Santoro A, Mule A, Rossi ED. Neuroendocrine neoplasms of the breast: a review of literature. Virchows Arch 2024; 485:197-212. [PMID: 38980337 PMCID: PMC11329594 DOI: 10.1007/s00428-024-03856-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 07/10/2024]
Abstract
Primary neuroendocrine neoplasms (NENs) of the breast are characterized by neuroendocrine architectural and cytological features, which must be supported by immunohistochemical positivity for neuroendocrine markers (such as Chromogranin and Synaptophysin). According to the literature, making a diagnosis of primary neuroendocrine breast cancer always needs to rule out a possible primary neuroendocrine neoplasm from another site. Currently, the latest 2022 version of the WHO of endocrine and neuroendocrine neoplasms has classified breast NENs as well-differentiated neuroendocrine tumours (NETs) and aggressive neuroendocrine carcinomas (NECs), differentiating them from invasive breast cancers of no special type (IBCs-NST). with neuroendocrine features. The current review article describes six cases from our series and a comprehensive review of the literature in the field of NENs of the breast.
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Affiliation(s)
- Federica Vegni
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Ilenia Sara De Stefano
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Federica Policardo
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Pietro Tralongo
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Angela Feraco
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Angela Carlino
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Giulia Ferraro
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Qianqian Zhang
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Giulia Scaglione
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Nicoletta D'Alessandris
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Elena Navarra
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Gianfranco Zannoni
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Angela Santoro
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Antonino Mule
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy
| | - Esther Diana Rossi
- Division of Anatomic Pathology and Histology-Fondazione, Policlinico Universitario "Agostino Gemelli"-IRCCS, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168, Rome, Italy.
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Cele N, Awolade P, Dhawan S, Khubone L, Raza A, Sharma AK, Singh P. Quinoline–1,3,4-Oxadiazole Conjugates: Synthesis, Anticancer Evaluation, and Molecular Modelling Studies. Polycycl Aromat Compd 2022. [DOI: 10.1080/10406638.2022.2117205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Nosipho Cele
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Paul Awolade
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Sanjeev Dhawan
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Lungisani Khubone
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Asif Raza
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, Hershey, PA, USA
| | - Arun K. Sharma
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, Hershey, PA, USA
| | - Parvesh Singh
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
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Wang Y, Yi J, Liu X. Roles of Dclk1 in the pathogenesis, diagnosis, prognosis and treatment of pancreatic cancer: A review. Expert Rev Gastroenterol Hepatol 2022; 16:13-19. [PMID: 34937474 DOI: 10.1080/17474124.2022.2020643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/16/2021] [Indexed: 11/11/2022]
Abstract
INTRODUCTION Pancreatic cancer (PC) is a malignant tumor with significantly increased incidence and poor prognosis. Its extremely poor prognosis is generally attributed to its early invasion and metastasis as well as the presence of chemotherapy resistance, which may be related to the potential role of cancer stem cells (CSCs). Doublecortin-like kinase 1 (Dclk1) has been recognized to be a marker of CSCs in PC, showing intimate association with its occurrence, metastasis, and poor prognosis. AREAS COVERED A review serves to provide a comprehensive overview of Dclk1 in the pathogenesis, diagnosis, prognosis, and treatment in PC. EXPERT OPINION Searching for potential key biomarkers for PC has been an urgent issue to be addressed. The expression of Dclk1 is increasing in PC, and its effect is linked to the mutant Kras, supporting that it may be a potential new target. Therefore, it highlights Dclk1 as a candidate biomarker and therapeutic target in future clinical application.
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Affiliation(s)
- Yifan Wang
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Jun Yi
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer Aided Diagnosis and Treatment for Digestive Disease, Xiangya Hospital, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China
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Agulto RL, Rogers MM, Tan TC, Ramkumar A, Downing AM, Bodin H, Castro J, Nowakowski DW, Ori-McKenney KM. Autoregulatory control of microtubule binding in doublecortin-like kinase 1. eLife 2021; 10:e60126. [PMID: 34310279 PMCID: PMC8352597 DOI: 10.7554/elife.60126] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 07/22/2021] [Indexed: 12/16/2022] Open
Abstract
The microtubule-associated protein, doublecortin-like kinase 1 (DCLK1), is highly expressed in a range of cancers and is a prominent therapeutic target for kinase inhibitors. The physiological roles of DCLK1 kinase activity and how it is regulated remain elusive. Here, we analyze the role of mammalian DCLK1 kinase activity in regulating microtubule binding. We found that DCLK1 autophosphorylates a residue within its C-terminal tail to restrict its kinase activity and prevent aberrant hyperphosphorylation within its microtubule-binding domain. Removal of the C-terminal tail or mutation of this residue causes an increase in phosphorylation within the doublecortin domains, which abolishes microtubule binding. Therefore, autophosphorylation at specific sites within DCLK1 has diametric effects on the molecule's association with microtubules. Our results suggest a mechanism by which DCLK1 modulates its kinase activity to tune its microtubule-binding affinity. These results provide molecular insights for future therapeutic efforts related to DCLK1's role in cancer development and progression.
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Affiliation(s)
- Regina L Agulto
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Melissa M Rogers
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Tracy C Tan
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Amrita Ramkumar
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Ashlyn M Downing
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Hannah Bodin
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
| | - Julia Castro
- Department of Molecular and Cellular Biology, University of California, DavisDavisUnited States
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Breast cancer with neuroendocrine differentiation: an update based on the latest WHO classification. Mod Pathol 2021; 34:1062-1073. [PMID: 33531618 DOI: 10.1038/s41379-021-00736-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 02/08/2023]
Abstract
Breast cancers with neuroendocrine (NE) differentiation are very heterogeneous, comprising broadly cancers that are morphologically similar to NE tumors (NET) of other anatomic sites, infiltrating breast carcinomas, no special type (IBC-NST) and other special subtypes with NE morphology and/or NE markers expression. Depending on the classification schemes, they are variably included into "NE breast cancers". The latest WHO classification harmonized NE breast cancers with NE neoplasms (NEN) of other organ systems, defined NEN into well-differentiated NET (low Nottingham grade) and poorly-differentiated NE carcinoma (NEC) (high Nottingham grade). Other IBC with NE differentiation are diagnosed based on solely the non-NEN component. Due to the changes in diagnostic criteria, variable results were obtained in the previous studies on NE breast cancers. Hence, the clinical value of NE differentiation in breast cancers is not well investigated and understood. In this review, the current understanding in the pathogenesis, clinical, prognostic, immunhistochemical, and molecular features of "NE breast cancers" is summarized. Controversial issues in their diagnosis and classification are also discussed.
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Yang WQ, Zhao WJ, Zhu LL, Xu SJ, Zhang XL, Liang Y, Ding XF, Kiselyov A, Chen G. XMD-17-51 Inhibits DCLK1 Kinase and Prevents Lung Cancer Progression. Front Pharmacol 2021; 12:603453. [PMID: 33762936 PMCID: PMC7982674 DOI: 10.3389/fphar.2021.603453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/15/2021] [Indexed: 11/13/2022] Open
Abstract
Doublecortin-like kinase 1 (DCLK1) is a cancer stem cell marker that is highly expressed in various types of human cancer, and a protein kinase target for cancer therapy that is attracting increasing interest. However, no drug candidates targeting DCLK1 kinase have been developed in clinical trials to date. XMD-17-51 was found herein to possess DCLK1 kinase inhibitory activities by cell-free enzymatic assay. In non-small cell lung carcinoma (NSCLC) cells, XMD-17-51 inhibited DCLK1 and cell proliferation, while DCLK1 overexpression impaired the anti-proliferative activity of XMD-17-51 in A549 cell lines. Consequently, XMD-17-51 decreased Snail-1 and zinc-finger-enhancer binding protein 1 protein levels, but increased those of E-cadherin, indicating that XMD-17-51 reduces epithelial-mesenchymal transition (EMT). Furthermore, sphere formation efficiency was significantly decreased upon XMD-17-51 treatment, and XMD-17-51 reduced the expression of stemness markers such as β-catenin, and pluripotency factors such as SOX2, NANOG and OCT4. However, the percentage of ALDH+ cells was increased significantly following treatment with XMD-17-51 in A549 cells, possibly due to EMT inhibition. In combination, the present data indicated that XMD-17-51 inhibited DCLK1 kinase activity in a cell-free assay with an IC50 of 14.64 nM, and decreased DCLK1 protein levels, cell proliferation, EMT and stemness in NSCLC cell lines. XMD-17-51 has the potential to be a candidate drug for lung cancer therapy.
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Affiliation(s)
- Wei-Qiang Yang
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Wei-Jun Zhao
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Liu-Lian Zhu
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | - Shuai-Jun Xu
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China.,Graduate School of Medicine, Hebei North University, Zhangjiakou, China
| | | | - Yong Liang
- Department of Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China
| | - Xiao-Fei Ding
- Department of Experimental and Clinical Medicine, School of Medicine, Taizhou University, Taizhou, China
| | - Alexander Kiselyov
- Department of Pharmaceutical Engineering, School of Pharmaceutical Chemical and Materials Engineering, Taizhou University, Taizhou, China
| | - Guang Chen
- Department of Pharmacology, School of Medicine, Taizhou University, Taizhou, China
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Krug K, Jaehnig EJ, Satpathy S, Blumenberg L, Karpova A, Anurag M, Miles G, Mertins P, Geffen Y, Tang LC, Heiman DI, Cao S, Maruvka YE, Lei JT, Huang C, Kothadia RB, Colaprico A, Birger C, Wang J, Dou Y, Wen B, Shi Z, Liao Y, Wiznerowicz M, Wyczalkowski MA, Chen XS, Kennedy JJ, Paulovich AG, Thiagarajan M, Kinsinger CR, Hiltke T, Boja ES, Mesri M, Robles AI, Rodriguez H, Westbrook TF, Ding L, Getz G, Clauser KR, Fenyö D, Ruggles KV, Zhang B, Mani DR, Carr SA, Ellis MJ, Gillette MA. Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy. Cell 2020; 183:1436-1456.e31. [PMID: 33212010 PMCID: PMC8077737 DOI: 10.1016/j.cell.2020.10.036] [Citation(s) in RCA: 321] [Impact Index Per Article: 64.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/14/2020] [Accepted: 10/21/2020] [Indexed: 02/08/2023]
Abstract
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
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Affiliation(s)
- Karsten Krug
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Eric J Jaehnig
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shankha Satpathy
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Lili Blumenberg
- Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Alla Karpova
- Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Meenakshi Anurag
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - George Miles
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Philipp Mertins
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Max Delbrück Center for Molecular Medicine in the Helmholtz Society and Berlin Institute of Health, Berlin, Germany
| | - Yifat Geffen
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Lauren C Tang
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - David I Heiman
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Song Cao
- Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Yosef E Maruvka
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Jonathan T Lei
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chen Huang
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ramani B Kothadia
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Antonio Colaprico
- Division of Biostatistics, Department of Public Health Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Chet Birger
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Jarey Wang
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Human Genetics, and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongchao Dou
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bo Wen
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhiao Shi
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuxing Liao
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Maciej Wiznerowicz
- Poznan University of Medical Sciences, Poznań 61-701, Poland; International Institute for Molecular Oncology, 60-203 Poznań, Poland
| | - Matthew A Wyczalkowski
- Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Xi Steven Chen
- Division of Biostatistics, Department of Public Health Science, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Jacob J Kennedy
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Amanda G Paulovich
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
| | - Mathangi Thiagarajan
- Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Christopher R Kinsinger
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Tara Hiltke
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Emily S Boja
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Thomas F Westbrook
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Molecular and Human Genetics, and Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Li Ding
- Department of Medicine and Genetics, Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Gad Getz
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02114, USA
| | - Karl R Clauser
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - David Fenyö
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Kelly V Ruggles
- Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Bing Zhang
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - D R Mani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
| | - Steven A Carr
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
| | - Matthew J Ellis
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Michael A Gillette
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
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Kang XL, He LR, Chen YL, Wang SB. Role of doublecortin-like kinase 1 and leucine-rich repeat-containing G-protein-coupled receptor 5 in patients with stage II/III colorectal cancer: Cancer progression and prognosis. World J Gastroenterol 2020; 26:6853-6866. [PMID: 33268966 PMCID: PMC7684452 DOI: 10.3748/wjg.v26.i43.6853] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/29/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are a subpopulation of cancer cells with the potential of self-renewal and differentiation. CSCs play critical roles in tumorigenesis, recurrence, metastasis, radiation tolerance and chemoresistance.
AIM To assess the expression patterns and clinical potential of doublecortin-like kinase 1 (DCLK1) and leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), as prognostic CSC markers of colorectal cancer (CRC).
METHODS The expression of DCLK1 and Lgr5 in CRC tissue sections from 92 patients was determined by immunohistochemistry. Each case was evaluated using a combined scoring method based on signal intensity staining (scored 0-3) and the proportion of positively stained cancer cells (scored 0-3). The final staining score was calculated as the intensity score multiplied by the proportion score. Low expression of DCLK1 and Lgr5 was defined as a score of 0-3; high expression of DCLK1 and Lgr5 was defined as a score of ≥ 4. Specimens were categorized as either high or low expression, and the correlation between the expression of DCLK1 or Lgr5 and clinicopathological factors was investigated.
RESULTS DCLK1 and Lgr5 expression levels were significantly positively correlated. CRC patients with high DCLK1, Lgr5 and DCLK1/Lgr5 expressions had poorer progression-free survival and overall survival. Moreover, high expression of DCLK1 was an independent prognostic factor for recurrence and overall survival in patients with CRC by multivariate analysis (P = 0.026 and P = 0.049, respectively).
CONCLUSION DCLK1 may be a potential CSC marker for the recurrence and survival of CRC patients.
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Affiliation(s)
- Xue-Ling Kang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
| | - Li-Rui He
- Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Yao-Li Chen
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Shu-Bin Wang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, China Cancer Institute of Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
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Fan M, Yan H, Gou M, Qian N, Dai G. Divergent expression of DCLK1 in gastrointestinal neuroendocrine tumors and primary hepatic, gallbladder, and pancreatic neuroendocrine tumors. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:2249-2258. [PMID: 33042329 PMCID: PMC7539880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 07/31/2020] [Indexed: 06/11/2023]
Abstract
Doublecortin-like kinase 1 (DCLK1) is reported to be a negative prognostic marker in colorectal cancer and is involved in tumorigenesis and progression through several miRNA pathways. In this study, We analyzed its expression in neuroendocrine tumor (NET) and explored its relation with survival outcome. 122 patients were enrolled in the study, including 60 cases of GI-NETs, 24 cases of primary hepatic NETs (PHNETs), 16 cases of gallbladder NETs (GBNETs) and 22 cases of pancreatic NETs (pNETs). IHC was performed for DCLK1 on tumor tissue. All patients underwent a baseline visit, histologic determination, and a follow-up for survival. In the 60 cases of GI-NETs, DCLK1 showed diffuse cytoplasmic expression. The positive rates of DCLK1, Syn and CgA were 100% (60/60), 100% (60/60) and 36.7% (22/60), respectively. However, DCLK1 showed negative staining in all of the 62 cases of PHNETs, GBNETs, and pNETs. The mean score of DCLK1, Syn, and CgA were (5.77±2.012), (5.13±2.078) and (2.68±2.797), respectively. DCLK1 was correlated with primary site (P<0.001) and Syn expression (P = 0.045). Additionally, in GI-NETs, we found that DCLK1 expression was associated with worse OS (log-rank = 5.212, P = 0.022). The divergent expression of DCLK1 in NETs suggests different functional roles of DCLK1 in different locations of NET within the digestive system. However, with the limited number of tumor samples, its outcome prediciton still needs further investigation. DCLK1 expression may aid in the diagnosis and prognosis of GI-NETs.
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Affiliation(s)
- Mengjiao Fan
- Oncology Department, Chinese PLA General Hospital Beijing, China
| | - Huan Yan
- Oncology Department, Chinese PLA General Hospital Beijing, China
| | - Miaomiao Gou
- Oncology Department, Chinese PLA General Hospital Beijing, China
| | - Niansong Qian
- Oncology Department, Chinese PLA General Hospital Beijing, China
| | - Guanghai Dai
- Oncology Department, Chinese PLA General Hospital Beijing, China
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Lai BSW, Tsang JY, Poon IK, Shao Y, Chan SK, Tam FK, Cheung SY, Shea KH, Tse GM. The Clinical Significance of Neuroendocrine Features in Invasive Breast Carcinomas. Oncologist 2020; 25:e1318-e1329. [PMID: 32472950 DOI: 10.1634/theoncologist.2020-0081] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 05/06/2020] [Indexed: 01/13/2023] Open
Abstract
The latest World Health Organization (WHO) classification categorized invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiations into neuroendocrine neoplasms (including well-differentiated neuroendocrine tumor [NET] and poorly differentiated neuroendocrine carcinoma [NEC]) and IBC no special type with NE features (IBC-NST-NE). However, little is documented of the clinical significance of this classification; also the precise thresholds and choices of NE markers were variable. In the current study, a large cohort of patients with IBC with NE differentiation were morphologically classified based on the WHO criteria and the clinical relevance of expression of different NE markers (synaptophysin [SYN], chromogranin [CG], and CD56) was evaluated. Among 1,372 IBCs, 52 NET (3.8%) and 172 IBC-NST-NE (12.5%) were identified. Compared with the IBC-no NE cases, NET and IBC-NST-NE were similarly associated with positive estrogen receptor (ER) expression and lower grade (p < .001). For patient outcome, IBC-NST-NE, but not NET, demonstrated significantly worse survival than the IBC-no NE cases. Based on high (≥50%) and low (<50%) expression for each NE marker, independent poor disease-free survival for SYNlo CGlo and SYNhi CGlo cancers (IBC-no NE cases as references, hazard ratio [HR], ≤1.429; p ≤ .026) was found. Interestingly, SYN and CG expression correlated with each other and they shared similar clinicopathologic characteristics; but not with with CD56. In addition, CD56-only positive cases were associated with hormone receptors negativity and basal markers positivity (p ≤ .019), and patients' outcome was similar to IBC-no NE cancers. Our findings suggested that NE markers expression may provide information to fine tune treatment strategy. The relevance of CD56 as NE marker requires further studies. IMPLICATIONS FOR PRACTICE: Invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiation are heterogeneous in clinicopathologic parameters, biomarker expression, and prognosis. However, there are no specific therapies targeting NE differentiation, and all carcinomas with any NE differentiation are treated similarly as other IBCs. The results of this study suggest that stratification based on NE marker expression levels may provide added prognostically pertinent information, aiding better treatment strategy. In addition, CD56-only positive carcinomas showed a different clinicopathologic and biomarker expression profile compared with those with chromogranin and synaptophysin expression. Relevance of CD56 as an NE marker requires further studies.
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Affiliation(s)
| | - Julia Y Tsang
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong
| | - Ivan K Poon
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong
| | - Yan Shao
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong
| | - Siu-Ki Chan
- Department of Pathology, Kwong Wah Hospital, Hong Kong
| | - Fiona K Tam
- Department of Pathology, Kwong Wah Hospital, Hong Kong
| | | | - Ka-Ho Shea
- Department of Pathology, Tuen Mun Hospital, Hong Kong
| | - Gary M Tse
- Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Ngan Shing Street, Shatin, NT, Hong Kong
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11
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Zhao S, Ma D, Xiao Y, Li XM, Ma JL, Zhang H, Xu XL, Lv H, Jiang WH, Yang WT, Jiang YZ, Zhang QY, Shao ZM. Molecular Subtyping of Triple-Negative Breast Cancers by Immunohistochemistry: Molecular Basis and Clinical Relevance. Oncologist 2020; 25:e1481-e1491. [PMID: 32406563 DOI: 10.1634/theoncologist.2019-0982] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 04/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Molecular subtyping of triple-negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs. MATERIALS AND METHODS By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC-based classifier, and applied it to another two cohorts (n = 183 and 214). RESULTS We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC-based luminal androgen receptor (IHC-LAR; AR-positive [+]), (b) IHC-based immunomodulatory (IHC-IM; AR-negative [-], CD8+), (c) IHC-based basal-like immune-suppressed (IHC-BLIS; AR-, CD8-, FOXC1+), (d) IHC-based mesenchymal (IHC-MES; AR-, CD8-, FOXC1-, DCLK1+), and (e) IHC-based unclassifiable (AR-, CD8-, FOXC1-, DCLK1-). The κ statistic indicated substantial agreement between the IHC-based classification and mRNA-based classification. Multivariate survival analysis suggested that our IHC-based classification was an independent prognostic factor for relapse-free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC-LAR subtype showed relative activation of HER2 pathway. The IHC-IM subtype tended to exhibit an immune-inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC-BLIS subtype showed high expression of a VEGF signature. The IHC-MES subtype displayed activation of JAK/STAT3 signaling pathway. CONCLUSION We developed an IHC-based approach to classify TNBCs into molecular subtypes. This IHC-based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes. IMPLICATIONS FOR PRACTICE An immunohistochemistry (IHC)-based classification approach was developed for triple-negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression-based classification. This IHC-based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype-specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
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Affiliation(s)
- Shen Zhao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Ding Ma
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Yi Xiao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Xiao-Mei Li
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Jian-Li Ma
- Department of Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Han Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Xiao-Li Xu
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Hong Lv
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Wen-Hua Jiang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Wen-Tao Yang
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Yi-Zhou Jiang
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
| | - Qing-Yuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
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Wang Z, Xia F, Labib M, Ahmadi M, Chen H, Das J, Ahmed SU, Angers S, Sargent EH, Kelley SO. Nanostructured Architectures Promote the Mesenchymal-Epithelial Transition for Invasive Cells. ACS NANO 2020; 14:5324-5336. [PMID: 32369335 DOI: 10.1021/acsnano.9b07350] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Dynamic modulation of cellular phenotypes between the epithelial and mesenchymal states-the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET)-plays an important role in cancer progression. Nanoscale topography of culture substrates is known to affect the migration and EMT of cancer cells. However, existing platforms heavily rely on simple geometries such as grooved lines or cylindrical post arrays, which may oversimplify the complex interaction between cells and nanotopography in vivo. Here, we use electrodeposition to construct finely controlled surfaces with biomimetic fractal nanostructures as a means of examining the roles of nanotopography during the EMT/MET process. We found that nanostructures in the size range of 100 to 500 nm significantly promote MET for invasive breast and prostate cancer cells. The "METed" cells acquired distinct expression of epithelial and mesenchymal markers, displayed perturbed morphologies, and exhibited diminished migration and invasion, even after the removal of a nanotopographical stimulus. The phosphorylation of GSK-3 was decreased, which further tuned the expression of Snail and modulated the EMT/MET process. Our findings suggest that invasive cancer cells respond to the geometries and dimensions of complex nanostructured architectures.
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Affiliation(s)
- Zongjie Wang
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, M5S 3G4, Canada
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, M5S 3G9, Canada
| | - Fan Xia
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Moloud Ahmadi
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Haijie Chen
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, M5S 3G4, Canada
| | - Jagotamoy Das
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Sharif U Ahmed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Stéphane Angers
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
| | - Edward H Sargent
- The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, M5S 3G4, Canada
| | - Shana O Kelley
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, M5S 3G9, Canada
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, M5S 3M2, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Canada
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Dastmalchi N, Safaralizadeh R, Baradaran B, Hosseinpourfeizi M, Baghbanzadeh A. An update review of deregulated tumor suppressive microRNAs and their contribution in various molecular subtypes of breast cancer. Gene 2019; 729:144301. [PMID: 31884105 DOI: 10.1016/j.gene.2019.144301] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/10/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Breast cancer (BC) is histologically classified into hormone-receptor+ (ER+, PR + ), human epidermal growth factor receptor-2+ (Her2 + ), and triple-negative breast cancer (TNBC) types. The important contribution of tumor-suppressive (TS) microRNAs (miRs) in BC development and treatment have been well-acknowledged in the literature. OBJECTIVE The present review focused on the contribution of recently examined TS miRs in the progression and treatment of various histological subtypes of BC. RESULTS In summary, various miRs have tumor-suppressive roles in BC, so that their aberrant expression leads to the abnormality in the cellular processes such as enhanced cell growth, decreased apoptosis, cell migration and metastasis, and decreased sensitivity to chemotherapy through deregulated expression of oncogene targets of TS miRs. CONCLUSION TS miRs could be regarded as a proper molecular target for target therapy of BC. However, further in vitro and in vivo investigations are required to confirm the exact molecular functions of TS miRs in BC cells to offer more efficient targeted therapies.
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Affiliation(s)
- Narges Dastmalchi
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Safaralizadeh
- Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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DCLK1 Plays a Metastatic-Promoting Role in Human Breast Cancer Cells. BIOMED RESEARCH INTERNATIONAL 2019; 2019:1061979. [PMID: 31223610 PMCID: PMC6541964 DOI: 10.1155/2019/1061979] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 04/16/2019] [Indexed: 01/10/2023]
Abstract
Background Doublecortin-like kinase 1 (DCLK1) has been universally identified as a cancer stem cell (CSC) marker and is found to be overexpressed in many types of cancers including breast cancer. However, there is little data regarding the functional role of DCLK1 in breast cancer metastasis. In the present study, we sought to investigate whether and how DCLK1 plays a metastatic-promoting role in human breast cancer cells. Methods We used Crispr/Cas9 technology to knock out DCLK1 in breast cancer cell line BT474, which basically possesses DCLK1 at a higher level, and stably overexpressed DCLK1 in another breast cancer cell line, T47D, that basically expresses DCLK1 at a lower level. We further analyzed the alterations of metastatic characteristics and the underlying mechanisms in these cells. Results It was shown that, compared with the corresponding control cells, DCLK1 overexpression led to an increase in metastatic behaviors including enhanced migration and invasion of T47D cells. By contrast, forced depletion of DCLK1 drastically inhibited these metastatic characteristics in BT474 cells. Mechanistically, the epithelial-mesenchymal transition (EMT) program, which is critical for cancer metastasis, was prominently activated in DCLK1-overexpressing cancer cells, evidenced by a decrease in an epithelial marker ZO-1 and an enhancement in several mesenchymal markers including ZEB1 and Vimentin. In addition, DCLK1 overexpression induced the ERK MAPK pathway, which resultantly enhanced the expression of MT1-MMP that is also involved in cancer metastasis. Knockout of DCLK1 could reverse these events, further supporting a metastatic-promoting role for DCLK1. Conclusions Collectively, our data suggested that DCLK1 overexpression may be responsible for the increased metastatic features in breast cancer cells. Targeting DCLK1 may become a therapeutic option for breast cancer metastasis.
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Shafiei S, Kalantari E, Saeednejad Zanjani L, Abolhasani M, Asadi Lari MH, Madjd Z. Increased expression of DCLK1, a novel putative CSC maker, is associated with tumor aggressiveness and worse disease-specific survival in patients with bladder carcinomas. Exp Mol Pathol 2019; 108:164-172. [PMID: 31028726 DOI: 10.1016/j.yexmp.2019.04.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 04/13/2019] [Accepted: 04/24/2019] [Indexed: 01/06/2023]
Abstract
Doublecortin-like kinase 1 (DCLK1) has been characterized as a novel potential cancer stem cell (CSC) marker in several types of cancer. It is considered as one of the most specific markers for distinguishing colorectal CSCs from normal stem cells. Yet, there are limited reports on the role of DCLK1 as a putative CSC marker in bladder cancer. Using immunohistochemistry, DCLK1 expression was examined in a well-defined tissue microarray series of 472 bladder cancer tissues. The association between DCLK1 protein expression and clinicopathological features, as well as survival outcomes, was assessed. Our findings showed strong, moderate, and weak DCLK1 expression in 123 (26.1%), 230 (48.7%), and 119 (25.2%) of the bladder cancer specimens, respectively. Higher expression of DCLK1 was significantly associated with increase in histological grade (P ≤ .001), pT stage (P = .014), lamina propria (P = .006), and lamina propria/muscularis (L/M) involvement (P = .014). On multivariate analysis, pT stage (P < .001), histological grade (P = .021), and lamina propria involvement (P = .001) were independent prognostic factors in DCLK1 expression. Moreover, the expression of DCLK1 was found to be an independent marker of poor prognosis for disease- specific survival (DSS) (P = .048) in bladder carcinomas. Our observations showed that DCLK1 expression was associated with more aggressive tumor behavior, more advanced disease, and poorer DSS in patients with bladder carcinomas. However, any potential clinical applications of DCLK1 as a novel target molecule in bladder cancer patients would require further investigations.
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Affiliation(s)
- Somayeh Shafiei
- Dep of Pathology, Iran University of Medical Sciences, (IUMS), Tehran, Iran
| | - Elham Kalantari
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | | | - Maryam Abolhasani
- Dep of Pathology, Iran University of Medical Sciences, (IUMS), Tehran, Iran; Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran; Hasheminejad Kidney, Iran University of Medical Sciences, (IUMS), Tehran, Iran
| | | | - Zahra Madjd
- Dep of Pathology, Iran University of Medical Sciences, (IUMS), Tehran, Iran; Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada..
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Involvement of an Orphan Transporter, SLC22A18, in Cell Growth and Drug Resistance of Human Breast Cancer MCF7 Cells. J Pharm Sci 2018; 107:3163-3170. [DOI: 10.1016/j.xphs.2018.08.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 01/05/2023]
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Deng H, Qianqian G, Ting J, Aimin Y. RETRACTED: miR-539 enhances chemosensitivity to cisplatin in non-small cell lung cancer by targeting DCLK1. Biomed Pharmacother 2018; 106:1072-1081. [PMID: 30119173 DOI: 10.1016/j.biopha.2018.07.024] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 07/02/2018] [Accepted: 07/03/2018] [Indexed: 12/27/2022] Open
Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. An Expression of Concern for this article was previously published while an investigation was conducted (see related editorial: https://doi.org/10.1016/j.biopha.2022.113812). This retraction notice supersedes the Expression of Concern published earlier. Concern was raised about the reliability of the flow cytometry data in Figures 2C, 3C and 6C, which appear to contain similar features as found in other publications, as detailed here: https://pubpeer.com/publications/96CACC6C7EAE327217D2319DC364C5; and here: https://docs.google.com/spreadsheets/d/1r0MyIYpagBc58BRF9c3luWNlCX8VUvUuPyYYXzxWvgY/edit#gid=262337249. Examples of suspected image duplication were also identified in Figures 4A+B, 6E+F, 7C. The journal requested the corresponding author comment on these concerns and provide the associated raw data. The authors did not respond to this request and therefore the Editor-in-Chief decided to retract the article.
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Affiliation(s)
- Huixing Deng
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Geng Qianqian
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ji Ting
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yang Aimin
- Department of Nuclear Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Takiyama A, Tanaka T, Kazama S, Nagata H, Kawai K, Hata K, Otani K, Nishikawa T, Sasaki K, Kaneko M, Emoto S, Murono K, Takiyama H, Nozawa H. DCLK1 Expression in Colorectal Polyps Increases with the Severity of Dysplasia. ACTA ACUST UNITED AC 2018; 32:365-371. [PMID: 29475922 DOI: 10.21873/invivo.11247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/29/2018] [Accepted: 01/30/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND The expression of doublecortin-like kinase 1 (DCLK1) has been investigated in cancer; however not in precancerous adenomatous polyps. MATERIALS AND METHODS Immunohistological expression of DCLK1 was evaluated in various grades of adenomas, cancerous polyps, and hyperplastic polyps in resected human tissue specimens. RESULTS Ninety-two specimens were positive for DCLK1 and 134 were negative. Cancerous polyps showed a high DCLK1 positivity rate compared to adenomas (68.4% vs. 36.8%; p<0.01). The rate of DCLK1 positivity was not significantly different among the three grades of adenomas (mild, moderate, and severe). DCLK1 was highly positive in advanced adenomas than low risk adenomas (49.6% vs. 29.3%; p<0.01). CONCLUSION The expression of DCLK1 was found in low-grade adenomas and increased with worsening severity of dysplasia. DCLK1 expression was highly observed in advanced adenomas, which had a clinically higher malignant potential.
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Affiliation(s)
- Aki Takiyama
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Toshiaki Tanaka
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shinsuke Kazama
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Hiroshi Nagata
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kensuke Otani
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Manabu Kaneko
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | | | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
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Dai T, Hu Y, Lv F, Ozawa T, Sun X, Huang J, Han X, Kishi H, Muraguchi A, Jin A. Analysis of the clinical significance of DCLK1 + colorectal cancer using novel monoclonal antibodies against DCLK1. Onco Targets Ther 2018; 11:5047-5057. [PMID: 30174443 PMCID: PMC6110630 DOI: 10.2147/ott.s169928] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Introduction Doublecortin-like kinase 1 (DCLK1) is considered a putative tumor stem cell (TSC) marker and a promising therapeutic target, as DCLK1+ progeny cells exhibit high expression in tumors. However, the biological function of DCLK1+ cells in tumorigenesis and tumor progression remains unclear. Materials and methods We generated rabbit monoclonal antibodies (mAbs) against DCLK1, DCLK1-42, and DCLK1-87 mAbs, using a novel chip-based immunospot array assay on a chip system. First, the specificity of two mAbs to DCLK1 was confirmed by Western blot, which were bound to DCLK1-long in normal colon cells and to DCLK1-short in a cancer cell line as well as colorectal cancer (CRC) cells. Results Precise localization analysis using immunofluorescence revealed that both mAbs had cytoplasmic signal and exhibited a high degree of overlap with microtubules. Furthermore, bacterial display technology indicated that the antigenic epitope region of DCLK1-87 mAb was consistent with that of a commercial anti-DCLK1 polyclonal antibody. In addition, DCLK1-42 mAb has the common polyclonal antibody characteristic of binding to more than one site on DCLK1. By immunohistochemistry, it was found that DCLK1-87 mAb was more specific for DCLK1+ cell labeling than a commercial anti-DCLK1 polyclonal antibody. DCLK1 labeled with DCLK1-87 mAb might be a potential TSC marker because the tissue expression site covers the ALDH1 area in CRC tissues. Finally, we analyzed 100 pairs of cancer tissues and matching paracancerous tissue samples from patients with CRC who received 100 months of follow-up with the DCLK1-87 mAb. The results showed that patients with high DCLK1 expression exhibited a longer survival time than that of patients with low DCLK1 expression (P=0.0029). Discussion Our results indicated that we successfully generated an efficient tool for the precise detection of DCLK1+ cells in cancer tissues. Moreover, we found that high DCLK1 expression in CRC patients appears to play a protective role against tumor progression.
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Affiliation(s)
- Tianqi Dai
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
| | - Yunlong Hu
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China, .,Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.,Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, People's Republic of China
| | - Fulian Lv
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
| | - Tatsuhiko Ozawa
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Xin Sun
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
| | - Jingjing Huang
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
| | - Xiaojian Han
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
| | - Hiroyuki Kishi
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Atsushi Muraguchi
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Aishun Jin
- Department of Immunology, College of Basic Medical Sciences, Harbin Medical University, Harbin, People's Republic of China,
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20
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Harada Y, Kazama S, Morikawa T, Emoto S, Murono K, Kaneko M, Sasaki K, Otani K, Nishikawa T, Tanaka T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Ishihara S, Watanabe T. Prognostic impact of doublecortin-like kinase 1 expression in locally advanced rectal cancer treated with preoperative chemoradiotherapy. APMIS 2018; 126:486-493. [DOI: 10.1111/apm.12852] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 04/30/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Yuzo Harada
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Shinsuke Kazama
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
- Department of Gastroenterological Surgery; Saitama Cancer Center; Saitama Japan
| | - Teppei Morikawa
- Department of Pathology; The University of Tokyo; Tokyo Japan
| | - Shigenobu Emoto
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Koji Murono
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Manabu Kaneko
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Kazuhito Sasaki
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Kensuke Otani
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Takeshi Nishikawa
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Toshiaki Tanaka
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Tomomichi Kiyomatsu
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Kazushige Kawai
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Keisuke Hata
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Hiroaki Nozawa
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
| | - Soichiro Ishihara
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
- Surgery Department; Sanno Hospital; International University of Health and Welfare; Tokyo Japan
| | - Toshiaki Watanabe
- Division of Surgical Oncology; Department of Surgery; Faculty of Medicine; The University of Tokyo; Tokyo Japan
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21
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Mohammadi Y, Tavangar SM, Saidijam M, Amini R, Etemadi K, Karimi Dermani F, Najafi R. DCLK1 plays an important role in colorectal cancer tumorgenesis through the regulation of miR-200c. Biomed Pharmacother 2018; 103:301-307. [PMID: 29656186 DOI: 10.1016/j.biopha.2018.04.042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/06/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023] Open
Abstract
Doublecortin-like kinase 1 (DCLK1) is a protein kinase that is known as a specific cancer stem cell (CSC) marker in colorectal cancer (CRC). Deregulation of DCLK1 expression has been reported in various cancers. We measured the protein expression of DCLK1 in 38 CRC and normal colon samples by immunohistochemistry (IHC). HCT-116 and SW-48 cells were transfected with DCLK1 siRNA and analyzed for expression of DCLK1 and miR-200c. The effects of DCLK1 knockdown on cell migration, invasion, sphere-forming, and apoptosis were explored. It was found that DCLK1 protein expression levels were significantly higher in CRC tissue than in normal colon specimens. Silencing of DCLK1 significantly inhibited cell migration, invasion, and sphere-forming potential; it also induced apoptosis as well as increased expression of miR-200c. Furthermore, silencing of miR-200c significantly up-regulated DCLK1 expression. Overall, our data demonstrated that DCLK1 plays an important role in cancer progression and is involved in the regulation of miR-200c expression.
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Affiliation(s)
- Yasaman Mohammadi
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Massoud Saidijam
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Amini
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Katayoon Etemadi
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Fatemeh Karimi Dermani
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research center for molecular medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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22
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Das CK, Linder B, Bonn F, Rothweiler F, Dikic I, Michaelis M, Cinatl J, Mandal M, Kögel D. BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells. Neoplasia 2018; 20:263-279. [PMID: 29462756 PMCID: PMC5852393 DOI: 10.1016/j.neo.2018.01.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 12/22/2017] [Accepted: 01/03/2018] [Indexed: 01/07/2023] Open
Abstract
Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549rDOX20) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468r5-FU2000) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549rDOX20 and MDA-MB-468r5-FU2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer.
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Affiliation(s)
- Chandan Kanta Das
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany; School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Benedikt Linder
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany
| | - Florian Bonn
- Institute of Biochemistry II, Goethe University Hospital, Frankfurt am Main, Germany
| | - Florian Rothweiler
- Institute for Medical Virology, Goethe University Hospital, Frankfurt am Main, Germany
| | - Ivan Dikic
- Institute of Biochemistry II, Goethe University Hospital, Frankfurt am Main, Germany; Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany
| | - Martin Michaelis
- Institute for Medical Virology, Goethe University Hospital, Frankfurt am Main, Germany; School of Biosciences, The University of Kent, Canterbury, Kent, UK
| | - Jindrich Cinatl
- Institute for Medical Virology, Goethe University Hospital, Frankfurt am Main, Germany
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, India
| | - Donat Kögel
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Germany.
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23
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Nishio K, Kimura K, Amano R, Nakata B, Yamazoe S, Ohira G, Miura K, Kametani N, Tanaka H, Muguruma K, Hirakawa K, Ohira M. Doublecortin and CaM kinase-like-1 as an independent prognostic factor in patients with resected pancreatic carcinoma. World J Gastroenterol 2017; 23:5764-5772. [PMID: 28883702 PMCID: PMC5569291 DOI: 10.3748/wjg.v23.i31.5764] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 05/11/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the effect of expression of doublecortin and CaM kinase-like-1 (DCLK1) in patients with pancreatic ductal adenocarcinoma (PDAC).
METHODS Tumor specimens were obtained from 136 patients with pancreatic cancer who had undergone resection without preoperative therapy between January 2000 and December 2013 at the Department of Surgical Oncology, Osaka City University. The resected specimens were analyzed for associations with clinicopathological data, including DCLK1 expression, epithelial mesenchymal transition (EMT) marker expression, and cancer stem cell (CSC) marker expression. Univariate and multivariate survival analyses were performed and we assessed the association between DCLK1 expression and clinicopathological factors, including the EMT marker and CSC marker.
RESULTS In total, 48.5% (66/136) of the pancreatic cancer samples were positive for DCLK1. Patients with DCLK1-positive tumors had significantly shorter survival times than those with DCLK1-negative tumors (median, 18.7 mo vs 49.5 mo, respectively; P < 0.0001). Positive DCLK1 expression correlated with histological grade (P = 0.0290), preoperative CA19-9 level (P = 0.0060), epithelial cell adhesion molecule (EpCAM) expression (P = 0.0235), and the triple-positive expression of CD44/CD24/EpCAM (P = 0.0139). On univariate survival analysis, five factors were significantly associated with worse overall survival: histological grade of G2 to G4 (P = 0.0091), high preoperative serum SPan-1 level (P = 0.0034), R1/2 (P < 0.0001), positive expression of DCLK1 (P < 0.0001) or CD44 (P = 0.0245). On multivariate survival analysis, R1/2 [odds ratio (OR) = 2.019, 95% confidence interval (CI): 1.380-2.933; P = 0.0004] and positive DCLK1 expression (OR = 1.848, 95%CI: 1.2854-2.661; P = 0.0009) were independent prognostic factors.
CONCLUSION DCLK1 expression was found to be an independent prognostic factor and it may play a crucial prognostic role by promoting acquisition of stemness.
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Affiliation(s)
- Kohei Nishio
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Kenjiro Kimura
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Ryosuke Amano
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Bunzo Nakata
- Department of Surgery, Kashiwara Municipal Hospital, Kashiwara City, Osaka 582-0005, Japan
| | - Sadaaki Yamazoe
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Go Ohira
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Kotaro Miura
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Naoki Kametani
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Hiroaki Tanaka
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Kazuya Muguruma
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Kosei Hirakawa
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
| | - Masaichi Ohira
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan
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24
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Increased DCLK1 correlates with the malignant status and poor outcome in malignant tumors: a meta-analysis. Oncotarget 2017; 8:100545-100557. [PMID: 29246000 PMCID: PMC5725042 DOI: 10.18632/oncotarget.20129] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 07/30/2017] [Indexed: 01/04/2023] Open
Abstract
Doublecortin-like kinase 1 (DCLK1) has been found to be involved in malignant biological behavior of cancers and poor prognosis of cancer patients. The aim of this meta-analysis was to systematically clarify the relationships between expression level of DCLK1 and clinicopathological characteristics in tumors and assess its clinical value in cancer diagnosis and prognosis. 18 eligible studies with a total of 2660 patients were identified by searching the electronic bibliographic databases. Pooled results showed that DCLK1 was highly expressed in tissues from cancer patients compared to normal tissues (OR, 10.00), and overexpression of DCLK1 was significantly correlated with advanced clinical stage (OR, 2.48), positive lymph node metastasis (OR, 2.18), poorly differentiated cancers (OR, 1.83) and poor overall survival (HR, 2.15). The overall combined sensitivity and specificity for DCLK1 in distinguishing malignant tumors were 0.58 and 0.90, respectively. The mean diagnostic odds ratio was 12.70, and the corresponding area under the summary receiver operating characteristic curve was 0.78. In summary, our study indicated that DCLK1 could be a risk factor for development of malignant tumors and may serve as a promising diagnostic and prognostic biomarker for malignant tumors.
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25
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Zhang S, Zhang G, Guo H. DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer. Tumour Biol 2017. [PMID: 28621231 DOI: 10.1177/1010428317703822] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
DCAMKL1 (doublecortin and CaM kinase-like 1) has been found to be overexpressed and function as an oncogene in several types of cancer, but there are limited reports on the role of DCAMKL1 in bladder cancer. The messenger RNA and protein expression of DCAMKL1 in bladder cancer tissues and cell lines was measured by quantitative reverse transcription polymerase chain reaction, western blotting, or immunohistochemistry. The correlation between DCAMKL1 protein expression and clinicopathological characteristics was analyzed. Univariate and multivariate Cox regression models were adopted to evaluate prognostic significance of DCAMKL1 in bladder cancer patients. In our results, DCAMKL1 messenger RNA and protein were overexpressed in bladder cancer tissues compared with adjacent normal tissues. DCAMKL1 protein overexpression was positively associated with clinical stage, muscularis invasion, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses suggested DCAMKL1 protein overexpression was an unfavorable prognostic factor in bladder cancer patients. In conclusion, DCAMKL1 is an independent poor prognostic factor for bladder cancer patients.
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Affiliation(s)
- Shiqing Zhang
- 1 Department of Urology, Jining No. 1 People's Hospital, Jining, China
| | - Guoqing Zhang
- 2 Department of Planning Immunization, Center for Disease Control and Prevention, Jining, China
| | - Hongbo Guo
- 1 Department of Urology, Jining No. 1 People's Hospital, Jining, China
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26
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Role of cancer stem-cell marker doublecortin-like kinase 1 in head and neck squamous cell carcinoma. Oral Oncol 2017; 67:109-118. [DOI: 10.1016/j.oraloncology.2017.02.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 01/22/2017] [Accepted: 02/09/2017] [Indexed: 01/24/2023]
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Doublecortin-like kinase 1 is a novel biomarker for prognosis and regulates growth and metastasis in basal-like breast cancer. Biomed Pharmacother 2017. [DOI: 10.1016/j.biopha.2017.01.082] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Kadletz L, Aumayr K, Heiduschka G, Schneider S, Enzenhofer E, Lill C. Overexpression of DCLK1 is predictive for recurrent disease in major salivary gland malignancies. Eur Arch Otorhinolaryngol 2016; 274:467-475. [PMID: 27470117 DOI: 10.1007/s00405-016-4227-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Accepted: 07/19/2016] [Indexed: 02/06/2023]
Abstract
Salivary gland carcinomas are a rare malignancy. Therefore, little is known about biomarkers and cancer stem cells in salivary gland malignancies. Double cortin-like kinase 1 (DCLK1) is a promising therapeutic target and cancer stem cell marker, predominantly investigated in pancreatic and colorectal cancer. The purpose of this study was to investigate the expression of DCLK1 in major and minor salivary gland carcinomas and its influence on survival. We examined a total of 80 patients with major or minor salivary gland cancer in this retrospective study. Immunohistochemistry with anti-DCLK1 antibody was applied to assess the expression of DCLK1. Moreover, we evaluated the impact of DCLK1 on overall and disease-free survival. DCLK1 expression could be detected in 66.3 % of all examined cases. Overexpression of DCLK1 was associated with reduced overall and disease-free survival in patients with major salivary gland cancer. Disease-free survival reached statistical significance (p = 0.0107). However, expression of DCLK1 had no influence on survival in patients with minor salivary gland cancer. Since treatment of recurrent disease in oncologic patients is utterly challenging, DCLK1 may be a promising prognostic biomarker that helps to identify patients with a high risk for recurrence of major salivary gland carcinoma.
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Affiliation(s)
- Lorenz Kadletz
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Klaus Aumayr
- Department of Pathology, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Gregor Heiduschka
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Sven Schneider
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Elisabeth Enzenhofer
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Claudia Lill
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
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Westphalen CB, Quante M, Wang TC. Functional implication of Dclk1 and Dclk1-expressing cells in cancer. Small GTPases 2016; 8:164-171. [PMID: 27458755 DOI: 10.1080/21541248.2016.1208792] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Doublecortin like kinase protein 1 (Dclk1) is a microtubule-associated protein with C-terminal serine/threonine kinase domain. Originally designated Doublecortin and CaM kinase-like 1 protein (Dcamkl1) or KIAA0369, Dclk1 was first described as a marker for radial glia cells in the context of microtubule polymerization and neuronal migration, possibly contributing to early neurogenesis. Additionally, Dclk1 was proposed as a marker of quiescent gastrointestinal and pancreatic stem cells, but in recent years has been recognized as a marker for tuft cells in the gastrointestinal tract. While Dclk1+ tuft cells are now considered as niche or sensory cells in the normal gut, growing evidence supports a role for Dclk1 function in a variety of malignancies, modulating the activity of multiple key pathways, including Kras signaling. Here, we review the recent advances in understanding of the importance of Dclk1 function in tumorigenesis and cancer.
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Affiliation(s)
- C Benedikt Westphalen
- a Department of Internal Medicine III , Ludwig Maximilians University Munich , Munich , Germany
| | - Michael Quante
- b Department of Internal Medicine II , Klinikum rechts der Isar II, Technische Universität München , Munich , Germany
| | - Timothy C Wang
- c Divison of Digestive and Liver Disease , Columbia University Medical Center , New York , NY , USA.,d Herberg Irving Comprehensive Cancer Center , Columbia University Medical Center , New York , NY , USA
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