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Chatzidavid S, Kontandreopoulou CN, Giannakopoulou N, Diamantopoulos PT, Stafylidis C, Kyrtsonis MC, Dimou M, Panayiotidis P, Viniou NA. The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review. Adv Hematol 2024; 2024:1370364. [PMID: 38435839 PMCID: PMC10907108 DOI: 10.1155/2024/1370364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/04/2024] [Accepted: 02/09/2024] [Indexed: 03/05/2024] Open
Abstract
Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers.
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Affiliation(s)
- Sevastianos Chatzidavid
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Thalassemia and Sickle Cell Disease Center, Laikon General Hospital, Athens, Greece
| | - Christina-Nefeli Kontandreopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Panagiotis T. Diamantopoulos
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Christos Stafylidis
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Marie-Christine Kyrtsonis
- Hematology Section of the First Department of Propaedeutic Internal Medicine, Laikon University Hospital, Athens, Greece
| | - Maria Dimou
- Hematology Section of the First Department of Propaedeutic Internal Medicine, Laikon University Hospital, Athens, Greece
| | - Panayiotis Panayiotidis
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital, Athens, Greece
| | - Nora-Athina Viniou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Hematology Department, Iatriko Kentro Palaiou Falirou, Athens, Greece
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2
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van Golen KL. Inflammatory breast cancer biomarkers and biology. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 384:63-76. [PMID: 38637100 DOI: 10.1016/bs.ircmb.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
Inflammatory breast cancer (IBC) is a unique breast cancer with a highly virulent course and low 5- and 10-year survival rates. Even though it only accounts for 1-5% of breast cancers it is estimated to account for 10% of breast cancer deaths annually in the United States. The accuracy of diagnosis and classification of this unique cancer is a major concern within the medical community. Early molecular and biological studies incidentally included IBC samples with other conventional breast cancers and were not informative as to the unique nature of the disease. Subsequent molecular studies that focused specifically on IBC demonstrated that IBC has a unique biology different from other forms of breast cancer. Additionally, a handful of unique signature genes that are hallmarks of IBC have also been suggested. Further understanding of IBC biology can help with diagnosis and treatment of the disease. The current article reviews the history and highlights of IBC studies.
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Affiliation(s)
- Kenneth L van Golen
- Department of Biological Sciences, The University of Delaware, Newark, DE, United States; The Center for Translational Cancer Research, Newark, DE, United States.
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3
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Song Y, Li C, Luo Y, Guo J, Kang Y, Yin F, Ye L, Sun D, Yu J, Zhang X. CCN6 improves hepatic steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis. Liver Int 2023; 43:357-369. [PMID: 36156376 DOI: 10.1111/liv.15430] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/20/2022] [Accepted: 09/20/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS CCN6 is a secretory protein with functions of maintaining mitochondrial homeostasis and anti-oxidative stress; and yet, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) is still obscure. We investigated the role and mechanism of CCN6 in the development of NASH. METHODS Human liver tissue samples were collected to detect the expression profile of CCN6. High-fat-high-cholesterol (HFHC) and methionine choline-deficient (MCD) diet were applied to mice to establish NASH animal models. Liver-specific overexpression of CCN6 was induced in mice by tail vein injection of adeno-associated virus (AAV), and then the effect of CCN6 on the course of NASH was observed. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model of steatosis, and the effect of CCN6 was investigated by knocking down the expression of CCN6 through small interfering RNA (siRNA) transfection. RESULTS We found that CCN6 expression was significantly downregulated in the liver of NASH. We confirmed that liver-specific overexpression of CCN6 significantly attenuated hepatic steatosis, inflammation response and fibrosis in NASH mice. Based on RNA-seq analysis, we revealed that CCN6 significantly affected the MAPK pathway. Then, by interfering with apoptosis signal-regulating kinase 1 (ASK1), we identified the ASK1/MAPK pathway pairs as the targets of CCN6 action. CONCLUSIONS CCN6 protects against hepatic steatosis, inflammation response and fibrosis by inhibiting the activation of ASK1 along with its downstream MAPK signalling. CCN6 may be a potential therapeutic target for the treatment of NASH.
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Affiliation(s)
- Yiran Song
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chenyang Li
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuxin Luo
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jinbo Guo
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yaxing Kang
- Department of Endocrinology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Fengrong Yin
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lihong Ye
- Department of Pathology, Shijiazhuang Fifth Hospital, Shijiazhuang, China
| | - Donglei Sun
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Yu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaolan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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4
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Zhang Y, Xie Y, Huang X, Zhang L, Shu K. Screening of Hub Genes in Hepatocellular Carcinoma Based on Network Analysis and Machine Learning. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:7300788. [PMID: 36479313 PMCID: PMC9722289 DOI: 10.1155/2022/7300788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/11/2022] [Accepted: 11/01/2022] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (LIHC) is the fifth common cancer worldwide, and it requires effective diagnosis and treatment to prevent aggressive metastasis. The purpose of this study was to construct a machine learning-based diagnostic model for the diagnosis of liver cancer. Using weighted correlation network analysis (WGCNA), univariate analysis, and Lasso-Cox regression analysis, protein-protein interactions network analysis is used to construct gene networks from transcriptome data of hepatocellular carcinoma patients and find hub genes for machine learning. The five models, including gradient boosting, random forest, support vector machine, logistic regression, and integrated learning, were to identify a multigene prediction model of patients. Immunological assessment, TP53 gene mutation and promoter methylation level analysis, and KEGG pathway analysis were performed on these groups. Potential drug molecular targets for the corresponding hepatocellular carcinomas were obtained by molecular docking for analysis, resulting in the screening of 2 modules that may be relevant to the survival of hepatocellular carcinoma patients, and the construction of 5 diagnostic models and multiple interaction networks. The modes of action of drug-molecule interactions that may be effective against hepatocellular carcinoma core genes CCNA2, CCNB1, and CDK1 were investigated. This study is expected to provide research ideas for early diagnosis of hepatocellular carcinoma.
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Affiliation(s)
- Yu Zhang
- School of Bioinformatics, Chongqing University of Posts and Telecommunications, 400000, China
| | - Yongfang Xie
- School of Bioinformatics, Chongqing University of Posts and Telecommunications, 400000, China
| | - Xiaorong Huang
- School of Bioinformatics, Chongqing University of Posts and Telecommunications, 400000, China
| | - Langlang Zhang
- School of Bioinformatics, Chongqing University of Posts and Telecommunications, 400000, China
| | - Kunxian Shu
- School of Bioinformatics, Chongqing University of Posts and Telecommunications, 400000, China
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5
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Yu X, Mao R, Feng W, Zhao Y, Qin J, Yang Y, Wang A, Shi Z. WISP3 suppresses ESCC progression by inhibiting the IGF-2-IGF1R-AKT signaling cascade. Exp Cell Res 2021; 409:112871. [PMID: 34672999 DOI: 10.1016/j.yexcr.2021.112871] [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: 04/04/2021] [Revised: 09/06/2021] [Accepted: 10/07/2021] [Indexed: 11/19/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a major health problem worldwide, especially in the Chinese population. However, the intrinsic molecular mechanisms of ESCC progression are largely unclear, thus there is an unmet need to identify essential genes governing this disease. Here, we discovered WISP3, an important member of the CCN family, is markedly downregulated in ESCC tissues compared to the normal esophageal epithelium. Downregulation of WISP3 in cancer tissue correlates with worse overall survival of ESCC patients. Using ESCC cell lines as models, we found that forced expression of WISP3 not only suppressed proliferation and migration of cancer cells in vitro, but also inhibited ESCC tumor growth and metastasis in vivo. On the contrary, WISP3 depletion strongly promoted the tumorigenicity of ESCC cells. Mechanistically, we found that WISP3 negates the activity of AKT via inhibiting the IGF-2-IGF1R signaling cascade, which mediates the tumor-suppressive function of WISP3 in esophageal cancers. Together, we identified a novel factor driving the development of ESCC, and revealed a potential therapeutic target for ESCC treatment.
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Affiliation(s)
- Xiaofu Yu
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Ruoying Mao
- The First Hospital of Zhejiang Province, Hangzhou, Zhejiang, 310000, China
| | - Wei Feng
- Department of Radiation Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Yazhen Zhao
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Jing Qin
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Yunshan Yang
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China
| | - Ansheng Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical College, 233004, China
| | - Zhong Shi
- Department of Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
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6
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Tran M, Leflein SA, Gonzalez ME, Kleer CG. The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas. J Cell Commun Signal 2021; 16:433-445. [PMID: 34811632 DOI: 10.1007/s12079-021-00657-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 11/08/2021] [Indexed: 11/28/2022] Open
Abstract
Metaplastic breast carcinoma (MBC) is an aggressive subtype of triple negative breast cancer with undefined precursors, limited response to chemotherapy, and frequent distant metastasis. Our laboratory has reported that CCN6/WISP3, a secreted protein that regulates growth factor signaling, is downregulated in over 85% of MBCs. Through generation of a mammary epithelial cell-specific Ccn6 knockout mouse model (MMTV-cre;Ccn6fl/fl) we have demonstrated that CCN6 is a tumor suppressor for MBC; MMTV-cre;Ccn6fl/fl mice develop tumors recapitulating the histopathology and proteogenomic landscape of human MBC, but the mechanisms need further investigation. In this study, we report that preneoplastic mammary glands of 8-week-old MMTV-Cre;Ccn6fl/fl female mice show significant downregulation of mitochondrial respiratory chain genes compared to controls, which are further downregulated in MBCs of MMTV-Cre;Ccn6fl/fl mice and humans. We found that CCN6 downregulation in non-tumorigenic breast cells reduces mitochondrial respiration and increases resistance to stress-induced apoptosis compared to controls. Intracellular ectopic CCN6 protein localizes to the mitochondria in MDA-MB-231 mesenchymal-like breast cancer cells, increases mitochondrial respiration and generation of reactive oxygen species, and reverses doxorubicin resistance of MBC cells. Our data highlight a novel function of CCN6 in the regulation of redox states in preneoplastic progression and suggest potential preventative and treatment strategies against MBC based on CCN6 upregulation.
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Affiliation(s)
- Mai Tran
- Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Shoshana A Leflein
- Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Maria E Gonzalez
- Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Celina G Kleer
- Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA. .,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
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7
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Leon KE, Buj R, Lesko E, Dahl ES, Chen CW, Tangudu NK, Imamura-Kawasawa Y, Kossenkov AV, Hobbs RP, Aird KM. DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A. J Cell Biol 2021; 220:e202008101. [PMID: 34037658 PMCID: PMC8160577 DOI: 10.1083/jcb.202008101] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 04/06/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.
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Affiliation(s)
- Kelly E. Leon
- Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, PA
| | - Raquel Buj
- Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Elizabeth Lesko
- Department of Dermatology, Penn State College of Medicine, Hershey, PA
| | - Erika S. Dahl
- Biomedical Sciences Graduate Program, Penn State College of Medicine, Hershey, PA
| | - Chi-Wei Chen
- Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Naveen Kumar Tangudu
- Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | | | | - Ryan P. Hobbs
- Department of Dermatology, Penn State College of Medicine, Hershey, PA
| | - Katherine M. Aird
- Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA
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PLEKHA7, an Apical Adherens Junction Protein, Suppresses Inflammatory Breast Cancer in the Context of High E-Cadherin and p120-Catenin Expression. Int J Mol Sci 2021; 22:ijms22031275. [PMID: 33525380 PMCID: PMC7865280 DOI: 10.3390/ijms22031275] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.
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9
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Zhu Y, Almuntashiri S, Han Y, Wang X, R. Somanath P, Zhang D. The Roles of CCN1/CYR61 in Pulmonary Diseases. Int J Mol Sci 2020; 21:ijms21217810. [PMID: 33105556 PMCID: PMC7659478 DOI: 10.3390/ijms21217810] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
CCN1 (cysteine-rich 61, connective tissue growth factor, and nephroblastoma-1), previously named CYR61 (cysteine-rich angiogenic inducer 61) belongs to the CCN family of matricellular proteins. CCN1 plays critical roles in the regulation of proliferation, differentiation, apoptosis, angiogenesis, and fibrosis. Recent studies have extensively characterized the important physiological and pathological roles of CCN1 in various tissues and organs. In this review, we summarize both basic and clinical aspects of CCN1 in pulmonary diseases, including acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), lung fibrosis, pulmonary arterial hypertension (PAH), lung infection, and lung cancer. We also emphasize the important challenges for future investigations to better understand the CCN1 and its role in physiology and pathology, as well as the questions that need to be addressed for the therapeutic development of CCN1 antagonists in various lung diseases.
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Affiliation(s)
- Yin Zhu
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; (Y.Z.); (S.A.); (Y.H.); (P.R.S.)
| | - Sultan Almuntashiri
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; (Y.Z.); (S.A.); (Y.H.); (P.R.S.)
| | - Yohan Han
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; (Y.Z.); (S.A.); (Y.H.); (P.R.S.)
| | - Xiaoyun Wang
- Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA;
| | - Payaningal R. Somanath
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; (Y.Z.); (S.A.); (Y.H.); (P.R.S.)
- Department of Medicine, Augusta University, Augusta, GA 30912, USA
| | - Duo Zhang
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA; (Y.Z.); (S.A.); (Y.H.); (P.R.S.)
- Correspondence: ; Tel.: +1-706-721-6491; Fax: +1-706-721-3994
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10
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Dobiasova B, Mego M. Biomarkers for Inflammatory Breast Cancer: Diagnostic and Therapeutic Utility. BREAST CANCER-TARGETS AND THERAPY 2020; 12:153-163. [PMID: 33116817 PMCID: PMC7569067 DOI: 10.2147/bctt.s231502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/03/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory breast cancer (IBC) is a rare and highly aggressive subtype of advanced breast cancer. The aggressive behavior, resistance to chemotherapy, angiogenesis, and high metastatic potential are key intrinsic characteristics of IBC caused by many specific factors. Pathogenesis and behavior of IBC are closely related to tumor surrounding inflammatory and immune cells, blood vessels, and extracellular matrix, which are all components of the tumor microenvironment (TME). The tumor microenvironment has a crucial role in the local immune r09esponse. The communication between intrinsic and extrinsic components of IBC and the abundance of cytokines and chemokines in the TME strongly contribute to the aggressiveness and high angiogenic potential of this tumor. Critical modes of interaction are cytokine-mediated communication and direct intercellular contact between cancer cells and tumor microenvironment with a variety of pathway crosstalk. This review aimed to summarize current knowledge of predictive and prognostic biomarkers in IBC.
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Affiliation(s)
- Barbora Dobiasova
- 2 Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Bratislava, Slovak Republic
| | - Michal Mego
- 2 Department of Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Bratislava, Slovak Republic
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11
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Wu J, Lv Q, Huang H, Zhu M, Meng D. Screening and Identification of Key Biomarkers in Inflammatory Breast Cancer Through Integrated Bioinformatic Analyses. Genet Test Mol Biomarkers 2020; 24:484-491. [PMID: 32598242 DOI: 10.1089/gtmb.2020.0047] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: Inflammatory breast cancer (IBC) is a rare type of breast cancer with poor prognoses, moreover its pathogenesis is not entirely clear. The aim of this study was to identify key genes of IBC, which might serve as diagnostic biomarkers and/or therapeutic targets. Methods: Two microarray datasets, GSE23720 and GSE45581, were obtained from the Gene Expression Omnibus database, and a differential expression analysis was performed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to understand the potential biological functions of the differentially expressed genes (DEGs). Next, a protein-protein interaction (PPI) network was constructed and visualized by Cytoscape. Functional modules and hub genes were screened using MCODE and cytohubba plug-ins, and the Cancer Genome Atlas survival analysis along with quantitative reverse transcriptional polymerase chain reactions of clinical samples was used to validate the effect that the hub genes have on IBC. Results: A total of 215 DEGs were identified, consisting of 105 upregulated and 110 downregulated genes. GO and KEGG analyses showed that the enriched terms and pathways were mainly associated with cell cycle, proliferation, drug metabolism, and oncogenesis. From the PPI network, we identified six hub genes, including Cell Division Cycle 45 (CDC45), Polo Like Kinase 1 (PLK1), BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B), Cell Division Cycle 20 (CDC20), Aurora Kinase A (AURKA), and Mitotic Arrest Deficient 2 Like 1 (MAD2L1). The survival analyses and expression validation studies verified the robustness of these hub genes. Conclusion: This study provides new insights into the understanding of the molecular mechanisms of IBC; in addition, the identified hub genes may serve as potential targets for diagnosis and treatment.
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Affiliation(s)
- Junqiang Wu
- Department of Breast Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Qing Lv
- Department of Breast Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Hu Huang
- Department of Breast Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Mingjie Zhu
- Department of Breast Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Dong Meng
- Department of Breast Surgery, The Affiliated Hospital of Jiangnan University, Wuxi, China
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12
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McMullen ER, Zoumberos NA, Kleer CG. Metaplastic Breast Carcinoma: Update on Histopathology and Molecular Alterations. Arch Pathol Lab Med 2020; 143:1492-1496. [PMID: 31765246 DOI: 10.5858/arpa.2019-0396-ra] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT— Metaplastic carcinoma is a rare, triple-negative carcinoma of the breast that exhibits transformation of part or all of its glandular carcinomatous component into a nonglandular, or metaplastic, component. The World Health Organization currently recognizes 5 variants of metaplastic carcinoma based on their histologic appearance. OBJECTIVE— To review the histologic classifications, differential diagnosis, prognosis, and recent laboratory studies of metaplastic breast carcinoma. DATA SOURCES.— We reviewed recently published studies that collectively examine metaplastic carcinomas, including results from our own research. CONCLUSIONS.— Metaplastic breast carcinoma has a broad spectrum of histologic patterns, often leading to a broad differential diagnosis. Diagnosis can typically be rendered by a combination of morphology and immunohistochemical staining for high-molecular-weight cytokeratins and p63. Recent studies elucidate new genes and pathways involved in the pathogenesis of metaplastic carcinoma, including the downregulation of CCN6 and WNT pathway gene mutations, and provide a novel MMTV-Cre;Ccn6fl/fl knockout disease-relevant mouse model to test new therapies.
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Affiliation(s)
- Emily R McMullen
- From the Department of Pathology (Drs McMullen, Zoumberos, and Kleer) and Rogel Cancer Center (Dr Kleer), University of Michigan Medical School, Ann Arbor
| | - Nicholas A Zoumberos
- From the Department of Pathology (Drs McMullen, Zoumberos, and Kleer) and Rogel Cancer Center (Dr Kleer), University of Michigan Medical School, Ann Arbor
| | - Celina G Kleer
- From the Department of Pathology (Drs McMullen, Zoumberos, and Kleer) and Rogel Cancer Center (Dr Kleer), University of Michigan Medical School, Ann Arbor
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13
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Di Bonito M, Cantile M, Botti G. Pathological and molecular characteristics of inflammatory breast cancer. Transl Cancer Res 2019; 8:S449-S456. [PMID: 35117122 PMCID: PMC8798351 DOI: 10.21037/tcr.2019.03.24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 03/18/2019] [Indexed: 11/11/2022]
Abstract
Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer characterized by the presence of many dermal tumor emboli in the papillary and reticular dermis of the skin overlying the breast. IBC patients, compared to other breast cancer patients, have more frequently metastatic axillary lymph nodes. IBC is often high grade, negative for hormone receptors and presents with amplification of the HER2 gene. Invasive IBC is frequently of ductal phenotype, even if a specific histological distinction for these lesions has not been described. The pathogenesis and evolution of IBC are strongly dependent upon tumor microenvironment, characterized by several macrophages/monocytes and lymphocytes. The tumor and microenvironment cells are well molecularly characterized, showing the main contributor of inflammatory pathways in tumor biology of IBC. In addition, several molecular alterations are described in this tumor, such as mutations of ERBB2, KRAS, BRAF, EGFR, PIK3CA, PTEN, AKT1, and AKT3 genes that could suggest a therapeutic stratification of IBC patients with the combination of different biological target therapies.
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Affiliation(s)
- Maurizio Di Bonito
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Monica Cantile
- Pathology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
| | - Gerardo Botti
- Scientific Direction, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy
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14
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Kretzmann JA, Evans CW, Moses C, Sorolla A, Kretzmann AL, Wang E, Ho D, Hackett MJ, Dessauvagie BF, Smith NM, Redfern AD, Waryah C, Norret M, Iyer KS, Blancafort P. Tumour suppression by targeted intravenous non-viral CRISPRa using dendritic polymers. Chem Sci 2019; 10:7718-7727. [PMID: 31588320 PMCID: PMC6761875 DOI: 10.1039/c9sc01432b] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/26/2019] [Indexed: 12/22/2022] Open
Abstract
This article demonstrates a fully synthetic strategy enabling CRISPR-mediated activation of tumour suppressor genes in vivo to reduce tumour burden.
Aberrant gene expression is a hallmark of cancer. Although transcription is traditionally considered ‘undruggable’, the development of CRISPR-associated protein 9 (Cas9) systems offers enormous potential to rectify cancer-associated transcriptional abnormalities in malignant cells. However delivery of this technology presents a critical challenge to overcome in order to realize clinical translation for cancer therapy. In this article we demonstrate for the first time, a fully synthetic strategy to enable CRISPR-mediated activation (CRISPRa) of tumour suppressor genes in vivo using a targeted intravenous approach. We show this via highly efficient transcriptional activation of two model tumour suppressor genes, Mammary Serine Protease Inhibitor (MASPIN, SERPINB5) and cysteine-rich 61/connective tissue growth factor/nephroblastoma-overexpressed 6 (CCN6, WISP3), in a mouse model of breast cancer. In particular, we demonstrate that targeted intravenous delivery of can be achieved using a novel nanoscale dendritic macromolecular delivery agent, with negligible toxicity and long lasting therapeutic effects, outlining a targeted effective formulation with potential to treat aggressive malignancies.
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Affiliation(s)
- Jessica A Kretzmann
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia . .,Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia .
| | - Cameron W Evans
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - Colette Moses
- Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia . .,School of Human Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia
| | - Anabel Sorolla
- Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia .
| | - Amy L Kretzmann
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - Edina Wang
- Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia .
| | - Diwei Ho
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - Mark J Hackett
- Curtin Institute for Functional Molecules and Interfaces , Curtin Health Innovation Research Institute , Department of Chemistry , Curtin University , Bentley , WA 6845 , Australia
| | - Benjamin F Dessauvagie
- Anatomical Pathology, PathWest Laboratory Medicine , Fiona Stanley Hospital , Murdoch , WA , Australia.,School of Medicine , The University of Western Australia , Crawley , WA , Australia
| | - Nicole M Smith
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - Andrew D Redfern
- School of Medicine , The University of Western Australia , Crawley , WA , Australia
| | - Charlene Waryah
- Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia .
| | - Marck Norret
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - K Swaminathan Iyer
- School of Molecular Sciences , The University of Western Australia , 35 Stirling Hwy , Crawley , WA 6009 , Australia .
| | - Pilar Blancafort
- Harry Perkins Institute of Medical Research , 6 Verdun St , Nedlands , WA 6009 , Australia .
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15
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Gao H, Yin FF, Guan DX, Feng YX, Zheng QW, Wang X, Zhu M, Zhang XL, Cheng SQ, Chen TW, Jiang H, Zhang EB, Wang JJ, Ni QZ, Yuan YM, Zhang FK, Ma N, Cao HJ, Wang YK, Li JJ, Xie D. Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling. Cell Prolif 2019; 52:e12583. [PMID: 30793395 PMCID: PMC6536422 DOI: 10.1111/cpr.12583] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 01/19/2019] [Accepted: 01/21/2019] [Indexed: 01/09/2023] Open
Abstract
Objectives Wnt1‐inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. Materials and Methods The expression of WISP3/CCN6 was analysed by qRT‐PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. Results The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of β‐catenin to the nucleus by activating glycogen synthase kinase‐3β (GSK3β). Moreover, constitutively active β‐catenin blocked the suppressive effects of WISP3 on HCC. Conclusions Our study showed that WISP3 suppressed the progression of HCC by negative regulation of β‐catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.
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Affiliation(s)
- Hong Gao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fen-Fen Yin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dong-Xian Guan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yu-Xiong Feng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qian-Wen Zheng
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Xiang Wang
- Department of Surgery, First People's Hospital Affiliated, Huzhou University, Huzhou, China
| | - Min Zhu
- Department of Surgery, First People's Hospital Affiliated, Huzhou University, Huzhou, China
| | - Xue-Li Zhang
- Department of General Surgery, Fengxian Hospital Affiliated to Southern Medical University, Shanghai, China
| | - Shu-Qun Cheng
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Tian-Wei Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hao Jiang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Er-Bin Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jing-Jing Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qian-Zhi Ni
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yan-Mei Yuan
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feng-Kun Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ning Ma
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Hui-Jun Cao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yi-Kang Wang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jing-Jing Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Dong Xie
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, China.,NHC Key Laboratory of Food Safety Risk Assessment, China National Center for Food Safety Risk Assessment, Beijing, China
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16
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Abstract
The CCN protein family is composed of six matricellular proteins, which serve regulatory roles rather than structural roles in the extracellular matrix. First identified as secreted proteins which are induced by oncogenes, the acronym CCN came from the names of the first three members: CYR61, CTGF, and NOV. All six members of the CCN family consist of four cysteine-rich modular domains. CCN proteins are known to regulate cell adhesion, proliferation, differentiation, and apoptosis. In addition, CCN proteins are associated with cardiovascular and skeletal development, injury repair, inflammation, and cancer. They function either through binding to integrin receptors or by regulating the expression and activity of growth factors and cytokines. Given their diverse roles related to the pathology of certain diseases such as fibrosis, arthritis, atherosclerosis, diabetic nephropathy, retinopathy, and cancer, there are many emerging studies targeting CCN protein signaling pathways in attempts to elucidate their potentials as therapeutic targets. [BMB Reports 2018; 51(10): 486-493].
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Affiliation(s)
- Hyungjoo Kim
- Department of Life Science, Hanyang University, Seoul 04763, Korea
| | - Seogho Son
- Department of Life Science, Hanyang University, Seoul 04763, Korea
| | - Incheol Shin
- Department of Life Science, Hanyang University, Seoul 04763, and Natural Science Institute, Hanyang University, Seoul 04763, Korea
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17
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Liu Y, Song Y, Ye M, Hu X, Wang ZP, Zhu X. The emerging role of WISP proteins in tumorigenesis and cancer therapy. J Transl Med 2019; 17:28. [PMID: 30651114 PMCID: PMC6335850 DOI: 10.1186/s12967-019-1769-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 01/02/2019] [Indexed: 12/14/2022] Open
Abstract
Accumulated evidence has demonstrated that WNT1 inducible signaling pathway protein (WISP) genes, which belong to members of the CCN growth factor family, play a pivotal role in tumorigenesis and progression of a broad spectrum of human cancers. Mounting studies have identified that WISP proteins (WISP1-3) exert different biological functions in various human malignancies. Emerging evidence indicates that WISP proteins are critically involved in cell proliferation, apoptosis, invasion and metastasis in cancers. Because the understanding of a direct function of WISP proteins in cancer development and progression has begun to emerge, in this review article, we describe the physiological function of WISP proteins in a variety of human cancers. Moreover, we highlight the current understanding of how the WISP protein is involved in tumorigenesis and cancer progression. Furthermore, we discuss that targeting WISP proteins could be a promising strategy for the treatment of human cancers. Hence, the regulation of WISP proteins could improve treatments for cancer patients.
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Affiliation(s)
- Yi Liu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Yizuo Song
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Miaomiao Ye
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Xiaoli Hu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
| | - Z. Peter Wang
- Center of Scientific Research, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027 Zhejiang China
- Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, 233030 Anhui China
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 USA
| | - Xueqiong Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, No. 109 Xueyuan Xi Road, Wenzhou, 325027 Zhejiang China
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18
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Mamouch F, Berrada N, Aoullay Z, El Khanoussi B, Errihani H. Inflammatory Breast Cancer: A Literature Review. World J Oncol 2018; 9:129-135. [PMID: 30524636 PMCID: PMC6279456 DOI: 10.14740/wjon1161] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 10/25/2018] [Indexed: 01/13/2023] Open
Abstract
The multidisciplinary management of inflammatory breast cancer (IBC), which is the most aggressive form of breast cancer due to its rapid proliferation, has changed over the past three decades thanks to advances in medical treatments that represent the basis of treatment, without eliminating the use of locoregional treatments including surgery and radiotherapy in the localized stages. The molecular profile determination of IBC allows the orientation towards new targeted therapeutic strategies with an impact on survival.
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Affiliation(s)
- Fouzia Mamouch
- Mohammed V University, Rabat, Morocco.,National Institute of Oncology, Rabat, Morocco
| | | | - Zineb Aoullay
- Mohammed V University, Rabat, Morocco.,National Institute of Oncology, Rabat, Morocco
| | | | - Hassan Errihani
- Mohammed V University, Rabat, Morocco.,National Institute of Oncology, Rabat, Morocco
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19
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McMullen ER, Gonzalez ME, Skala SL, Tran M, Thomas D, Djomehri SI, Burman B, Kidwell KM, Kleer CG. CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast. Breast Cancer Res Treat 2018; 172:577-586. [PMID: 30220054 DOI: 10.1007/s10549-018-4960-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 09/05/2018] [Indexed: 01/02/2023]
Abstract
PURPOSE Metaplastic breast carcinomas are an aggressive subtype of triple-negative breast cancer (TNBC) in which part or all of the adenocarcinoma transforms into a non-glandular component (e.g., spindled, squamous, or heterologous). We discovered that mammary-specific Ccn6/Wisp3 knockout mice develop mammary carcinomas with spindle and squamous differentiation that share upregulation of the oncofetal proteins IGF2BP2 (IMP2) and HMGA2 with human metaplastic carcinomas. Here, we investigated the functional relationship between CCN6, IGF2BP2, and HMGA2 proteins in vitro and in vivo, and their expression in human tissue samples. METHODS MMTV-cre;Ccn6fl/fl tumors and spindle TNBC cell lines were treated with recombinant CCN6 protein or vehicle. IGF2BP2 was downregulated using shRNAs in HME cells with stable CCN6 shRNA knockdown, and subjected to invasion and adhesion assays. Thirty-one human metaplastic carcinomas were arrayed in a tissue microarray (TMA) and immunostained for CCN6, IGF2BP2, and HMGA2. RESULTS CCN6 regulates IGF2BP2 and HMGA2 protein expression in MMTV-cre;Ccn6fl/fl tumors, in MDA-MB-231 and - 468, and in HME cells. CCN6 recombinant protein reduced IGF2BP2 and HMGA2 protein expression, and decreased growth of MMTV-cre;Ccn6fl/fl tumors in vivo. IGF2BP2 shRNA knockdown was sufficient to reverse the invasive abilities conferred by CCN6 knockdown in HME cells. Analyses of the TCGA Breast Cancer Cohort (n = 1238) showed that IGF2BP2 and HMGA2 are significantly upregulated in metaplastic carcinoma compared to other breast cancer subtypes. In clinical samples, low CCN6 is frequent in tumors with high IGF2BP2/HMGA2 with spindle and squamous differentiation. CONCLUSIONS These data shed light into the pathogenesis of metaplastic carcinoma and demonstrate a novel CCN6/IGF2BP2/HMGA2 oncogenic pathway with biomarker and therapeutic implications.
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Affiliation(s)
- Emily R McMullen
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Maria E Gonzalez
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Stephanie L Skala
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Mai Tran
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Dafydd Thomas
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Sabra I Djomehri
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Boris Burman
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Kelley M Kidwell
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Department of Biostatistics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Celina G Kleer
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
- Department of Pathology, University of Michigan Medical School, 4217 Rogel Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
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20
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Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas. J Cell Commun Signal 2018; 12:13-19. [PMID: 29357008 DOI: 10.1007/s12079-018-0451-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 02/07/2023] Open
Abstract
Located at 6q22-23, Ccn6 (WISP3) encodes for a matrix-associated protein of the CCN family, characterized by regulatory, rather than structural, roles in development and cancer. CCN6, the least studied member of the CCN family, shares the conserved multimodular structure of CCN proteins, as well as their tissue and cell-type specific functions. In the breast, CCN6 is a critical regulator of epithelial-to-mesenchymal transitions (EMT) and tumor initiating cells. Studies using human breast cancer tissue samples demonstrated that CCN6 messenger RNA and protein are expressed in normal breast epithelia but reduced or lost in aggressive breast cancer phenotypes, especially inflammatory breast cancer and metaplastic carcinomas. Metaplastic carcinomas are mesenchymal-like triple negative breast carcinomas, enriched for markers of EMT and stemness. RNAseq analyses of the TCGA Breast Cancer cohort show reduced CCN6 expression in approximately 50% of metaplastic carcinomas compared to normal breast. Our group identified frameshift mutations of Ccn6 in a subset of human metaplastic breast carcinoma. Importantly, conditional, mammary epithelial-cell specific ccn6 (wisp3) knockout mice develop invasive high-grade mammary carcinomas that recapitulate human spindle cell metaplastic carcinomas, demonstrating a tumor suppressor function for ccn6. Our studies on CCN6 functions in metaplastic carcinoma highlight the potential of CCN6 as a novel therapeutic approach for this specific type of breast cancer.
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21
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Raposo TP, Arias-Pulido H, Chaher N, Fiering SN, Argyle DJ, Prada J, Pires I, Queiroga FL. Comparative aspects of canine and human inflammatory breast cancer. Semin Oncol 2018. [PMID: 29526258 DOI: 10.1053/j.seminoncol.2017.10.012] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory breast cancer (IBC) in humans is the most aggressive form of mammary gland cancer and shares clinical, pathologic, and molecular patterns of disease with canine inflammatory mammary carcinoma (CIMC). Despite the use of multimodal therapeutic approaches, including targeted therapies, the prognosis for IBC/CIMC remains poor. The aim of this review is to critically analyze IBC and CIMC in terms of biology and clinical features. While rodent cancer models have formed the basis of our understanding of cancer biology, the translation of this knowledge into improved outcomes has been limited. However, it is possible that a comparative "one health" approach to research, using a natural canine model of the disease, may help advance our knowledge on the biology of the disease. This will translate into better clinical outcomes for both species. We propose that CIMC has the potential to be a useful model for developing and testing novel therapies for IBC. Further, this strategy could significantly improve and accelerate the design and establishment of new clinical trials to identify novel and improved therapies for this devastating disease in a more predictable way.
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Affiliation(s)
- Teresa P Raposo
- Division of Cancer and Stem Cells, Faculty of Medicine, University of Nottingham, United Kingdom
| | - Hugo Arias-Pulido
- Department of Microbiology and Immunology and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA
| | - Nabila Chaher
- Department of Pathology, Centre Pierre et Marie Curie, 1, Avenue Battendier, Place May 1st, Algiers, Algeria
| | - Steven N Fiering
- Department of Microbiology and Immunology and Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA
| | - David J Argyle
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, Easter Bush Campus, Midlothian, University of Edinburgh, United Kingdom
| | - Justina Prada
- Departament of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal; Animal and Veterinary research Centre (CECAV), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Isabel Pires
- Departament of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal; Animal and Veterinary research Centre (CECAV), University of Trás-os-Montes and Alto Douro, Vila Real, Portugal
| | - Felisbina Luísa Queiroga
- Departament of Veterinary Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal; Center for the Study of Animal Sciences, CECA-ICETA, University of Porto, Porto, Portugal; Center for Research and Technology of Agro-Environment and Biological Sciences, University of Trás-os-Montes and Alto Douro, Vila Real, Portugal.
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22
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The matricellular protein CCN6 (WISP3) decreases Notch1 and suppresses breast cancer initiating cells. Oncotarget 2018; 7:25180-93. [PMID: 26933820 PMCID: PMC5041896 DOI: 10.18632/oncotarget.7734] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 02/08/2016] [Indexed: 01/04/2023] Open
Abstract
Increasing evidence supports that the epithelial to mesenchymal transition (EMT) in breast cancer cells generates tumor initiating cells (TICs) but the contribution of the tumor microenvironment to these programs needs further elucidation. CCN6 (WISP3) is a secreted matrix-associated protein (36.9 kDa) of the CCN family (named after CTGF, Cyr61 and Nov) that is reduced or lost in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. CCN6 exerts breast cancer growth and invasion inhibitory functions, but the mechanisms remain to be defined. In the present study we discovered that ectopic CCN6 overexpression in triple negative (TN) breast cancer cells and in cells derived from patients is sufficient to induce a mesenchymal to epithelial transition (MET) and to reduce TICs. In vivo, CCN6 overexpression in the TIC population of MDA-MB-231 cells delayed tumor initiation, reduced tumor volume, and inhibited the development of metastasis. Our studies reveal a novel CCN6/Slug signaling axis that regulates Notch1 signaling activation, epithelial cell phenotype and breast TICs, which requires the conserved thrombospondin type 1 (TSP1) motif of CCN6. The relevance of these data to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely correlated with Notch1 intracellular activated form (NICD1) in 69.5% of invasive breast carcinomas. These results demonstrate that CCN6 regulates epithelial and mesenchymal states transition and TIC programs, and pinpoint one responsible mechanism.
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23
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Lin CC, Chen PC, Lein MY, Tsao CW, Huang CC, Wang SW, Tang CH, Tung KC. WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells. Oncotarget 2017; 7:9993-10005. [PMID: 26824419 PMCID: PMC4891098 DOI: 10.18632/oncotarget.7014] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 01/01/2016] [Indexed: 01/19/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.
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Affiliation(s)
- Ching-Chia Lin
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Po-Chun Chen
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan
| | - Ming-Yu Lein
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Wen Tsao
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | | | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
| | - Kwong-Chung Tung
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
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24
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MMTV-cre;Ccn6 knockout mice develop tumors recapitulating human metaplastic breast carcinomas. Oncogene 2016; 36:2275-2285. [PMID: 27819674 PMCID: PMC5398917 DOI: 10.1038/onc.2016.381] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/29/2016] [Accepted: 09/04/2016] [Indexed: 02/07/2023]
Abstract
Metaplastic breast carcinoma is an aggressive form of invasive breast cancer with histological evidence of epithelial to mesenchymal transition (EMT). However, the defining molecular events are unknown. Here we show that CCN6 (WISP3), a secreted matricellular protein of the CCN (CYR61/CTGF/NOV) family, is significantly down regulated in clinical samples of human spindle cell metaplastic breast carcinoma. We generated a mouse model of mammary epithelial-specific Ccn6 deletion by developing a floxed Ccn6 mouse which was bred with an MMTV-Cre mouse. Ccn6fl/fl; MMTV-Cre mice displayed severe defects in ductal branching and abnormal age-related involution compared to littermate controls. Ccn6fl/fl ;MMTV-Cre mice developed invasive high grade mammary carcinomas with bona fide EMT, histologically similar to human metaplastic breast carcinomas. Global gene expression profiling of Ccn6fl/fl mammary carcinomas and comparison of orthologous genes with a human metaplastic carcinoma signature revealed a significant overlap of 87 genes (p=5×10−11). Among the shared deregulated genes between mouse and human are important regulators of epithelial morphogenesis including Cdh1, Ck19, Cldn3 and 4, Ddr1, and Wnt10a. These results document a causal role for Ccn6 deletion in the pathogenesis of metaplastic carcinomas with histological and molecular similarities with human disease. We provide a platform to study new targets in the diagnosis and treatment of human metaplastic carcinomas, and a new disease relevant model in which to test new treatment strategies.
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25
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Dual roles of CCN proteins in breast cancer progression. J Cell Commun Signal 2016; 10:217-222. [PMID: 27520547 DOI: 10.1007/s12079-016-0345-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Accepted: 07/30/2016] [Indexed: 01/10/2023] Open
Abstract
The tumor microenvironment has a powerful effect on the development and progression of human breast cancer, which may be used therapeutically. Despite efforts to understand the complex role of the tumor microenvironment in breast cancer development, the specific players and their contributions to tumorigenesis need further investigation. The CCN family of matricellular proteins comprises six members (CCN1-6; CYR61, CTGF, NOV, WISP1-3) with central roles in development, inflammation, and tissue repair. CCN proteins also exert functions during pathological processes including fibrosis and cancer by regulating extracellular signals in the cellular environment. Studies have demonstrated that all six CCN proteins exert functions in breast tumorigenesis. Although CCN proteins share a multimodular structure in which most cysteine residues are conserved within structural motifs, they may have opposing functions in breast cancer progression. A better understanding of the functions of each CCN member will assist in the development of specific therapeutic approaches for breast cancer.
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26
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Caceres S, Peña L, Lacerda L, Illera MJ, de Andres PJ, Larson RA, Gao H, Debeb BG, Woodward WA, Reuben JM, Illera JC. Canine cell line, IPC-366, as a good model for the study of inflammatory breast cancer. Vet Comp Oncol 2016; 15:980-995. [DOI: 10.1111/vco.12238] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 02/29/2016] [Accepted: 03/29/2016] [Indexed: 12/20/2022]
Affiliation(s)
- S. Caceres
- Department of Animal Physiology; Complutense University of Madrid (UCM); Madrid Spain
| | - L. Peña
- Department of Animal Medicine, Surgery and Pathology, School of Veterinary Medicine; Complutense University of Madrid (UCM); Madrid Spain
| | - L. Lacerda
- Department of Radiation Oncology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - M. J. Illera
- Department of Animal Physiology; Complutense University of Madrid (UCM); Madrid Spain
| | - P. J. de Andres
- Department of Animal Medicine, Surgery and Pathology, School of Veterinary Medicine; Complutense University of Madrid (UCM); Madrid Spain
| | - R. A. Larson
- Department of Radiation Oncology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - H. Gao
- Department of Hematopathology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - B. G. Debeb
- Department of Radiation Oncology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - W. A. Woodward
- Department of Radiation Oncology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - J. M. Reuben
- Department of Hematopathology; The University of Texas MD Anderson Cancer Center; Houston TX USA
| | - J. C. Illera
- Department of Animal Physiology; Complutense University of Madrid (UCM); Madrid Spain
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Chuang JY, Chen PC, Tsao CW, Chang AC, Lein MY, Lin CC, Wang SW, Lin CW, Tang CH. WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression. Oncotarget 2016; 6:4239-52. [PMID: 25738362 PMCID: PMC4414186 DOI: 10.18632/oncotarget.2978] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 12/19/2014] [Indexed: 11/25/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by poor prognosis and a low survival rate. VEGF-A is the most established angiogenic factor involved in the angiogenic-regulated tumor progression. WISP-1/CCN4 is an extracellular matrix-related protein that belongs to the Cyr61, CTGF, Nov (CCN) family and regulates many biological functions, such as angiogenesis. Previous studies indicated the role of WISP-1 in tumor progression. However, the angiogenic property of WISP-1 in the cancer microenvironment has never been discussed. Here, we provide novel insights regarding the role of WISP-1 in the angiogenesis through promoting VEGF-A expression. In this study, the correlation of WISP-1 and VEGF-A was confirmed by IHC staining of specimens from patients with OSCC. In vitro results indicated that WISP-1 induced VEGF-A expression via the integrin αvβ3/FAK/c-Src pathway, which transactivates the EGFR/ERK/HIF1-α signaling pathway in OSCC. This pathway in turn induces the recruitment of endothelial progenitor cells and triggers the neovascularization in the tumor microenvironment. Our in vivo data revealed that tumor-secreted WISP-1 promoted the angiogenesis through VRGF expression and increased angiogenesis-related tumor growth. Our study offers new information that highlights WISP-1 as a potential novel therapeutic target for OSCC.
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Affiliation(s)
- Jing-Yuan Chuang
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Po-Chun Chen
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan
| | - Ching-Wen Tsao
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - An-Chen Chang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
| | - Ming-Yu Lein
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ching-Chia Lin
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.,Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan.,Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
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Sawyer AJ, Kyriakides TR. Matricellular proteins in drug delivery: Therapeutic targets, active agents, and therapeutic localization. Adv Drug Deliv Rev 2016; 97:56-68. [PMID: 26763408 DOI: 10.1016/j.addr.2015.12.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 12/17/2015] [Accepted: 12/17/2015] [Indexed: 02/06/2023]
Abstract
Extracellular matrix is composed of a complex array of molecules that together provide structural and functional support to cells. These properties are mainly mediated by the activity of collagenous and elastic fibers, proteoglycans, and proteins such as fibronectin and laminin. ECM composition is tissue-specific and could include matricellular proteins whose primary role is to modulate cell-matrix interactions. In adults, matricellular proteins are primarily expressed during injury, inflammation and disease. Particularly, they are closely associated with the progression and prognosis of cardiovascular and fibrotic diseases, and cancer. This review aims to provide an overview of the potential use of matricellular proteins in drug delivery including the generation of therapeutic agents based on the properties and structures of these proteins as well as their utility as biomarkers for specific diseases.
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29
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Lu Y, Wang X, Sun X, Feng W, Guo H, Tang C, Deng A, Bao Y. WISP3 is highly expressed in a subset of colorectal carcinomas with a better prognosis. Onco Targets Ther 2016; 9:287-93. [PMID: 26834488 PMCID: PMC4716761 DOI: 10.2147/ott.s97025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Outlier genes with marked overexpression in subsets of cancers like ERBB2 have potential for the identification of gene classifiers and therapeutic targets for the appropriate subpopulation. In this study, using the cancer outlier profile analysis strategy, we identified WNT1-inducible-signaling pathway protein 3 (WISP3) as an outlier gene that is highly expressed in a subset of colorectal cancers (CRCs) from The Cancer Genome Atlas dataset. A meta-cancer outlier profile analysis and immunohistochemistry experiment to validate the outlier expression model of WISP3 in CRC was then performed. Our immunohistochemical results indicated that WISP3 was more frequently seen in the small tumors, and there was a significant association between its overexpression with a good prognosis. Furthermore, in the multivariable model, WISP3 outlier expression retained significance for overall survival. In summary, in this study, we identified an outlier gene WISP3 overexpressed in a subset of CRC having less aggressive characteristics and a better prognosis. We suggest WISP3 may provide more accurate and precise information regarding CRC population classification.
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Affiliation(s)
| | - Xiang Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
| | - Xinrong Sun
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
| | - Wenming Feng
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
| | - Huihui Guo
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
| | - Chengwu Tang
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
| | - Anmei Deng
- Department of Laboratory Diagnostic, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China
| | - Ying Bao
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Huzhou Teachers College, The First People's Hospital of Huzhou, Huzhou
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Abstract
Locally advanced breast cancer (LABC) constitutes a heterogeneous entity that includes advanced-stage primary tumours, cancers with extensive nodal involvement and inflammatory breast carcinomas. Although the definition of LABC can be broadened to include some large operable breast tumours, we use this term to strictly refer to inoperable cancers that are included in the above-mentioned categories. The prognosis of such tumours is often unfavourable; despite aggressive treatment, many patients eventually develop distant metastases and die from the disease. Advances in systemic therapy, including radiation treatment, surgical techniques and the development of new targeted agents have significantly improved clinical outcomes for patients with this disease. Notwithstanding these advances, LABC remains an important clinical problem, particularly in developing countries and those without widely adapted breast cancer awareness programmes. The optimal management of LABC requires a multidisciplinary approach, a well-coordinated treatment schedule and close cooperation between medical, surgical and radiation oncologists. In this Review, we discuss the current state of the art and possible future treatment strategies for patients with LABC.
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31
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Li XJ, Zha QB, Xu XY, Xia L, Zhang Z, Ren ZJ, Tang JH. Lack of prognostic value of human epidermal growth factor-like receptor 2 status in inflammatory breast cancer (IBC): a meta-analysis. Asian Pac J Cancer Prev 2014; 15:9615-9. [PMID: 25520077 DOI: 10.7314/apjcp.2014.15.22.9615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer which is more likely to be her-2/ neu amplified. While the her-2/neu status has been utilised to predict prognosis, the published data are inconsistent. The present meta-analysis was conducted to determine whether the her-2/neu status predicts outcomes. Papers were selected from the PubMed database based on defined inclusion and exclusion criteria. Parameters such as total patients, follow-up time and outcome statistics (i.e. overall survival (OS), relapse-free survival (RFS) were collected. The analysis included 6 studies with 2,838 IBC patients. The summary hazards ratio (HR) estimating the association of OS with HER-2-positive disease was 0.96 (95% confidence interval (95%CI: 0.85-1.10)), with similar findings for RFS (HR=0.81, 95%CI: 0.61-1.09). No obvious statistical heterogeneity was detected. This meta-analysis suggests that HER-2-positive status is not an independent adverse prognostic factor for survival among IBC patient cases.
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Affiliation(s)
- Xiu-Juan Li
- Department of General Surgery, Jiangsu Cancer Hospital, The Affiliated Hospital of Nanjing Medical University, Nanjing, China E-mail : ,
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32
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Renieri A, Mencarelli MA, Cetta F, Baldassarri M, Mari F, Furini S, Piu P, Ariani F, Dragani TA, Frullanti E. Oligogenic germline mutations identified in early non-smokers lung adenocarcinoma patients. Lung Cancer 2014; 85:168-74. [PMID: 24954872 DOI: 10.1016/j.lungcan.2014.05.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 05/28/2014] [Indexed: 01/15/2023]
Abstract
OBJECTIVES A polygenic model is commonly assumed for the predisposition to common cancers. With respect to lung cancer, Genome Wide Association Studies (GWAS) have identified three loci at 15q25, 5p15.33, and 6p21. However, the relative risks associated with alleles at these loci are low; in addition, the data are limited to smokers, and have not been quite reproducible. MATERIALS AND METHODS In order to investigate genetic susceptibility we have adopted an entirely novel patient selection strategy. First, we have selected for adenocarcinoma (ADCA) histology only; second, we have selected non-smokers; third we have selected patients who developed ADCA of lung before the age of 60 and who had an older unaffected sib: we have identified 31 such sib-pairs. Among them, we selected two patients with very early age at disease onset (37- and 49-years old), and having a healthy sibling available for genome comparison older than at least 7 years. RESULTS On germline DNA samples of four subjects of two such pairs we have carried out whole exome sequencing. Truncating mutations were detected in 8 'cancer genes' in one affected, and in 5 cancer genes in the other affected subject: but none in the two healthy sibs (p=0.0026). Some of these mutant genes (such as BAG6, SPEN and WISP3) are recognized as major cancer players in lung tumors; others have been previously identified in other human cancers (JAK2, TCEB3C, NELFE, TAF1B, EBLN2), in mouse models (GON4L, NOP58, and RBMX) or in genome-wide association studies (KIAA2018, ZNF311). CONCLUSIONS This study identifies for the first time in non-smokers with lung adenocarcinoma specific sets of germline mutations that, together, may predispose to this tumor.
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Affiliation(s)
- Alessandra Renieri
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Istituto Toscano Tumori, Florence, Italy.
| | | | | | - Margherita Baldassarri
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy
| | - Francesca Mari
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy
| | - Simone Furini
- Department of Medical Biotechnology, University of Siena, Siena, Italy
| | - Pietro Piu
- Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy
| | | | | | - Elisa Frullanti
- Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
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33
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Cheng TY, Wu MS, Hua KT, Kuo ML, Lin MT. Cyr61/CTGF/Nov family proteins in gastric carcinogenesis. World J Gastroenterol 2014; 20:1694-1700. [PMID: 24587648 PMCID: PMC3930969 DOI: 10.3748/wjg.v20.i7.1694] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/07/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death. The poor survival rate may reflect the relatively aggressive tumor biology of GC. Recently, the importance of the tumor microenvironment in carcinogenesis has emerged. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis. The Cyr61/CTGF/Nov (CCN) proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes. The evidence suggests that CCN family proteins contribute to GC carcinogenic processes. Here, we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.
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Abstract
The CCN genes encode secreted signaling proteins that participate in fundamental processes including cell adhesion, proliferation and differentiation, embryogenesis, tissue remodeling and patterning. Abnormal expression of CCN proteins is associated with several pathological conditions, including vascular diseases, fibrosis and cancer. Understanding the structural and functional basis for the variety of biological properties attributed to CCN proteins is an important challenge. It will help the understanding of their roles in the control of cellular proliferation, differentiation and death, thereby allowing their use for early diagnosis and therapy. In an attempt to evaluate the relevance of CCN3 as a useful tool in modern biomedical technologies, the biological properties of the CCN proteins and the data that established their potential usefulness will briefly be reviewed.
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Affiliation(s)
- Bernard Perbal
- Laboratoire d'Oncologie, Virale et Moléculaire, UFR de Biochimie, Université Paris 7-D. Diderot, 2 Place Jussieu 75 005, Paris, France.
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Wu CL, Tsai HC, Chen ZW, Wu CM, Li TM, Fong YC, Tang CH. Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma. Cell Signal 2013; 25:2812-22. [DOI: 10.1016/j.cellsig.2013.09.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 09/02/2013] [Accepted: 09/02/2013] [Indexed: 12/30/2022]
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Apoptosis signal-regulating kinase 1 is involved in WISP-1-promoted cell motility in human oral squamous cell carcinoma cells. PLoS One 2013; 8:e78022. [PMID: 24205072 PMCID: PMC3804520 DOI: 10.1371/journal.pone.0078022] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/12/2013] [Indexed: 11/21/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) has a tendency to migrate and metastasize. WNT1-inducible signaling pathway protein 1 (WISP-1) is a cysteine-rich protein that belongs to the Cyr61, CTGF, Nov (CCN) family of matrix cellular proteins. The effect of WISP-1 on human OSCC cells, however, is unknown. Here, we showed that WISP-1 increased cell migration and intercellular adhesion molecule-1 (ICAM-1) expression in OSCC cells. Pretreatment of cells with integrin αvβ3 monoclonal antibody (mAb) significantly abolished WISP-1–induced cell migration and ICAM-1 expression. On the other hand, WISP-1–mediated cell motility and ICAM-1 upregulation were attenuated by ASK1, JNK, and p38 inhibitor. Furthermore, WISP-1 also enhanced activator protein 1 (AP-1) activation, and the integrin αvβ3 mAb, and ASK1, JNK, and p38 inhibitors reduced WISP-1–mediated AP-1 activation. Moreover, WISP-1 and ICAM-1 expression correlated with the tumor stage of patients with OSCC. Our results indicate that WISP-1 enhances the migration of OSCC cells by increasing ICAM-1 expression through the αvβ3 integrin receptor and the ASK1, JNK/p38, and AP-1 signal transduction pathways.
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37
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Mineva ND, Paulson KE, Naber SP, Yee AS, Sonenshein GE. Epigallocatechin-3-gallate inhibits stem-like inflammatory breast cancer cells. PLoS One 2013; 8:e73464. [PMID: 24039951 PMCID: PMC3770659 DOI: 10.1371/journal.pone.0073464] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2013] [Accepted: 07/22/2013] [Indexed: 01/09/2023] Open
Abstract
Inflammatory Breast Cancer (IBC) is a highly aggressive form of cancer characterized by high rates of proliferation, lymphangiogenesis and metastasis, and an overall poor survival. As regular green tea consumption has been associated with improved prognosis of breast cancer patients, including decreased risk of recurrence, here the effects of the green tea polyphenol epigallocatechin-3-gallate (EGCG) were tested on two IBC lines: SUM-149 and SUM-190. EGCG decreased expression of genes that promote proliferation, migration, invasion, and survival. Consistently, growth, invasive properties, and survival of IBC cells were reduced by EGCG treatment. EGCG also reduced lymphangiogenesis-promoting genes, in particular VEGF-D. Conditioned media from EGCG-treated IBC cells displayed decreased VEGF-D secretion and reduced ability to promote lymphangiogenesis in vitro as measured by hTERT-HDLEC lymphatic endothelial cell migration and tube formation. Tumorsphere formation by SUM-149 cells was robustly inhibited by EGCG, suggesting effects on self-renewal ability. Stem-like SUM-149 cells with high aldehyde dehydrogenase (ALDH) activity, previously implicated in poor patient prognosis, were isolated. EGCG treatment reduced growth and induced apoptosis of the stem-like SUM-149 cells in culture. In an orthotopic mouse model, EGCG decreased growth of pre-existing tumors derived from ALDH-positive stem-like SUM-149 cells and their expression of VEGF-D, which correlated with a significant decrease in peritumoral lymphatic vessel density. Thus, EGCG inhibits the overall aggressive IBC phenotype. Reduction of the stem-like cell compartment by EGCG may explain the decreased risk of breast cancer recurrence among green tea drinkers. Recent clinical trials demonstrate the efficacy of green tea polyphenol extracts in treatment of prostate cancer and lymphocytic leukemia with low toxicity. Given the poor prognosis of IBC patients, our findings suggest further exploration of EGCG or green tea in combinatorial treatments against active IBC disease or in maintenance regimens to avoid recurrence is warranted.
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Affiliation(s)
- Nora D. Mineva
- Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - K. Eric Paulson
- Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Stephen P. Naber
- Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, Massachusetts, United States of America
| | - Amy S. Yee
- Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Gail E. Sonenshein
- Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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Hann S, Kvenvold L, Newby BN, Hong M, Warman ML. A Wisp3 Cre-knockin allele produces efficient recombination in spermatocytes during early prophase of meiosis I. PLoS One 2013; 8:e75116. [PMID: 24040393 PMCID: PMC3769254 DOI: 10.1371/journal.pone.0075116] [Citation(s) in RCA: 8] [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: 06/18/2013] [Accepted: 08/09/2013] [Indexed: 12/13/2022] Open
Abstract
Individuals with the autosomal recessive skeletal disorder Progressive Pseudorheumatoid Dysplasia have loss-of-function mutations in WISP3, and aberrant WISP3 expression has been detected in tumors from patients with colon and breast cancer. In mice however, neither absence nor over-expression of WISP3 was found to cause a phenotype, and endogenous Wisp3 expression has been difficult to detect. To confirm that Wisp3 knockout mice have no phenotype and to identify potential sites of endogenous Wisp3 expression, we generated mice with a knockin allele (Wisp3 (GFP-Cre)) designed to express Green Fluorescent Protein (GFP) and Cre-recombinase instead of WISP3. Heterozygous and homozygous knockin mice were fertile and indistinguishable from their wild-type littermates, confirming that mice lacking Wisp3 have no phenotype. We could not detect GFP-expression from the knockin allele, but we could detect Cre-expression after crossing mice with the knockin allele to Cre-reporter mice; the double heterozygous offspring had evidence of Cre-mediated recombination in several tissues. The only tissue that had high levels of Cre-mediated recombination was the testis, where recombination in spermatocytes occurred by early prophase of meiosis I. As a consequence, males that were double heterozygous for a Wisp3 (GFP-Cre) and a floxed allele only contributed a recombined allele to their offspring. We detected no evidence of Cre-mediated recombination in the female ovary, although when double heterozygous females contributed the reporter allele to their offspring it had recombined ~7% of the time. Wisp3 (GFP-Cre) expression therefore occurs less frequently and most likely at a later stage of oocyte development in female mice compared to male mice. We conclude that although WISP3 is dispensable in mice, male mice with a Wisp3 (GFP-Cre) allele (Jackson Laboratory stock # 017685) will be useful for studying early prophase of meiosis I and for efficiently recombining floxed alleles that are passed to offspring.
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Affiliation(s)
- Steven Hann
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- * E-mail:
| | - Laura Kvenvold
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Brittney N. Newby
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Minh Hong
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
| | - Matthew L. Warman
- Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, Massachusetts, United States of America
- Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
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Abstract
Inflammatory breast cancer (IBC) is an uncommon and aggressive presentation of locally advanced breast cancer that is potentially curable when localized but may be associated with distant metastasis in up to one-third of patients at presentation. The diagnosis of IBC is made based on clinical features, including the presence of skin edema and erythema involving at least one-third of the breast, with or without a mass, and usually associated with dermal lymphatic invasion (DLI) on skin biopsy. Management requires combined modality therapy, including neoadjuvant chemotherapy with an anthracycline and taxane-based regimen, followed by surgery and radiotherapy, plus concurrent anti-HER2 therapy for HER2-positive disease, and endocrine therapy for at least 5 years after surgery for estrogen-receptor-positive disease (Fig. 1). There have been few large clinical trials focused on IBC; therefore, most data regarding treatment are derived from retrospective analyses, small studies, and extrapolation of results from trials of noninflammatory locally advanced breast cancer. Patients with IBC should be encouraged to enroll in clinical trials whenever possible. In addition, further research into the biology of IBC may help to elucidate the mechanisms underlying its aggressive clinical behavior and to assist in the development of therapies targeted for this specific population.
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Affiliation(s)
- Della Makower
- Department of Oncology, Montefiore Medical Center, 600 East 233rd St, 6th floor, Bronx, NY 10466, USA.
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40
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Mohamed MM, Al-Raawi D, Sabet SF, El-Shinawi M. Inflammatory breast cancer: New factors contribute to disease etiology: A review. J Adv Res 2013; 5:525-36. [PMID: 25685520 PMCID: PMC4294279 DOI: 10.1016/j.jare.2013.06.004] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2013] [Revised: 05/16/2013] [Accepted: 06/07/2013] [Indexed: 12/11/2022] Open
Abstract
Inflammatory breast cancer (IBC) is a highly metastatic and fatal form of breast cancer. In fact, IBC is characterized by specific morphological, phenotypic, and biological properties that distinguish it from non-IBC. The aggressive behavior of IBC being more common among young women and the low survival rate alarmed researchers to explore the disease biology. Despite the basic and translational studies needed to understand IBC disease biology and identify specific biomarkers, studies are limited by few available IBC cell lines, experimental models, and paucity of patient samples. Above all, in the last decade, researchers were able to identify new factors that may play a crucial role in IBC progression. Among identified factors are cytokines, chemokines, growth factors, and proteases. In addition, viral infection was also suggested to participate in the etiology of IBC disease. In this review, we present novel factors suggested by different studies to contribute to the etiology of IBC and the proposed new therapeutic insights.
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Affiliation(s)
- Mona M Mohamed
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Diaa Al-Raawi
- Department of Zoology, Faculty of Science, Sana'a University, Yemen
| | - Salwa F Sabet
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
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41
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CCN6 knockdown disrupts acinar organization of breast cells in three-dimensional cultures through up-regulation of type III TGF-β receptor. Neoplasia 2013; 14:1067-74. [PMID: 23226100 DOI: 10.1593/neo.121322] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 09/19/2012] [Accepted: 09/25/2012] [Indexed: 01/15/2023] Open
Abstract
While normal cells in the human breast are organized into acinar structures, disruption of the acinar architecture is a hallmark of cancer. In a three-dimensional model of morphogenesis, we show that down-regulation of the matrix-associated tumor suppressor protein CCN6 (WNT1-inducible-signaling pathway protein 3) disrupts breast epithelial cell polarity and organization into acini through up-regulation of the type III transforming growth factor-β receptor (TβRIII or betaglycan). Down-regulation of CCN6 in benign breast cells led to loss of tissue polarity and resulted in cellular disorganization with loss of α6 integrin-rich basement membrane and the basolateral polarity protein E-cadherin. Silencing of TβRIII with shRNA and siRNA rescued the ability of breast epithelial cells to form polarized acinar structures with reduced matrix invasion and restored the correct expression of α6 integrin and E-cadherin. Conversely, CCN6 overexpression in aggressive breast cancer cells reduced TβRIII in vitro and in a xenograft model of CCN6 overexpression. The relevance of our studies to human breast cancer is highlighted by the finding that CCN6 protein levels are inversely associated with TβRIII protein in 64%of invasive breast carcinomas. These results reveal a novel function of the matricellular protein CCN6 and establish a mechanistic link between CCN6 and TβRIII in maintaining acinar organization in the breast.
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42
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Cahill N, Rosenquist R. Uncovering the DNA methylome in chronic lymphocytic leukemia. Epigenetics 2013; 8:138-48. [PMID: 23321535 DOI: 10.4161/epi.23439] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Over the past two decades, aberrant DNA methylation has emerged as a key player in the pathogenesis of chronic lymphocytic leukemia (CLL), and knowledge regarding its biological and clinical consequences in this disease has evolved rapidly. Since the initial studies relating DNA hypomethylation to genomic instability in CLL, a plethora of reports have followed showing the impact of DNA hypermethylation in silencing vital single gene promoters and the reversible nature of DNA methylation through inhibitor drugs. With the recognition that DNA hypermethylation events could potentially act as novel prognostic and treatment targets in CLL, the search for aberrantly methylated genes, gene families and pathways has ensued. Subsequently, the advent of microarray and next-generation sequencing technologies has supported the hunt for such targets, allowing exploration of the methylation landscape in CLL at an unprecedented scale. In light of these analyses, we now understand that different CLL prognostic subgroups are characterized by differential methylation profiles; we recognize DNA methylation of a number of signaling pathways genes to be altered in CLL, and acknowledge the role of DNA methylation outside of traditional CpG island promoters as fundamental players in the regulation of gene expression. Today, the significance and timing of altered DNA methylation within the complex epigenetic network of concomitant epigenetic messengers such as histones and miRNAs is an intensive area of research. In CLL, it appears that DNA methylation is a rather stable epigenetic mark occurring rather early in the disease pathogenesis. However, other consequences, such as how and why aberrant methylation marks occur, are less explored. In this review, we will not only provide a comprehensive summary of the current literature within the epigenetics field of CLL, but also highlight some of the novel findings relating to when, where, why and how altered DNA methylation materializes in CLL.
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Affiliation(s)
- Nicola Cahill
- Department of Immunology, Genetics and Pathology; Uppsala University; Uppsala, Sweden
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43
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Cahill N, Bergh AC, Kanduri M, Göransson-Kultima H, Mansouri L, Isaksson A, Ryan F, Smedby KE, Juliusson G, Sundström C, Rosén A, Rosenquist R. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments. Leukemia 2012; 27:150-8. [DOI: 10.1038/leu.2012.245] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Pal A, Huang W, Li X, Toy KA, Nikolovska-Coleska Z, Kleer CG. CCN6 modulates BMP signaling via the Smad-independent TAK1/p38 pathway, acting to suppress metastasis of breast cancer. Cancer Res 2012; 72:4818-28. [PMID: 22805309 DOI: 10.1158/0008-5472.can-12-0154] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CCN6 (WISP3) is an extracellular matrix protein that exerts tumor suppressive functions in breast cancer, where its decreased expression is a feature of advanced disease. However, neither its role nor mechanism of action in breast cancer metastasis has been established. Bone morphogenetic proteins (BMPs), which constitute ligands of the TGF-β superfamily, are multifunctional cytokines that induce epithelial-mesenchymal transition, cell invasion, and metastasis. In this study, we identify a CCN6-BMP4-TAK1 kinase signaling pathway that controls the ability of the p38 MAP kinase to regulate acinar morphogenesis and invasion of breast cells. ShRNA-mediated attenuation of CCN6 in human mammary epithelial cells led to BMP4 upregulation as a major response to exposure to the TGF-β superfamily. CCN6 attenuation also induced BMP4-mediated activation of the Smad-independent TAK1 and p38 kinases. Conversely, ectopic expression of CCN6 in breast cancer cells antagonized BMP4-mediated TAK1/p38 activation and invasive capacity, both by binding BMP4 protein as well as decreasing BMP4 protein levels. Effects on BMP4 and p38 were confirmed in vivo where they correlated with decreased metastasis. In clinical specimens, we found that CCN6 expression was inversely associated with BMP4 and phospho-p38 levels in 69% of invasive breast carcinomas examined, consistent with the functional results. Together our findings identify a novel modifier pathway through which CCN6 acts to limit breast cancer invasion and metastasis.
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Affiliation(s)
- Anupama Pal
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
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45
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Matricellular proteins: a sticky affair with cancers. JOURNAL OF ONCOLOGY 2012; 2012:351089. [PMID: 22481923 PMCID: PMC3306981 DOI: 10.1155/2012/351089] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 11/02/2011] [Accepted: 11/02/2011] [Indexed: 12/17/2022]
Abstract
The multistep process of metastasis is a major hallmark of cancer progression involving the cointeraction and coevolution of the tumor and its microenvironment. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins, which are a family of nonstructural proteins in the extracellular matrix (ECM) that exert regulatory roles via a variety of molecular mechanisms. Matricellular proteins provide signals that support tumorigenic activities characteristic of the metastastic cascade such as epithelial-to-mesenchymal (EMT) transition, angiogenesis, tumor cell motility, proliferation, invasion, evasion from immune surveillance, and survival of anoikis. Herein, we review the current understanding of the following matricellular proteins and highlight their pivotal and multifacted roles in metastatic progression: angiopoietin-like protein 4 (ANGPTL4), CCN family members cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) and CCN6, osteopontin (OPN), secreted protein acidic and rich in cysteine (SPARC), tenascin C (TNC), and thrombospondin-1 and -2 (TSP1, TSP2). Insights into the signaling mechanisms resulting from the interaction of these matricellular proteins and their respective molecular partner(s), as well as their subsequent contribution to tumor metastasis, are discussed. In addition, emerging evidences of their promising potential as therapeutic options and/or targets in the treatment of cancer are also highlighted.
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46
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Ohshiro K, Schwartz AM, Levine PH, Kumar R. Alternate estrogen receptors promote invasion of inflammatory breast cancer cells via non-genomic signaling. PLoS One 2012; 7:e30725. [PMID: 22295107 PMCID: PMC3266301 DOI: 10.1371/journal.pone.0030725] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/27/2011] [Indexed: 11/18/2022] Open
Abstract
Although Inflammatory Breast Cancer (IBC) is a rare and an aggressive type of locally advanced breast cancer with a generally worst prognosis, little work has been done in identifying the status of non-genomic signaling in the invasiveness of IBC. The present study was performed to explore the status of non-genomic signaling as affected by various estrogenic and anti-estrogenic agents in IBC cell lines SUM149 and SUM190. We have identified the presence of estrogen receptor α (ERα) variant, ERα36 in SUM149 and SUM190 cells. This variant as well as ERβ was present in a substantial concentration in IBC cells. The treatment with estradiol (E2), anti-estrogenic agents 4-hydroxytamoxifen and ICI 182780, ERβ specific ligand DPN and GPR30 agonist G1 led to a rapid activation of p-ERK1/2, suggesting the involvement of ERα36, ERβ and GPR30 in the non-genomic signaling pathway in these cells. We also found a substantial increase in the cell migration and invasiveness of SUM149 cells upon the treatment with these ligands. Both basal and ligand-induced migration and invasiveness of SUM149 cells were drastically reduced in the presence of MEK inhibitor U0126, implicating that the phosphorylation of ERK1/2 by MEK is involved in the observed motility and invasiveness of IBC cells. We also provide evidence for the upregulation of p-ERK1/2 through immunostaining in IBC patient samples. These findings suggest a role of non-genomic signaling through the activation of p-ERK1/2 in the hormonal dependence of IBC by a combination of estrogen receptors. These findings only explain the failure of traditional anti-estrogen therapies in ER-positive IBC which induces the non-genomic signaling, but also opens newer avenues for design of modified therapies targeting these estrogen receptors.
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Affiliation(s)
- Kazufumi Ohshiro
- Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C., United States of America
| | - Arnold M. Schwartz
- Department of Pathology, The George Washington University Medical Center, Washington, D.C., United States of America
| | - Paul H. Levine
- Department of Epidemiology and Biostatistics, The George Washington University Medical Center, Washington, D.C., United States of America
| | - Rakesh Kumar
- Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, D.C., United States of America
- * E-mail:
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47
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Fong YC, Lin CY, Su YC, Chen WC, Tsai FJ, Tsai CH, Huang CY, Tang CH. CCN6 enhances ICAM-1 expression and cell motility in human chondrosarcoma cells. J Cell Physiol 2011; 227:223-32. [PMID: 21391218 DOI: 10.1002/jcp.22720] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN6 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, and Nov) family of matricellular proteins. However, the effects of CCN6 on human chondrosarcoma cells are largely unknown. In this study, we found that CCN6 increased the migration and the expression of intercellular adhesion molecule-1 (ICAM-1) in human chondrosarcoma cells. αvβ3 and αvβ5 integrin monoclonal antibody and mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) inhibited the CCN6-induced increase of the migration and ICAM-1 up-regulation of chondrosarcoma cells. CCN6 stimulation increased the phosphorylation of focal adhesion kinase (FAK), MEK, and extracellular signal-regulated kinase (ERK). In addition, activator protein-1 (AP-1) inhibitors suppressed the cell migration and ICAM-1 expression enhanced by CCN6. Moreover, CCN6 increased AP-1 luciferase activity and binding of c-Jun to the AP-1 element on the ICAM-1 promoter. Taken together, our results indicate that CCN6 enhances the migration of chondrosarcoma cells by increasing ICAM-1 expression through the αvβ3 and αvβ5 integrin receptor, FAK, MEK, ERK, c-Jun, and AP-1 signal transduction pathway.
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Affiliation(s)
- Yi-Chin Fong
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
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48
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Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discov 2011; 10:945-63. [PMID: 22129992 DOI: 10.1038/nrd3599] [Citation(s) in RCA: 513] [Impact Index Per Article: 36.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Members of the CCN family of matricellular proteins are crucial for embryonic development and have important roles in inflammation, wound healing and injury repair in adulthood. Deregulation of CCN protein expression or activities contributes to the pathobiology of various diseases - many of which may arise when inflammation or tissue injury becomes chronic - including fibrosis, atherosclerosis, arthritis and cancer, as well as diabetic nephropathy and retinopathy. Emerging studies indicate that targeting CCN protein expression or signalling pathways holds promise in the development of diagnostics and therapeutics for such diseases. This Review summarizes the biology of CCN proteins, their roles in various pathologies and their potential as therapeutic targets.
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Tzeng HE, Chen JC, Tsai CH, Kuo CC, Hsu HC, Hwang WL, Fong YC, Tang CH. CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway. J Cell Physiol 2011; 226:3181-9. [PMID: 21344378 DOI: 10.1002/jcp.22672] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN3, also called nephroblastoma overexpressed gene (NOV), regulates proliferation and differentiation of cancer cells. However, the effect of CCN3 on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that CCN3 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). αvβ3 or αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase (PI3K) inhibitors (Ly294002 and wortmannin) and Akt inhibitor inhibited the CCN3-induced increase of the migration and MMP-13 upregulation of chondrosarcoma cells. CCN3 stimulation increased the phosphorylation of focal adhesion kinase (FAK), PI3K, and Akt. In addition, NF-κB inhibitors also suppressed the cell migration and MMP-13 expression enhanced by CCN3. Moreover, CCN3 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-13 promoter. Taken together, our results indicate that CCN3 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the αvβ3/αvβ5 integrin receptor, FAK, PI3K, Akt, p65, and NF-κB signal transduction pathway.
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Affiliation(s)
- Huey-En Tzeng
- Division of Hematology/Oncology, Taichung Veterans General Hospital, Taichung, Taiwan
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50
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On how CCN6 suppresses breast cancer growth and invasion. J Cell Commun Signal 2011; 6:5-10. [PMID: 21842227 PMCID: PMC3271195 DOI: 10.1007/s12079-011-0148-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 08/04/2011] [Indexed: 12/30/2022] Open
Abstract
Living cells communicate with their microenvironment and exchange information through signaling pathways in order to carry out most biological processes. The CCN family of proteins has the ability to coordinate the extracellular and intracellular signaling pathways and epithelial-stromal cross-talks. CCN proteins have been shown to play roles in multiple processes including cancer, either as tumor suppressors or oncogenes. Particularly, loss of CCN6 expression has been reported in highly aggressive breast cancer types, especially in inflammatory breast cancer and breast cancer with axillary lymph node metastasis. Recent findings can better explain the biological relevance of CCN6 as a tumor suppressor protein in breast tumorigenesis. CCN6 loss triggers the process of epithelial to mesenchymal transition (EMT), which converts epithelial cells into migratory and invasive mesenchymal-like cells at least in part through modulation of IGF-1 receptor signaling pathway. Emerging data support the hypothesis that CCN6 also exerts growth factor independent functions, especially related to cell survival and anoikis resistance. Thus, our work provides new insights into the functions and mechanisms of tumor suppression exerted by CCN6 in the breast.
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