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Yu W, Srivastava R, Srivastava S, Ma Y, Shankar S, Srivastava RK. Oncogenic Role of SATB2 In Vitro: Regulator of Pluripotency, Self-Renewal, and Epithelial-Mesenchymal Transition in Prostate Cancer. Cells 2024; 13:962. [PMID: 38891096 PMCID: PMC11171950 DOI: 10.3390/cells13110962] [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: 01/01/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Special AT-rich sequence binding protein-2 (SATB2) is a nuclear matrix protein that binds to nuclear attachment regions and is involved in chromatin remodeling and transcription regulation. In stem cells, it regulates the expression of genes required for maintaining pluripotency and self-renewal and epithelial-mesenchymal transition (EMT). In this study, we examined the oncogenic role of SATB2 in prostate cancer and assessed whether overexpression of SATB2 in human normal prostate epithelial cells (PrECs) induces properties of cancer stem cells (CSCs). The results demonstrate that SATB2 is highly expressed in prostate cancer cell lines and CSCs, but not in PrECs. Overexpression of SATB2 in PrECs induces cellular transformation which was evident by the formation of colonies in soft agar and spheroids in suspension. Overexpression of SATB2 in PrECs also resulted in induction of stem cell markers (CD44 and CD133), pluripotency-maintaining transcription factors (cMYC, OCT4, SOX2, KLF4, and NANOG), CADHERIN switch, and EMT-related transcription factors. Chromatin immunoprecipitation assay demonstrated that SATB2 can directly bind to promoters of BCL-2, BSP, NANOG, MYC, XIAP, KLF4, and HOXA2, suggesting SATB2 is capable of directly regulating pluripotency/self-renewal, cell survival, and proliferation. Since prostate CSCs play a crucial role in cancer initiation, progression, and metastasis, we also examined the effects of SATB2 knockdown on stemness. SATB2 knockdown in prostate CSCs inhibited spheroid formation, cell viability, colony formation, cell motility, migration, and invasion compared to their scrambled control groups. SATB2 knockdown in CSCs also upregulated the expression of E-CADHERIN and inhibited the expression of N-CADHERIN, SNAIL, SLUG, and ZEB1. The expression of SATB2 was significantly higher in prostate adenocarcinoma compared to normal tissues. Overall, our data suggest that SATB2 acts as an oncogenic factor where it is capable of inducing malignant changes in PrECs by inducing CSC characteristics.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA (Y.M.)
| | - Rashmi Srivastava
- Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798, USA
| | | | - Yiming Ma
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA (Y.M.)
| | - Sharmila Shankar
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA (Y.M.)
- John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Southeast Louisiana Veterans Health Care System, 2400 Canal Street, New Orleans, LA 70119, USA
| | - Rakesh K. Srivastava
- Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 66128, USA (Y.M.)
- GLAX LLC, 3500 S Dupont Highway, Dover, DE 19901, USA
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Pan B, Cheng X, Tan W, Liu R, Wu X, He J, Fan Q, Zhang Y, Cheng J, Deng Y. Pan-cancer analysis shows that IBSP is a potential prognostic and immunotherapeutic biomarker for multiple cancer types including osteosarcoma. Front Immunol 2023; 14:1188256. [PMID: 37457709 PMCID: PMC10339805 DOI: 10.3389/fimmu.2023.1188256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/07/2023] [Indexed: 07/18/2023] Open
Abstract
Background IBSP is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family that plays a vital role in bone formation, renewal and repair. Emerging evidence revealed that IBSP participated in the tumorigenesis and progression in some cancers. However, its significance in tumour prognosis and immunotherapy is still unknown. Methods In the current study, we studied the role of IBSP in tumorigenesis, tumor diagnosis, genomic heterogeneity, methylation modifications, immune infiltration, and therapy response in pan-cancer. In addition, we constructed a risk score model to assessed the prognostic classification efficiency of IBSP using the co-expression genes of IBSP in osteosarcoma (OS), and analyzed the expression and role of IBSP in OS through a series of assays in vitro. Results IBSP was upregulated in various cancers compared to the paired normal tissues, and it was strongly correlated with the prognosis, pathological stage, diagnostic accuracy, genomic heterogeneity, methylation modification, immune infiltration, immune and checkpoint. Moreover, the predictive model we established in combination with the clinical characteristics of OS patients showed high survival predictive power in these individuals. The assays in vitro showed that IBSP promoted the proliferation, migration and invasion of OS cells, which further confirmed IBSP's role in cancers. Conclusions Our research revealed the multifunctionality of IBSP in the tumorigenesis, progression and therapy in various cancers, which demonstrated that IBSP may serve as a potential prognostic biomarker and a novel immunotherapy target in pan-cancer.
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Affiliation(s)
- Boyu Pan
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaoyun Cheng
- Department of Pulmonary and Critical Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Tan
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Renfeng Liu
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xin Wu
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jinpeng He
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qizhi Fan
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Zhang
- Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jun Cheng
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Youwen Deng
- Department of Spine Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Laser Capture Microdissection: A Gear for Pancreatic Cancer Research. Int J Mol Sci 2022; 23:ijms232314566. [PMID: 36498893 PMCID: PMC9741023 DOI: 10.3390/ijms232314566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/24/2022] Open
Abstract
The advancement in molecular techniques has been attributed to the quality and significance of cancer research. Pancreatic cancer (PC) is one of the rare cancers with aggressive behavior and a high mortality rate. The asymptomatic nature of the disease until its advanced stage has resulted in late diagnosis as well as poor prognosis. The heterogeneous character of PC has complicated cancer development and progression studies. The analysis of bulk tissues of the disease was insufficient to understand the disease, hence, the introduction of the single-cell separating technique aided researchers to decipher more about the specific cell population of tumors. This review gives an overview of the Laser Capture Microdissection (LCM) technique, one of the single-cell separation methods used in PC research.
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Loosen SH, Hoening P, Puethe N, Luedde M, Spehlmann M, Ulmer TF, Cardenas DV, Roy S, Tacke F, Trautwein C, Neumann UP, Luedde T, Roderburg C. Elevated serum levels of bone sialoprotein (BSP) predict long-term mortality in patients with pancreatic adenocarcinoma. Sci Rep 2019; 9:1489. [PMID: 30728413 PMCID: PMC6365503 DOI: 10.1038/s41598-018-38352-2] [Citation(s) in RCA: 4] [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: 10/12/2018] [Accepted: 12/16/2018] [Indexed: 01/20/2023] Open
Abstract
Patients with pancreatic adenocarcinoma (PDAC) still face a very limited prognosis. At early stage, surgical tumor resection might offer long-term survival but disease recurrence is common and the existing stratification algorithms are often unsuitable to identify patients who particularly benefit from surgery. Here, we investigated the potential role of bone sialoprotein (BSP) as a circulating marker in patients undergoing resection of PDAC. We used ELISA to determine serum concentrations of BSP in a cohort of 132 PDAC patients as well as 39 healthy controls. Circulating BSP levels were significantly higher in PDAC patients compared to healthy controls. Notably, elevated preoperative BSP levels above the ideal cut-off value of 4743 pg/ml turned out as a significant predictor for an impaired postoperative survival. The potential of preoperative BSP levels as a prognostic marker was further underlined by uni- and multivariate Cox-regression analyses including various tumour- and patient-specific. Finally, high tumoral BSP expression was also associated with a significantly impaired long-term survival. In conclusion, we identified a novel role of circulating BSP as a biomarker in PDAC patients undergoing tumor resection. Such data might help to establish new preoperative stratification strategies to better identify patients who particularly benefit from tumor resection.
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Affiliation(s)
- Sven H Loosen
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Pia Hoening
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Niklas Puethe
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Mark Luedde
- Department of Internal Medicine III, University Hospital of Schleswig Holstein, Campus Kiel, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany
| | - Martina Spehlmann
- Department of Internal Medicine III, University Hospital of Schleswig Holstein, Campus Kiel, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany
| | - Tom F Ulmer
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - David V Cardenas
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Sanchari Roy
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Ulf P Neumann
- Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany.
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Giannoni P, Muraglia A, Giordano C, Narcisi R, Cancedda R, Quarto R, Chiesa R. Osteogenic Differentiation of Human Mesenchymal Stromal Cells on Surface-Modified Titanium Alloys for Orthopedic and Dental Implants. Int J Artif Organs 2018; 32:811-20. [DOI: 10.1177/039139880903201107] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose Surface properties of titanium alloys, used for orthopedic and dental applications, are known to affect implant interactions with host tissues. Osteointegration, bone growth and remodeling in the area surrounding the implants can be implemented by specific biomimetic treatments; these allow the preparation of micro/nanostructured titanium surfaces with a thickened oxide layer, doped with calcium and phosphorus ions. We have challenged these experimental titanium alloys with primary human bone marrow stromal cells to compare the osteogenic differentiation outcomes of the cells once they are seeded onto the modified surfaces, thus simulating a prosthetic device-biological interface of clinical relevance. Methods A specific anodic spark discharge was the biomimetic treatment of choice, providing experimental titanium disks treated with different alkali etching approaches. The disks, checked by electron microscopy and spectroscopy, were subsequently used as substrates for the proliferation and osteogenic differentiation of human cells. Expression of markers of the osteogenic lineage was assessed by means of qualitative and quantitative PCR, by cytochemistry, immunohistochemistry Western blot and matrix metalloprotease activity analyses. Results Metal surfaces were initially less permissive for cell growth. Untreated control substrates were less efficient in sustaining mineralized matrix deposition upon osteogenic induction of the cells. Interestingly, bone sialo protein and matrix metalloprotease 2 levels were enhanced on experimental metals compared to control surfaces, particularly for titanium oxide coatings etched with KOH. Discussion As a whole, the KOH-modification of titanium surfaces seems to allow the best osteogenic differentiation of human mesenchymal stromal cells, representing a possible plus for future clinical prosthetic applications.
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Affiliation(s)
- Paolo Giannoni
- Stem Cell Laboratory, Advanced Biotechnology Center, Genoa - Italy
| | | | - Carmen Giordano
- Giulio Natta Department of Industrial Chemistry and Chemical Engineering, Milan Polytechnic University, Milan - Italy
| | - Roberto Narcisi
- Stem Cell Laboratory, Advanced Biotechnology Center, Genoa - Italy
| | - Ranieri Cancedda
- Laboratory of Regenerative Medicine, National Cancer Research Institute, University of Genoa - Italy
| | - Rodolfo Quarto
- Stem Cell Laboratory, Advanced Biotechnology Center, Genoa - Italy
| | - Roberto Chiesa
- Giulio Natta Department of Industrial Chemistry and Chemical Engineering, Milan Polytechnic University, Milan - Italy
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Kaleağasıoğlu F, Berger MR. SIBLINGs and SPARC families: Their emerging roles in pancreatic cancer. World J Gastroenterol 2014; 20:14747-14759. [PMID: 25356037 PMCID: PMC4209540 DOI: 10.3748/wjg.v20.i40.14747] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer has a considerably poor prognosis with a 5-year survival probability of less than 5% when all stages are combined. Pancreatic cancer is characterized by its dense stroma, which is involved in the critical interplay with the tumor cells throughout tumor progression and furthermore, creates a barrier restricting efficient penetration of therapeutics. Alterations in a large number of genes are reflected by a limited number of signaling pathways, which are potential targets. Understanding more about the molecular basis of this devastating cancer type regarding tumor microenvironment, distinct subpopulations of cells, epithelial-to-mesenchymal transition and inflammation will lead to the development of various targeted therapies for controlling tumor growth and metastasis. In this complex scenario of pancreatic cancer, especially members of the “small integrin binding ligand N-linked glycoproteins” (SIBLINGs) and “secreted protein acidic and rich in cysteine” (SPARC) families have emerged due to their prominent roles in properties including proliferation, differentiation, apoptosis, adhesion, migration, angiogenesis, wound repair and regulation of extracellular matrix remodeling. SIBLINGs consist of five members, which include osteopontin (OPN), bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein. The SPARC family of modular extracellular proteins is comprised of SPARC/osteonectin (ON) and SPARC-like 1 (hevin); secreted modular calcium binding proteins; testicans and follistatin-like protein. In this review, we especially focus on OPN and ON, elaborating on their special and growing importance in pancreatic cancer diagnosis and prognosis.
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Lamour V, Nokin MJ, Henry A, Castronovo V, Bellahcène A. [SIBLING proteins: molecular tools for tumor progression and angiogenesis]. Med Sci (Paris) 2013; 29:1018-25. [PMID: 24280506 DOI: 10.1051/medsci/20132911019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The small integrin-binding ligand N-linked glycoprotein (SIBLING) family consists of osteopontin (OPN), bonesialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP) and matrix extracellular phosphoglycoprotein (MEPE). These proteins, initially identified in bone and teeth, share many structural characteristics. It is now well established that they are over expressed in many tumors and play a critical role at different steps of cancer development. In this review, we describe the roles of SIBLING proteins at different stages of cancer progression including cancer cell adhesion, proliferation, migration, invasion, metastasis and angiogenesis.
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Affiliation(s)
- Virginie Lamour
- Laboratoire de recherche sur les métastases, GIGA (groupe interdisciplinaire de génoprotéomique appliquée)-Cancer, Université de Liège, Building 23, Sart Tilman, 4000 Liège, Belgique
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Xu T, Qin R, Zhou J, Yan Y, Lu Y, Zhang X, Fu D, Lv Z, Li W, Xia C, Hu G, Ding X, Chen J. High bone sialoprotein (BSP) expression correlates with increased tumor grade and predicts a poorer prognosis of high-grade glioma patients. PLoS One 2012; 7:e48415. [PMID: 23119009 PMCID: PMC3485236 DOI: 10.1371/journal.pone.0048415] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Accepted: 09/25/2012] [Indexed: 01/02/2023] Open
Abstract
Objectives To investigate the expression and prognostic value of bone sialoprotein (BSP) in glioma patients. Methods We determined the expression of BSP using real-time RT-PCR and immunohistochemistry in tissue microarrays containing 15 normal brain and 270 glioma samples. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were performed by the stepwise forward Cox regression model. Results Both BSP mRNA and protein levels were significantly elevated in high-grade glioma tissues compared with those of normal brain and low-grade glioma tissues, and BSP expression positively correlated with tumor grade (P<0.001). Univariate and multivariate analysis showed high BSP expression was an independent prognostic factor for a shorter progression-free survival (PFS) and overall survival (OS) in both grade III and grade IV glioma patients [hazard ratio (HR) = 2.549 and 3.154 for grade III glioma, and HR = 1.637 and 1.574 for grade IV glioma, respectively]. Patients with low BSP expression had a significantly longer median OS and PFS than those with high BSP expression. Small extent of resection and lineage of astrocyte served as independent risk factors of both shorter PFS and OS in grade III glioma patients; GBM patients without O6-methylguanine (O6-meG) DNA methyltransferase (MGMT) methylation and Karnofsky performance score (KPS) less than 70 points were related to poor prognosis. Lack of radiotherapy related to shorter OS but not affect PFS in both grade III and grade IV glioma patients. Conclusion High BSP expression occurs in a significant subset of high-grade glioma patients and predicts a poorer outcome. The study identifies a potentially useful molecular marker for the categorization and targeted therapy of gliomas.
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Affiliation(s)
- Tao Xu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Rong Qin
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jinxu Zhou
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yong Yan
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Yicheng Lu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiaoping Zhang
- Department of Nuclear Medicine, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai, China
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Da Fu
- Department of Nuclear Medicine, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai, China
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Zhongwei Lv
- Department of Nuclear Medicine, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai, China
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Weiqing Li
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Chunyan Xia
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Guohan Hu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xuehua Ding
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Juxiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
- * E-mail:
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Coleman R, Costa L, Saad F, Cook R, Hadji P, Terpos E, Garnero P, Brown J, Body JJ, Smith M, Lee KA, Major P, Dimopoulos M, Lipton A. Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol 2011; 80:411-32. [PMID: 21411334 DOI: 10.1016/j.critrevonc.2011.02.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Revised: 02/09/2011] [Accepted: 02/17/2011] [Indexed: 01/23/2023] Open
Abstract
Biochemical markers of bone turnover provide insight into ongoing rates of skeletal metabolism and tumor-bone interactions in patients with malignant bone disease. This article reviews the available recent evidence assessing the potential of bone markers for detecting and monitoring malignant bone lesions in patients with advanced cancers, and for assessing overall skeletal health and response to antiresorptive therapies in patients at all stages of cancer progression. Most data thus far are for urinary N-terminal cross-linked telopeptide of type I collagen (NTX) in predicting risks of skeletal morbidity and death and monitoring response to zoledronic acid in patients with bone metastases. Ongoing studies are evaluating such correlations for other markers and therapies. Emerging evidence suggests that bone markers may help identify patients at high risk for bone metastasis or bone lesion progression, thereby allowing improved follow-up. Results from ongoing clinical trials evaluating such potential applications of bone markers are awaited.
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Affiliation(s)
- Robert Coleman
- Cancer Research Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, University of Sheffield, Whitham Road,Sheffield, England, UK.
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Bellahcène A, Castronovo V, Ogbureke KUE, Fisher LW, Fedarko NS. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nat Rev Cancer 2008; 8:212-26. [PMID: 18292776 PMCID: PMC2484121 DOI: 10.1038/nrc2345] [Citation(s) in RCA: 353] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Numerous components and pathways are involved in the complex interplay between cancer cells and their environment. The family of glycophosphoproteins comprising osteopontin, bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein and matrix extracellular phosphoglycoprotein - small integrin-binding ligand N-linked glycoproteins (SIBLINGs) - are emerging as important players in many stages of cancer progression. From their detection in various human cancers to the demonstration of their key functional roles during malignant transformation, invasion and metastasis, the SIBLINGs are proteins with potential as diagnostic and prognostic tools, as well as new therapeutic targets.
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Affiliation(s)
- Akeila Bellahcène
- Metastasis Research Laboratory, University of Liege, Tour de Pathologie, -1, Bât. B23, Sart Tilman via 4000 Liège, Belgium
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Kayed H, Jiang X, Keleg S, Jesnowski R, Giese T, Berger MR, Esposito I, Löhr M, Friess H, Kleeff J. Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer. Br J Cancer 2007; 97:1106-15. [PMID: 17876328 PMCID: PMC2360444 DOI: 10.1038/sj.bjc.6603984] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-β1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (P<0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-β1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-β1 and BMP2 in an auto- and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment.
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Affiliation(s)
- H Kayed
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - X Jiang
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - S Keleg
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - R Jesnowski
- Molecular Gastroenterology Unit, German Cancer Research Centre, Heidelberg, Germany
- Department of Medicine II, University of Heidelberg, Mannheim, Germany
| | - T Giese
- Institute of Immunology, University of Heidelberg, Heidelberg, Germany
| | - M R Berger
- Unit of Toxicology and Chemotherapy, German Cancer Research Centre, Heidelberg, Germany
| | - I Esposito
- Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - M Löhr
- Molecular Gastroenterology Unit, German Cancer Research Centre, Heidelberg, Germany
- Department of Medicine II, University of Heidelberg, Mannheim, Germany
| | - H Friess
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
| | - J Kleeff
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany
- Department of Surgery, Technical University of Munich, Ismaningerstrasse 22, Munich 81675, Germany. E-mail:
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