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Lee S, Ricci B, Tran J, Eul E, Ye J, Ren Q, Clever D, Wang J, Wong P, Haas MS, Stewart SA, Ma CX, Fehniger TA, Faccio R. Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer. Nat Commun 2025; 16:1183. [PMID: 39885132 PMCID: PMC11782527 DOI: 10.1038/s41467-025-56420-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 01/14/2025] [Indexed: 02/01/2025] Open
Abstract
Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.
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Affiliation(s)
- Seunghyun Lee
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Biancamaria Ricci
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jennifer Tran
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Emily Eul
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jiayu Ye
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Qihao Ren
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - David Clever
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Julia Wang
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO, USA
| | - Pamela Wong
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | | | - Sheila A Stewart
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Cynthia X Ma
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Todd A Fehniger
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Roberta Faccio
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
- Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
- Shriners Hospitals for Children St Louis, St Louis, MO, USA.
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Despotidis M, Lyros O, Driva TS, Sarantis P, Kapetanakis EI, Mylonakis A, Mamilos A, Sakellariou S, Schizas D. DKK1 and Its Receptors in Esophageal Adenocarcinoma: A Promising Molecular Target. Diagnostics (Basel) 2025; 15:85. [PMID: 39795613 PMCID: PMC11720708 DOI: 10.3390/diagnostics15010085] [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: 11/07/2024] [Revised: 12/26/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
Esophageal adenocarcinoma (EAC) is an aggressive gastrointestinal (GI) malignancy with increasing incidence. Despite the recent progress in targeted therapies and surgical approaches, the survival rates of esophageal adenocarcinoma patients remain poor. The Dickkopf (DKK) proteins are secretory proteins known mainly as antagonists of the Wnt/β-catenin signaling pathway, which is considered an oncogene. However, it has been shown that in several GI cancers, including esophageal cancer, DKK1 may act as an oncogene itself through Wnt-independent signaling pathways. LRP5\6 and Kremen1/2 (Krm1/2) are transmembrane receptors to which the DKK proteins are mainly known to bind. CKAP4 (cytoskeleton-associated protein 4) is a novel receptor of DKK1, and the DKK1-CKAP4 pathway seems to be crucial in the role of DKK1 as an oncogene. The aim of this review is to feature the essential role of DKK1 and its receptors in carcinogenesis with a focus on EAC in an era of urgent need for specific biomarkers along with improved targeted therapies.
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Affiliation(s)
- Markos Despotidis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
| | - Orestis Lyros
- Fourth Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Tatiana S. Driva
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.S.D.); (S.S.)
| | - Panagiotis Sarantis
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Emmanouil I. Kapetanakis
- Department of Thoracic Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Adam Mylonakis
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
| | - Andreas Mamilos
- Institute of Pathology, University of Regensburg, 93053 Bavaria, Germany;
- Department of Pathology, German Oncology Center, Limassol 4108, Cyprus
| | - Stratigoula Sakellariou
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (T.S.D.); (S.S.)
| | - Dimitrios Schizas
- First Department of Surgery, National and Kapodistrian University of Athens, Laikon General Hospital, 11527 Athens, Greece; (A.M.); (D.S.)
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3
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Gál E, Parvaneh S, Miklós V, Hegyi P, Kemény L, Veréb Z, Venglovecz V. Investigating the influence of taurochenodeoxycholic acid (TCDCA) on pancreatic cancer cell behavior: An RNA sequencing approach. J Biotechnol 2024; 391:20-32. [PMID: 38815810 DOI: 10.1016/j.jbiotec.2024.05.010] [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: 01/18/2024] [Revised: 05/13/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
Pancreatic cancer (PC) poses a substantial global health challenge, ranking as the fourth leading cause of cancer-related deaths due to its high mortality rate. Late-stage diagnoses are common due to the absence of specific symptoms. Pancreatic ductal adenocarcinoma (PDAC) accounts for the majority of PC cases. Recent research has suggested a potential link between elevated serum levels of bile acids (BAs) and tumorigenesis of PDAC. This study aims to understand how taurochenodeoxycholic acid (TCDCA), a secondary BA, influences PDAC using RNA sequencing techniques on the Capan-1 cell line. We identified 2,950 differentially expressed genes (DEGs) following TCDCA treatment, with 1,597 upregulated and 1,353 downregulated genes. These DEGs were associated with critical PDAC pathways, including coagulation, angiogenesis, cell migration, and signaling regulation. Furthermore, we reviewed relevant literature highlighting genes like DKK-1, KRT80, UPLA, and SerpinB2, known for their roles in PDAC tumorigenesis and metastasis. Our study sheds light on the complex relationship between BAs and PDAC, offering insights into potential diagnostic markers and therapeutic targets. Further research is needed to unravel these findings' precise mechanisms and clinical implications, potentially improving PDAC diagnosis and treatment.
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Affiliation(s)
- Eleonóra Gál
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Shahram Parvaneh
- Regenerative Medicine and Cellular Pharmacology Research Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Vanda Miklós
- University Biobank, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research Development and Innovation, University of Szeged, Szeged, Hungary; Centre for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute for Pancreatic Disorders, Semmelweis University, Budapest, Hungary
| | - Lajos Kemény
- Regenerative Medicine and Cellular Pharmacology Research Laboratory, Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary; Interdisciplinary Research Development and Innovation, Center of Excellence, University of Szeged, Szeged, Hungary; HCEMM-USZ Skin Research Group, HCEMM, Szeged, Hungary
| | - Zoltán Veréb
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary.
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Translational Pancreatology Research Group, Interdisciplinary Center of Excellence for Research Development and Innovation, University of Szeged, Szeged, Hungary
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4
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Rinella L, Fiorentino G, Compagno M, Grange C, Cedrino M, Marano F, Bosco O, Vissio E, Delsedime L, D'Amelio P, Bussolati B, Arvat E, Catalano MG. Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer. Cancer Gene Ther 2024; 31:1266-1279. [PMID: 38740881 DOI: 10.1038/s41417-024-00783-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/29/2024] [Accepted: 04/29/2024] [Indexed: 05/16/2024]
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis and remains an incurable fatal disease. Therefore, the identification of molecular markers involved in cancer progression is urgently needed to develop more-effective therapies. The present study investigated the role of the Wnt signaling modulator Dickkopf-1 (DKK1) in the growth and metastatic progression of mCRPC. DKK1 silencing through siRNA and deletion via CRISPR/Cas9 editing were performed in two different metastatic castration-resistant prostate cancer cell lines (PC3 and DU145). A xenograft tumor model was used to assess tumor growth and metastases. In in vitro experiments, both DKK1 silencing and deletion reduced cell growth and migration of both cell lines. DKK1 knockout clones (DKK1-KO) exhibited cell cycle arrest, tubulin reorganization, and modulation of tumor metastasis-associated genes. Furthermore, in DKK1-KO cells, E-cadherin re-expression and its membrane co-localization with β-catenin were observed, contributing to reduced migration; Cadherin-11, known to increase during epithelial-mesenchymal transition, was down-regulated in DKK1-KO cells. In the xenograft mouse model, DKK1 deletion not only reduced tumor growth but also inhibited the formation of lung metastases. In conclusion, our findings support the key role of DKK1 in the growth and metastatic dissemination of mCRPC, both in vitro and in vivo.
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Affiliation(s)
- Letizia Rinella
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Mara Compagno
- Center for Experimental Research and Medical Studies (CeRMS), Molinette Hospital, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Cristina Grange
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Massimo Cedrino
- Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Francesca Marano
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ornella Bosco
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Elena Vissio
- Unit of Pathology, Molinette Hospital, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Luisa Delsedime
- Unit of Pathology, Molinette Hospital, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | | | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Emanuela Arvat
- Department of Medical Sciences, University of Turin, Turin, Italy
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Faccio R, Lee S, Ricci B, Tran J, Ye J, Clever D, Eul E, Wang J, Wong P, Ma C, Fehniger T. Cancer-associated fibroblast-derived Dickkopf-1 suppresses NK cell cytotoxicity in breast cancer. RESEARCH SQUARE 2024:rs.3.rs-4202878. [PMID: 38659818 PMCID: PMC11042392 DOI: 10.21203/rs.3.rs-4202878/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Breast cancer is poorly immunogenic, hence able to evade T cell recognition and respond poorly to immune checkpoint blockade. Breast cancer cells can also evade NK cell-mediated immune surveillance, but the mechanism remains enigmatic. Dickkopf-1 (DKK1) is a Wnt/b-catenin inhibitor, whose levels are increased in breast cancer patients and correlate with reduced overall survival. DKK1 is expressed by cancer-associated fibroblasts (CAFs) in orthotopic breast tumors and patient samples, and at higher levels by bone cells. While bone-derived DKK1 contributes to the systemic elevation of DKK1 in tumor-bearing mice, CAFs represent the primary source of DKK1 at the tumor site. Systemic or bone-specific DKK1 targeting reduces primary tumor growth. Intriguingly, specific deletion of CAF-derived DKK1 also limits breast cancer progression, regardless of its elevated levels in circulation and in the bone. DKK1 does not support tumor proliferation directly but rather suppresses the activation and tumoricidal activity of NK cells. Importantly, increased DKK1 levels and reduced number of cytotoxic NK cells are detected in breast cancer patients with progressive bone metastases compared to those with stable disease. Our findings indicate that DKK1 creates a tumor-supporting environment through the suppression of NK cells in breast cancer.
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Affiliation(s)
| | | | | | | | - Jiayu Ye
- Washington University in St. Louis
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Investigation of the Antitumor Effects of Tamoxifen and Its Ferrocene-Linked Derivatives on Pancreatic and Breast Cancer Cell Lines. Pharmaceuticals (Basel) 2022; 15:ph15030314. [PMID: 35337112 PMCID: PMC8950591 DOI: 10.3390/ph15030314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/26/2022] [Accepted: 03/02/2022] [Indexed: 12/17/2022] Open
Abstract
Tamoxifen is a long-known anti-tumor drug, which is the gold standard therapy in estrogen receptor (ER) positive breast cancer patients. According to previous studies, the conjugation of the original tamoxifen molecule with different functional groups can significantly improve its antitumor effect. The purpose of this research was to uncover the molecular mechanisms behind the cytotoxicity of different ferrocene-linked tamoxifen derivates. Tamoxifen and its ferrocene-linked derivatives, T5 and T15 were tested in PANC1, MCF7, and MDA-MB-231 cells, where the incorporation of the ferrocene group improved the cytotoxicity on all cell lines. PANC1, MCF7, and MDA-MB-231 express ERα and GPER1 (G-protein coupled ER 1). However, ERβ is only expressed by MCF7 and MDA-MB-231 cells. Tamoxifen is a known agonist of GPER1, a receptor that can promote tumor progression. Analysis of the protein expression profile showed that while being cytotoxic, tamoxifen elevated the levels of different tumor growth-promoting factors (e.g., Bcl-XL, Survivin, EGFR, Cathepsins, chemokines). On the other hand, the ferrocene-linked derivates were able to lower these proteins. Further analysis showed that the ferrocene-linked derivatives significantly elevated the cellular oxidative stress compared to tamoxifen treatment. In conclusion, we were able to find two molecules possessing better cytotoxicity compared to their unmodified parent molecule while also being able to counter the negative effects of the presence of the GPER1 through the ER-independent mechanism of oxidative stress induction.
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Giralt I, Gallo-Oller G, Navarro N, Zarzosa P, Pons G, Magdaleno A, Segura MF, Sábado C, Hladun R, Arango D, Sánchez de Toledo J, Moreno L, Gallego S, Roma J. Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo. Int J Mol Sci 2021; 22:12921. [PMID: 34884726 PMCID: PMC8657544 DOI: 10.3390/ijms222312921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/24/2021] [Accepted: 11/26/2021] [Indexed: 12/18/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.
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Affiliation(s)
- Irina Giralt
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Gabriel Gallo-Oller
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Natalia Navarro
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Patricia Zarzosa
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Guillem Pons
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Ainara Magdaleno
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Miguel F. Segura
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Constantino Sábado
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (C.S.); (R.H.)
| | - Raquel Hladun
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (C.S.); (R.H.)
| | - Diego Arango
- Group of Molecular Oncology, IRB Lleida, 25198 Lleida, Spain;
| | - José Sánchez de Toledo
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
| | - Lucas Moreno
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (C.S.); (R.H.)
| | - Soledad Gallego
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
- Pediatric Oncology and Hematology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (C.S.); (R.H.)
| | - Josep Roma
- Laboratory of Translational Research in Child and Adolescent Cancer, Vall d’Hebron Research Institute, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; (I.G.); (G.G.-O.); (N.N.); (P.Z.); (G.P.); (A.M.); (M.F.S.); (J.S.d.T.); (L.M.)
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Kim SY, Lee HS, Bang SM, Han DH, Hwang HK, Choi GH, Chung MJ, Kim SU. Serum Dickkopf-1 in Combined with CA 19-9 as a Biomarker of Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:1828. [PMID: 33921232 PMCID: PMC8069292 DOI: 10.3390/cancers13081828] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Dickkopf-related protein 1 (DKK-1) has a diagnostic and prognostic value in various malignant tumors. We investigated the diagnostic and prognostic performance of DKK-1 in combination with carbohydrate antigen 19-9 (CA 19-9) in cholangiocarcinoma (CCC) patients. Serum DKK-1 levels were measured using enzyme-linked immunosorbent assay. The receiver operating characteristic (ROC) curve, area under ROC (AUROC) analyses, Kaplan-Meier method, and Cox proportional hazard model were used to evaluate the diagnostic and prognostic performance of DKK-1 in combination with CA 19-9. We checked DKK-1 levels in 356 CCC patients and found that DKK-1 was significantly elevated only in 79 intrahepatic CCC (ICC) patients compared to controls (340.5 vs. 249.8 pg/mL, p = 0.002). The optimal cutoff level of DKK-1 used to identify ICC patients was 258.0 pg/mL (AUROC = 0.637, sensitivity = 59.5%, specificity = 56.9%, positive predictive value (PPV) = 40.5%, negative predictive value (NPV) = 74.0%, positive likelihood ratio (LR) = 1.38, and negative LR = 0.71). Using this cutoff, 47 (59.5%) patients were correctly diagnosed with ICC. DKK-1 in combination with CA 19-9 showed a better diagnostic performance (AUROC = 0.793, sensitivity = 74.7%, specificity = 56.3%, PPV = 45.7, NPV = 81.8, positive LR = 1.71, and negative LR = 0.45) than CA 19-9 alone. The low DKK-1 and CA 19-9 expression group had a significantly longer overall survival (OS) than the high expression group (p = 0.006). The higher level of DKK-1 and CA 19-9 was independently associated with shorter OS (hazard ratio = 3.077, 95% confidence interval 1.389-6.819, p = 0.006). The diagnostic and prognostic performance of DKK-1 in combination with CA 19-9 might be better than those of CA 19-9 alone in ICC patients.
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Affiliation(s)
- Si-Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Hee-Seung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Seung-Min Bang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Dai-Hoon Han
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Ho-Kyoung Hwang
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Gi-Hong Choi
- Department of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Seoul 120-752, Korea; (D.-H.H.); (H.-K.H.); (G.-H.C.)
| | - Moon-Jae Chung
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
| | - Seung-Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea; (S.-Y.K.); (H.-S.L.); (S.-M.B.)
- Yonsei Liver Center, Severance Hospital, Seoul 120-752, Korea
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Zhu G, Song J, Chen W, Yuan D, Wang W, Chen X, Liu H, Su H, Zhu J. Expression and Role of Dickkopf-1 (Dkk1) in Tumors: From the Cells to the Patients. Cancer Manag Res 2021; 13:659-675. [PMID: 33536782 PMCID: PMC7847771 DOI: 10.2147/cmar.s275172] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 09/26/2020] [Indexed: 12/14/2022] Open
Abstract
Dickkopf-1 (Dkk1) is a secretory antagonist of the classical Wnt signaling pathway. Many studies have reported that Dkk1 is abnormally expressed in tumor cells, and abnormal expression of Dkk1 can inhibit cell proliferation or induce apoptosis through pro-apoptotic factors, However, due to the differences in tumor environment and the complex regulatory mechanisms in different tumors, Dkk1 has different effects on the progression of different tumors. In many tumors, high expression of Dkk1 may promote tumor metastasis. However, Dkk1, which is highly expressed in other tumors, can inhibit tumor invasion and metastasis. More and more evidence shows that Dkk1 plays a complex and different role in tumor occurrence, development and metastasis in different tumor environments and through a variety of complex regulatory mechanisms. Therefore, Dkk1 may not only be a useful biomarker of metastasis, but also a target for studying the metabolic mechanism of tumor cells and treating tumors in many tumor types. Therefore, this article reviews the research progress on the expression, mechanism and function of Dkk1 in different tumors, and at the same time, based on the public database data, we made a further analysis of the expression of Dkk1 in different tumors.
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Affiliation(s)
- Guohua Zhu
- Guizhou Medical University, Guiyang, Guizhou Province 550002, People's Republic of China.,Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China
| | - Jukun Song
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China.,Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People's Republic of China
| | - Weimin Chen
- Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People's Republic of China
| | - Dongbo Yuan
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China.,Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People's Republic of China
| | - Wei Wang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China
| | - Xiaoyue Chen
- Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People's Republic of China
| | - Hen Liu
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China.,Zunyi Medical University, Zunyi, Guizhou Province 563000, People's Republic of China
| | - Hao Su
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China.,Zunyi Medical University, Zunyi, Guizhou Province 563000, People's Republic of China
| | - Jianguo Zhu
- Guizhou Medical University, Guiyang, Guizhou Province 550002, People's Republic of China.,Department of Urology, Guizhou Provincial People's Hospital, Guiyang, Guizhou Province 550002, People's Republic of China.,Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People's Republic of China.,Zunyi Medical University, Zunyi, Guizhou Province 563000, People's Republic of China
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10
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Jiang X, Hui F, Qin X, Wu Y, Liu H, Gao J, Li X, Xu Y, Zhang Y. Diagnosis Accuracy and Prognostic Significance of the Dickkopf-1 Protein in Gastrointestinal Carcinomas: Systematic Review and Network Meta-analysis. J Cancer 2020; 11:7091-7100. [PMID: 33193872 PMCID: PMC7646173 DOI: 10.7150/jca.49970] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/06/2020] [Indexed: 12/17/2022] Open
Abstract
Objective: To evaluate the diagnosis accuracy and prognostic significance of bio-marker dickkopf-1(DKK-1) protein in GIC, and also sub-type of hepatocellular carcinoma (HCC), pancreas carcinomas (PC), oesophageal carcinoma (EPC) and Adenocarcinoma of esophago-gastric junction (AEGJ), etc. Methods: Electronic databases were searched from inception to May 2020. Patients were diagnosed with gastrointestinal carcinomas, and provided data on the correlation between high and low DKK-1 expression and diagnosis or prognosis. Results: Forty-three publications involving 9318 participants were included in the network meta-analysis, with 31 of them providing data for diagnosis value and 18 records were eligible for providing prognosis value of DKK-1. DKK-1 has a moderate diagnostic value for overall GIC, HCC and PC. In addition, for the combined diagnosis value of DKK-1 +AFP, high diagnostic accuracy value could be determined in HCC and early HCC group, respectively. Whereas, diagnosis efficiency of DKK-1+CA19-9 was also better than that of DKK-1 alone with AUC value is above 0.95. For the prognosis meta-analysis of histopathological stratification, we found that EPC and AEGJ ranked the best for the histopathological stratification of prognosis from network meta-analysis. This systematic review protocol was registered with the PROSPERO registry (No.CRD42020167910). Conclusion: DKK-1 has good diagnostic accuracy, especially combination of DKK-1+AFP in HCC and DKK-1+CA19-9 in PC, whereas modest prognostic significant in GIC. Future head-to-head researches are warranted for DKK-1 expression in HCC and PC tissue.
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Affiliation(s)
- Xiaowen Jiang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Fuhai Hui
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiaochun Qin
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yuting Wu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Haihan Liu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Jing Gao
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiang Li
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yali Xu
- Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yingshi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, 110016, China
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11
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Li J, Gao Y, Yue W. The Clinical Diagnostic and Prognostic Value of Dickkopf-1 in Cancer. Cancer Manag Res 2020; 12:4253-4260. [PMID: 32606922 PMCID: PMC7292247 DOI: 10.2147/cmar.s254596] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/19/2020] [Indexed: 12/25/2022] Open
Abstract
The Wnt signaling pathway extensively participates in diverse processes such as embryonic development, maintenance of homeostasis and tumor pathogenesis. Dickkopf-1 (DKK1), a Wnt inhibitor, plays a vital role for over the past decades regarding its role in the regulation of several types of cancers. However, studies have shown that DKK1 is expressed differently in cancer and plays a role as a cancer-promoting factor or a tumor suppressor, which is worthy of further exploration. We herein study whether DKK1 is highly expressed in all cancers and plays a crucial role in promoting cancer. Furthermore, we discussed as to which stages of cancer development it plays in. Finally, the present detection methods were introduced and indicated the clinical application of DKK1 in tumor development.
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Affiliation(s)
- Jie Li
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of China
| | - Yan Gao
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of China
| | - Wentao Yue
- Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of China
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12
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Wei R, Rodrìguez RA, Mullor MDMR, Tan Z, Gui Y, Hu J, Zhu T, Huang X, Zhu Y, Xu J. Analyzing the prognostic value of DKK1 expression in human cancers based on bioinformatics. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:552. [PMID: 32411775 PMCID: PMC7214893 DOI: 10.21037/atm-20-3263] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Background The Dickkopf1 (DKK1) gene encodes a protein that belongs to the Dickkopf family. The protein can inhibit the Wnt signaling pathway which plays a key role in the carcinogenesis and progression of various types of cancers. Based on this, we hypothesized that the differential expression of DKK1 may figure significantly in cancers by regulating Wnt signaling pathway transduction. In this study, we conducted bioinformatics analysis to evaluate the prognostic and therapeutic value of DKK1 expression level in human cancers. Methods The expression level was analyzed by using the Oncomine database and Gene Expression Profiling Interactive Analysis tool. The analysis of prognosis was conducted by using the UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), and DriverDBv3 databases. We also investigated using DKK1 promoter methylation to define cancer types through the UALCAN database. Meanwhile, the related functional networks of DKK1 were analyzed by using the GeneMANIA interactive tool and Cytoscape software. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted using the Metascape online website, and we used the cBioPotartal database to explored DKK1 expression, aberrant information, and the co-expression genes in the subgroups of lung cancer. Finally, we performed the overall survival (OS) meta-analysis of the DKK1 expression in lung squamous cell carcinoma (LUSC) via the Lung Cancer Explorer (LCE). Results DKK1 was differentially expressed in different types of human cancers. DKK1 was overexpressed in human cancers including head and neck squamous cell carcinoma (HNSC), LUSC, and pancreatic adenocarcinoma (PAAD). Overexpression of DKK1 indicated adverse OS in bladder urothelial carcinoma (BLCA), HNSC, and PADD, but no difference in OS was found between the LUSC and healthy groups. The high expression of DKK1 was also associated with shorter disease-free survival (DFS) in HNSC, LUSC, and PAAD. Gene regulation network analysis indicated that DKK1 was mainly involved in Wnt signaling pathways and several other signaling pathways. Conclusions Our findings showed that DKK1 is significantly expressed in various cancers and could be a biomarker for targeted therapy and a predictor for prognosis of these specific cancers. The bioinformatics analysis revealed a significant overexpression of DKK1 in HNSC, LUSC, and PAAD, with DKK1 overexpression being associated with adverse outcome in these patients, but how DKK1 expression levels relate to hematological malignancies and prognosis is still unclear. These new insights into the function of DKK1 may provide a basis for new targeted drug therapy and an avenue for further investigation into the mechanisms underlying carcinogenesis of DKK1 in different cancer types.
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Affiliation(s)
- Ruqiong Wei
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Raquel Alarcòn Rodrìguez
- Faculty of Health Sciences, University of Almerìa, Carretera de Sacramento s/n, 04120 Almeria, Spain
| | | | - Zhibiao Tan
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yuchang Gui
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Jincui Hu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Tingpei Zhu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xiaoxiao Huang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Yanyan Zhu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Jianwen Xu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
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13
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Shin W, Hinojosa CD, Ingber DE, Kim HJ. Human Intestinal Morphogenesis Controlled by Transepithelial Morphogen Gradient and Flow-Dependent Physical Cues in a Microengineered Gut-on-a-Chip. iScience 2019; 15:391-406. [PMID: 31108394 PMCID: PMC6526295 DOI: 10.1016/j.isci.2019.04.037] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 12/28/2018] [Accepted: 04/29/2019] [Indexed: 12/12/2022] Open
Abstract
We leveraged a human gut-on-a-chip (Gut Chip) microdevice that enables independent control of fluid flow and mechanical deformations to explore how physical cues and morphogen gradients influence intestinal morphogenesis. Both human intestinal Caco-2 and intestinal organoid-derived primary epithelial cells formed three-dimensional (3D) villi-like microarchitecture when exposed to apical and basal fluid flow; however, 3D morphogenesis did not occur and preformed villi-like structure involuted when basal flow was ceased. When cells were cultured in static Transwells, similar morphogenesis could be induced by removing or diluting the basal medium. Computational simulations and experimental studies revealed that the establishment of a transepithelial gradient of the Wnt antagonist Dickkopf-1 and flow-induced regulation of the Frizzled-9 receptor mediate the histogenesis. Computational simulations also predicted spatial growth patterns of 3D epithelial morphology observed experimentally in the Gut Chip. A microengineered Gut Chip may be useful for studies analyzing stem cell biology and tissue development.
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Affiliation(s)
- Woojung Shin
- Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Christopher D Hinojosa
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA
| | - Donald E Ingber
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA
| | - Hyun Jung Kim
- Department of Biomedical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA; Department of Medical Engineering, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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14
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Weng YC, Ma J, Zhang J, Wang JC. Long non-coding RNA LINC01133 silencing exerts antioncogenic effect in pancreatic cancer through the methylation of DKK1 promoter and the activation of Wnt signaling pathway. Cancer Biol Ther 2018; 20:368-380. [PMID: 30580676 DOI: 10.1080/15384047.2018.1529110] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Recent studies have acknowledged the critical roles played by long non-coding RNAs (lncRNAs) in the development and progression of pancreatic cancer. Therefore, the present study aimed to elucidate the mechanism underlying on how LINC01133 regulates the Wnt signaling pathway in pancreatic cancer. A microarray-based gene expression analysis was performed to identify the differentially expressed lncRNAs in pancreatic cancer. In addition, ectopic expression assays, knockdown experiments and gene reporter assays were conducted to clarify the role of LINC01133 in pancreatic cancer and to understand the interaction between LINC01133 and the methylation of DKK1 promoter. The expression of LINC01133, DKK1, and other genes related to the Wnt signaling pathway was also measured. EDU staining, scratch test and Transwell assay were employed to measure the proliferation, migration and invasion of pancreatic cancer cells, respectively. GSE32676 and GSE16515 revealed that LINC01133 was upregulated in pancreatic cancer, which was also associated with increased DKK1 methylation and higher expression of genes related to the Wnt signaling pathway, although the expression of DKK1 decreased in pancreatic cancer. In addition, LINC01133 bound to the promoter region of DKK1, resulting in the trimethylation of H3K27 and decreased DKK1 expression, while the expression of Wnt-5a, MMP-7, and β-catenin increased upon LINC01133 binding. Finally, over-expressed LINC01133 enhanced the growth, proliferation, migration, metastasis, and invasion of pancreatic cancer cells. The present study clarified the distinct effect of LINC01133 on pancreatic cancer. In summary, by inducing the methylation of DKK1 promoter, LINC01133 silencing suppresses the development of pancreatic cancer cells through the Wnt signaling pathway.
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Affiliation(s)
- Yuan-Chi Weng
- a Department of General Surgery , Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China
| | - Jin Ma
- b Department of Gastroenterology , Luwan Branch of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China
| | - Jun Zhang
- a Department of General Surgery , Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China
| | - Jian-Cheng Wang
- a Department of General Surgery , Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China
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15
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Tang Y, Zhang Z, Tang Y, Chen X, Zhou J. Identification of potential target genes in pancreatic ductal adenocarcinoma by bioinformatics analysis. Oncol Lett 2018; 16:2453-2461. [PMID: 30013637 PMCID: PMC6036577 DOI: 10.3892/ol.2018.8912] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/22/2018] [Indexed: 12/29/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most complicated and fatally pathogenic human malignancies. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of PDAC. The aim of the present study was to identify the key genes and signaling pathways associated with PDAC using bioinformatics analysis. Four transcriptome microarray datasets (GSE15471, GSE55643, GSE62165 and GSE91035) were acquired from Gene Expression Omnibus datasets, which included 226 PDAC samples and 65 normal pancreatic tissue samples. We screened differentially expressed genes (DEGs) with GEO2R and investigated their biological function by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis. The overall survival data was obtained from UALCAN, which calculated the data shared with The Cancer Genome Atlas. In addition, a protein-protein interaction (PPI) network of the DEGs was constructed by STRING and Cytoscape software. The four sets of DEGs exhibited an intersection consisting of 205 genes (142 up-regulated and 63 down-regulated), which may be associated with PDAC. GO analysis showed that the 205 DEGs were significantly enriched in the plasma membrane, cell adhesion molecule activity and the Energy pathways, and glycine, serine, threonine metabolism were the most enriched pathways according to KEGG pathway analysis. Kaplan-Meier survival analysis revealed that 22 of 205 common genes were significantly associated with the overall survival of pancreatic cancer patients. In the PPI network and sub-network, DKK1 and HMGA2 were considered as hub genes with high connectivity degrees. DKK1 and HMGA2 are strongly associated with WNT3A and TP53 separately, which indicates that they may play an important role in the Wnt and P53 signaling pathways. Using integrated bioinformatics analysis, we identified DKK1 and HMGA2 as candidate genes in PDAC, which may improve our understanding of the mechanisms of the pathogenesis and integration; the two genes may be therapeutic targets and prognostic markers for PDAC.
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Affiliation(s)
- Yuchen Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Pancreatic Disease Research Center, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Zixiang Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Pancreatic Disease Research Center, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Yaocheng Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Xinyu Chen
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
| | - Jian Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.,Pancreatic Disease Research Center, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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16
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Jimenez-Luna C, Torres C, Ortiz R, Dieguez C, Martinez-Galan J, Melguizo C, Prados JC, Caba O. Proteomic biomarkers in body fluids associated with pancreatic cancer. Oncotarget 2018; 9:16573-16587. [PMID: 29662668 PMCID: PMC5893263 DOI: 10.18632/oncotarget.24654] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 02/25/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease that represents the fourth leading cancer-related death worldwide. There has been very little improvement in survival rates over recent years, and surgical resection remains the only reliable curative approach. Factors that contribute to this dismal prognosis for PC include its rapid progression and invasion, the absence of specific symptoms, and the little impact of available chemotherapy. Importantly, the management of this malignancy is also limited by the lack of highly specific and sensitive biomarkers for its diagnosis and follow-up, and their identification is therefore considered a promising strategy to improve outcomes in these patients. Numerous translational studies have explored the usefulness of body fluids as a non-invasive source of PC-specific biomarkers, and innovations in proteomic methods and technologies have provided a myriad of protein biomarkers for different cancers. The adoption of a proteomic approach has improved understanding of the biology of PC and contributed to the potential identification of protein biomarkers for this disease. This review considers the most recent research efforts to develop novel proteomic biomarkers in body fluids for PC.
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Affiliation(s)
- Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Carolina Torres
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Raul Ortiz
- Department of Health Sciences, Jaen University, Jaen, Spain
| | - Carmelo Dieguez
- Department of Gastroenterology, San Cecilio University Hospital, Granada, Spain
| | | | - Consolacion Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Jose C. Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Octavio Caba
- Department of Health Sciences, Jaen University, Jaen, Spain
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17
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Shi XD, Yu XH, Wu WR, Xu XL, Wang JY, Xu LB, Zhang R, Liu C. Dickkopf-1 expression is associated with tumorigenity and lymphatic metastasis in human hilar cholangiocarcinoma. Oncotarget 2018; 7:70378-70387. [PMID: 27608843 PMCID: PMC5342559 DOI: 10.18632/oncotarget.11859] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022] Open
Abstract
Dickkopf-1 (DKK1) is involved in tumorigenesis and the invasion of several tumors. However, its biological function in human hilar cholangiocarcinoma (HCCA) has not yet been documented. This study was designed to investigate the clinical significance and biological function of DKK1 in HCCA. The expression of DKK1 was investigated in thirty-seven human HCCA biopsy samples by immunohistochemistry. To further explore the biological effects of DKK1 in HCCA, transient and stable knockdown of DKK1 in two human HCCA cells (QBC939 and FRH0201) were established using small interfering or short hairpin RNA expression vector. In the present study, immunohistochemistry revealed that DKK1 was up-regulated in human HCCA tissues (24/37, 64.9%). High levels of DKK1 in human HCCA correlated with metastasis to the hilar lymph nodes (P=0.038). Genetic depletion of DKK1 in HCCA cells resulted in significantly inhibited proliferation, colony formation and migration compared with controls. Most importantly, DKK1 down-regulation impaired tumor formation capacity of HCCA cells in vivo. Subsequent investigations revealed that β-catenin is an important target of DKK1 and DKK1 exerts its pro-invasion function at least in part through the β-catenin/ matrix metalloproteinase-7 (MMP-7) signaling pathway. Consistently, in human HCCA tissues, DKK1 level was positively correlated with β-catenin and MMP-7 expression, as well as tumor hilar lymphatic metastasis. Taken together, our findings indicate that DKK1 may be a crucial regulator in the tumorigenicity and invasion of human HCCA, DKK1 exerts its pro-invasion function at least in part through the β-catenin/ MMP-7 signaling pathway, suggesting DKK1 as a potential therapeutic target for HCCA.
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Affiliation(s)
- Xiang-de Shi
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xian-Huan Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Wen-Rui Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Xiao-Lin Xu
- Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Jie-Yu Wang
- Department of Hematology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Lei-Bo Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Rui Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.,Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, 45147, Germany
| | - Chao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
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18
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Kagey MH, He X. Rationale for targeting the Wnt signalling modulator Dickkopf-1 for oncology. Br J Pharmacol 2017; 174:4637-4650. [PMID: 28574171 PMCID: PMC5727329 DOI: 10.1111/bph.13894] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/12/2017] [Accepted: 05/19/2017] [Indexed: 12/15/2022] Open
Abstract
Wnt signalling is a fundamental pathway involved in embryonic development and adult tissue homeostasis. Mutations in the pathway frequently lead to developmental defects and cancer. As such, therapeutic intervention of this pathway has generated tremendous interest. Dickkopf-1 (DKK1) is a secreted inhibitor of β-catenin-dependent Wnt signalling and was originally characterized as a tumour suppressor based on the prevailing view that Wnt signalling promotes cancer pathogenesis. However, DKK1 appears to increase tumour growth and metastasis in preclinical models and its elevated expression correlates with a poor prognosis in a range of cancers, indicating that DKK1 has more complex cellular and biological functions than originally appreciated. Here, we review current evidence for the cancer-promoting activity of DKK1 and recent insights into the effects of DKK1 on signalling pathways in both cancer and immune cells. We discuss the rationale and promise of targeting DKK1 for oncology. LINKED ARTICLES This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
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Affiliation(s)
| | - Xi He
- The F. M. Kirby Neurobiology Center, Boston Children's Hospital, Department of NeurologyHarvard Medical SchoolBostonMAUSA
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19
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Ma C, Lu YF. Role of Dickkopf-1 in gastrointestinal tumors. Shijie Huaren Xiaohua Zazhi 2017; 25:2615-2620. [DOI: 10.11569/wcjd.v25.i29.2615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
As an endogenous inhibitor of the Wnt signaling pathway, Dickkopf-1 (DKK1) plays an important role in the occurrence and development of tumors. However, the role of DKK1 in different tumor types is different, as it is lowly expressed in some tumor types, but over-expressed in others. In recent years, there have been many studies on the role of DKK1 in gastrointestinal tumors. In this paper, we review the latest progress in the understanding of the role of DKK1 in gastrointestinal tumors.
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Affiliation(s)
- Chao Ma
- Department of Gastroenterology, the Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
| | - Yong-Fu Lu
- Department of Gastroenterology, the Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
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Liu DJ, Xie YX, Liu XX, Huo YM, Yang MW, Fu XL, Liu W, Yang JY, Li J, Hua R, Liu PF, Sun YW, Zhang JF. The role of Dickkopf-1 as a potential prognostic marker in pancreatic ductal adenocarcinoma. Cell Cycle 2017; 16:1622-1629. [PMID: 28749252 DOI: 10.1080/15384101.2017.1356510] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Dickkopf-1(DKK-1), the downstream target of β-catenin/T-cell factor, participates in a negative feedback loop in the Wnt signaling and reported as an important biomarker in many tumors. In this study, we analyzed the expression of DKK-1 in pancreatic ductal adenocarcinoma (PDAC) patients at both mRNA and protein levels. We used real-time PCR to detect the expression of DKK-1 in 32 PDAC and paired adjacent non-tumor tissues, results suggested that the expression of DKK-1 was increased in PDAC tissues. We found the similar results in the analysis of 3 independent microarray data sets. Immunohistochemical staining of 311 pairs of PDAC tissues suggested that DKK-1 expression was significantly associated with T classification (P = 0.039) and lymph node metastasis (P = 0.035). Furthermore, Kaplan-Meier analysis for DKK-1 expression demonstrated that patients with higher DKK-1 level had shorter overall survival (OS) and relapse-free survival (RFS) time in Ren Ji cohort and online PDAC database at both mRNA and protein levels. Univariable and multivariable Cox regression analysis confirmed that DKK-1 as well as lymph node metastasis and histology were independent predictors of OS in patients with PDAC. This study demonstrated that DKK-1 may be a predictor for prognosis in PDAC patients.
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Affiliation(s)
- De-Jun Liu
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Yue-Xia Xie
- b Central Laboratory , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Xiao-Xing Liu
- c Department of Radiation Oncology , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Yan-Miao Huo
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Min-Wei Yang
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Xue-Liang Fu
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Wei Liu
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Jian-Yu Yang
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Jiao Li
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Rong Hua
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Pei-Feng Liu
- b Central Laboratory , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Yong-Wei Sun
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Jun-Feng Zhang
- a Biliary-Pancreatic Surgery Department , Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China
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Kikuchi A, Fumoto K, Kimura H. The Dickkopf1-cytoskeleton-associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy. Br J Pharmacol 2017; 174:4651-4665. [PMID: 28514532 DOI: 10.1111/bph.13863] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/28/2017] [Accepted: 05/04/2017] [Indexed: 12/17/2022] Open
Abstract
Dickkopf 1 (DKK1) is a secreted protein and antagonizes oncogenic Wnt signalling by binding to the Wnt co-receptor, low-density lipoprotein receptor-related protein 6. DKK1 has also been suggested to regulate its own signalling, associated with tumour aggressiveness. However, the underlying mechanism by which DKK1 promotes cancer cell proliferation has remained to be clarified for a long time. The cytoskeleton-associated protein 4 (CKAP4), originally identified as an endoplasmic reticulum membrane protein, was recently found to act as a novel DKK1 receptor. DKK1 stimulates cancer cell proliferation when CKAP4 is expressed on the cell surface membrane. Although there are no tyrosine residues in the intracellular region of CKAP4, CKAP4 forms a complex with PI3K upon the binding of DKK1, leading to the activation of Akt. Both DKK1 and CKAP4 are frequently expressed in pancreatic and lung tumours, and their simultaneous expression is negatively correlated with prognosis. Knockdown of CKAP4 in cancer cells and treatment of mice with the anti-CKAP4 antibody inhibit Akt activity in cancer cells and suppress xenograft tumour formation, suggesting that CKAP4 may represent a therapeutic target for cancers expressing both DKK1 and CKAP4. This review will provide details of the novel DKK1-CKAP4 signalling axis that promotes cancer proliferation and discuss the possibility of targeting this pathway in future cancer drug development. LINKED ARTICLES This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
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Affiliation(s)
- Akira Kikuchi
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Katsumi Fumoto
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hirokazu Kimura
- Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Ouyang Y, Pan J, Tai Q, Ju J, Wang H. Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA-Seq. Tumour Biol 2016; 37:10827-38. [PMID: 26880586 DOI: 10.1007/s13277-015-4379-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 11/04/2015] [Indexed: 11/27/2022] Open
Abstract
The promotion of tumor development by Dickkopf 4 (DKK4) is receiving increased attention. However, the association between DKK4 and pancreatic cancer remains unclear. DKK4 expression was measured in pancreatic ductal adenocarcinoma tissues using qRT-PCR and immunohistochemistry. A DKK4-overexpressing pancreatic cancer cell line was established, and the differentially expressed genes (DEGs) that were induced by DKK4 were identified using transcriptome sequencing. The association between the identified DEGs and pancreatic cancer was assessed using gene ontology (GO), pathway analysis, pathway interaction networks, differentially expressed gene interaction network analysis, and co-expression gene networks. Finally, the accuracy of the analyses was validated using serial paraffin and frozen sections of clinical samples. DKK4 is highly expressed in pancreatic cancer tissues. DEGs of overexpression DKK4 of PANC-1 are mostly upregulated. GO and pathway analysis showed that DKK4 are associated with tumor and organ development and immune inflammation. The mitogen-activated protein kinase (MAPK) signaling pathway was the main signal transduction pathway that showed significant enrichment in overexpression DKK4 of PANC-1. The results of GO, pathway analyses, and differentially expressed gene interaction network identified genes that are closely associated with tumor development, including MAPK3, PIK3R3, VAV3, JAG1, and Notch3. The immunohistochemistry and immunofluorescence results suggested that DKK4 is co-expressed with MAPK3 and VAV3 in pancreatic cancer tissues. The results presented here show for the first time that DKK4 is highly expressed in pancreatic cancer tissues. Bioinformatics analysis of a DKK4-overexpressing of PANC-1 identified several oncogenes that are closely associated with tumors, and the MAPK signaling pathway is the core signal transduction pathway. DKK4 can be co-expressed with MAPK3 and VAV3 in pancreatic ductal adenocarcinoma tissues. Thus, DKK4 may have function on the development and progression of pancreatic cancer.
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Affiliation(s)
- Yongsheng Ouyang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Juncheng Pan
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China
| | - Qiang Tai
- Organ transplantation centre, First Affiliated Hospital Sun Yat-sen University, 58 #, 2nd ZhongShan Road, Guangzhou, GD, 510080, China.
| | - Jingfang Ju
- Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA.
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People's Republic of China.
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Guo Q, Qin W. DKK3 blocked translocation of β-catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc-3 cell. J Cell Mol Med 2015; 19:2832-41. [PMID: 26395974 PMCID: PMC4687707 DOI: 10.1111/jcmm.12675] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 08/03/2015] [Indexed: 12/12/2022] Open
Abstract
The Wnt/β-catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf-related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non-cancerous tissues. Dickkopf-related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of β-catenin induced by hypoxia in pancreatic cancer Bxpc-3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell-like phenotype of pancreatic cancer Bxpc-3 cell in hypoxic conditions through reversing epithelial-mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc-3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating β-catenin/EMT signalling in pancreatic cancer Bxpc-3 cell.
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Affiliation(s)
- Qingqu Guo
- Department of Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wenjie Qin
- Department of Surgery, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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24
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Cid-Arregui A, Juarez V. Perspectives in the treatment of pancreatic adenocarcinoma. World J Gastroenterol 2015; 21:9297-9316. [PMID: 26309356 PMCID: PMC4541382 DOI: 10.3748/wjg.v21.i31.9297] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/12/2015] [Accepted: 07/18/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incurable lethal disease whose incidence rate is growing. There is no effective screening for detection of early stage tumors and, in most cases, PDAC is diagnosed at advanced disease stages, when radical pancreatic resection is not possible. The aggressive nature of pancreatic tumor cells lies in the complex genetic mechanisms behind their uncontrolled capability to grow and metastasize, which involve essential adaptive changes in cellular metabolism, signaling, adhesion and immunoediting. In addition, PDAC cells promote a dense functional stroma that facilitates tumor resistance to chemotherapy and radiation. During the last two decades, gemcitabine has been the reference for the systemic treatment of PDAC. However, recently, a regimen combining fluorouracil, irinotecan, oxaliplatin, and leucovorin (FOLFIRINOX) and another combining albumin-bound paclitaxel with gemcitabine have shown clear therapeutic advantage in advanced PDAC, with survival outcomes of 11.3 and 8.5 mo on phase III trials, respectively, over single-agent gemcitabine. With the pending issue of their higher toxicities, these regimens set the reference for ongoing and future clinical studies in advanced PDAC. In addition, the efficacy of oral fluoropyrimidine (S-1) has been well documented in Asiatic PDAC patients. The development of therapeutic approaches other than cytotoxic drugs has proven difficult in the past, with only one drug (erlotinib) approved to date. Besides, a number of agents targeting signaling pathways in tumor or stroma cells are being investigated. Likewise, immunotherapies that target PDAC in various ways are the subject of a number of clinical trials. The search for reliable biomarkers with diagnostic and prognostic value using genomics and mass spectrometry methods may facilitate monitoring and refinement of therapies. This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.
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Otto B, Koenig AM, Tolstonog GV, Jeschke A, Klaetschke K, Vashist YK, Wicklein D, Wagener C, Izbicki JR, Streichert T. Molecular changes in pre-metastatic lymph nodes of esophageal cancer patients. PLoS One 2014; 9:e102552. [PMID: 25048826 PMCID: PMC4105535 DOI: 10.1371/journal.pone.0102552] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 06/20/2014] [Indexed: 01/02/2023] Open
Abstract
Lymph node metastasis indicates poor prognosis in esophageal cancer. To understand the underlying mechanisms, most studies so far focused on investigating the tumors themselves and/or invaded lymph nodes. However they neglected the potential events within the metastatic niche, which precede invasion. Here we report the first description of these regulations in patients on transcription level. We determined transcriptomic profiles of still metastasis-free regional lymph nodes for two patient groups: patients classified as pN1 (n = 9, metastatic nodes exist) or pN0 (n = 5, no metastatic nodes exist). All investigated lymph nodes, also those from pN1 patients, were still metastasis-free. The results show that regional lymph nodes of pN1 patients differ decisively from those of pN0 patients – even before metastasis has taken place. In the pN0 group distinct immune response patterns were observed. In contrast, lymph nodes of the pN1 group exhibited a clear profile of reduced immune response and reduced proliferation, but increased apoptosis, enhanced hypoplasia and morphological conversion processes. DKK1 was the most significant gene associated with the molecular mechanisms taking place in lymph nodes of patients suffering from metastasis (pN1). We assume that the two molecular profiles observed constitute different stages of a progressive disease. Finally we suggest that DKK1 might play an important role within the mechanisms leading to lymph node metastasis.
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Affiliation(s)
- Benjamin Otto
- Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Chemistry, Center for Diagnostic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail:
| | - Alexandra M. Koenig
- Department of General, Visceral and Thoracic Surgery, Center for Surgical Sciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Genrich V. Tolstonog
- Department of Otolaryngology – Head and Neck Surgery, CHUV, University of Lausanne, Lausanne, Switzerland
| | - Anke Jeschke
- Department of Osteology and Biomechanics, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kristin Klaetschke
- Department of Clinical Chemistry, Center for Diagnostic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Yogesh K. Vashist
- Department of General, Visceral and Thoracic Surgery, Center for Surgical Sciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel Wicklein
- Department of Anatomy and Experimental Morphology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Wagener
- Department of Clinical Chemistry, Center for Diagnostic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R. Izbicki
- Department of General, Visceral and Thoracic Surgery, Center for Surgical Sciences, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Streichert
- Department of Clinical Chemistry, Center for Diagnostic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Huang Y, Yang X, Zhao F, Shen Q, Wang Z, Lv X, Hu B, Yu B, Fan J, Qin W. Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence. Med Oncol 2014; 31:966. [PMID: 24878698 DOI: 10.1007/s12032-014-0966-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Accepted: 04/15/2014] [Indexed: 12/25/2022]
Abstract
Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan-Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.
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Affiliation(s)
- Yan Huang
- Medical College of Nantong University, Nantong, China
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Li S, Qin X, Guo X, Cui A, He Y, Wei S, Wang X, Shan B. Dickkopf-1 is oncogenic and involved in invasive growth in non small cell lung cancer. PLoS One 2013; 8:e84944. [PMID: 24391982 PMCID: PMC3877398 DOI: 10.1371/journal.pone.0084944] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 11/19/2013] [Indexed: 11/28/2022] Open
Abstract
Dickkopf-1 (DKK1) is an inhibitor of the Wnt/β-catenin signaling pathway. However, the role of DKK1 in the progression of non small cell lung cancer (NSCLC) is not fully understood. In this study, RT-PCR and Western blot were used to examine the expression of DKK1 in a panel of ten human NSCLC cell lines and NSCLC tissues. DKK1 expression was highly transactivated in the great majority of these cancer lines. The expression of DKK1 was upregulated on both mRNA and protein levels in NSCLC tissues compared with the adjacent normal lung tissues. Immunohistochemistry and immunofluoresence revealed that DKK1 was mainly distributed in the cytoplasm in both carcinoma tissues and cell lines. DKK1 protein expression was also evaluated in paraffin sections from 102 patients with NSCLC by immunohistochemistry, and 65(63.73%)tumors were DKK1 positive. Relative analysis showed a significant relationship between DKK1 positive expression and lymph node metastasis(P<0.05). Patients with DKK1-positive tumors had poorer DFS than those with negative ESCC (5-year DFS; 15.4% versus 27%, P = 0.007). To further explore the biological effects of DKK1 in NSCLC cells, we over-expressed DKK1 in NSCLC 95C cell using eukaryotic expression vector pCMV-Tab-2b and performed a knockdown of DKK1 in LTEP-a-2 cell using a short hairpin RNA expression vector pSilencer 5.1. DKK1 did not have any effect on proliferation, but seemed to play a role in migration and invasion capability. Overexpression of DKK1 promotes migratory and invasive activity of 95C, while DKK1 knockdown resulted in the suppression of migration and invasion potentials of LTEP-a-2 cell. Taken together, these results indicate that DKK1 may be a crucial regulator in the progression of NSCLC. DKK1 might be a potential therapeutic target in NSCLC.
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Affiliation(s)
- Shujun Li
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xuebo Qin
- Hebei Chest Hospital, Shijiazhuang, China
| | - Xin Guo
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Airong Cui
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuzheng He
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Sen Wei
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaolu Wang
- The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baoen Shan
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Van den Broeck A, Vankelecom H, Van Eijsden R, Govaere O, Topal B. Molecular markers associated with outcome and metastasis in human pancreatic cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2012; 31:68. [PMID: 22925330 PMCID: PMC3511800 DOI: 10.1186/1756-9966-31-68] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Accepted: 08/20/2012] [Indexed: 01/21/2023]
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer in which differences in survival rates might be related to a variety in gene expression profiles. Although the molecular biology of PDAC begins to be revealed, genes or pathways that specifically drive tumour progression or metastasis are not well understood. Methods We performed microarray analyses on whole-tumour samples of 2 human PDAC subpopulations with similar clinicopathological features, but extremely distinct survival rates after potentially curative surgery, i.e. good outcome (OS and DFS > 50 months, n = 7) versus bad outcome (OS < 19 months and DFS < 7 months, n = 10). Additionally, liver- and peritoneal metastases were analysed and compared to primary cancer tissue (n = 11). Results The integrin and ephrin receptor families were upregulated in all PDAC samples, irrespective of outcome, supporting an important role of the interaction between pancreatic cancer cells and the surrounding desmoplastic reaction in tumorigenesis and cancer progression. Moreover, some components such as ITGB1 and EPHA2 were upregulated in PDAC samples with a poor outcome, Additionally, overexpression of the non-canonical Wnt/β-catenin pathway and EMT genes in PDAC samples with bad versus good outcome suggests their contribution to the invasiveness of pancreatic cancer, with β-catenin being also highly upregulated in metastatic tissue. Conclusions Components of the integrin and ephrin pathways and EMT related genes, might serve as molecular markers in pancreatic cancer as their expression seems to be related with prognosis.
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Affiliation(s)
- Anke Van den Broeck
- Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
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29
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Youssefpour H, Li X, Lander AD, Lowengrub JS. Multispecies model of cell lineages and feedback control in solid tumors. J Theor Biol 2012; 304:39-59. [PMID: 22554945 PMCID: PMC3436435 DOI: 10.1016/j.jtbi.2012.02.030] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 02/15/2012] [Accepted: 02/29/2012] [Indexed: 12/18/2022]
Abstract
We develop a multispecies continuum model to simulate the spatiotemporal dynamics of cell lineages in solid tumors. The model accounts for protein signaling factors produced by cells in lineages, and nutrients supplied by the microenvironment. Together, these regulate the rates of proliferation, self-renewal and differentiation of cells within the lineages, and control cell population sizes and distributions. Terminally differentiated cells release proteins (e.g., from the TGFβ superfamily) that feedback upon less differentiated cells in the lineage both to promote differentiation and decrease rates of proliferation (and self-renewal). Stem cells release a short-range factor that promotes self-renewal (e.g., representative of Wnt signaling factors), as well as a long-range inhibitor of this factor (e.g., representative of Wnt inhibitors such as Dkk and SFRPs). We find that the progression of the tumors and their response to treatment is controlled by the spatiotemporal dynamics of the signaling processes. The model predicts the development of spatiotemporal heterogeneous distributions of the feedback factors (Wnt, Dkk and TGFβ) and tumor cell populations with clusters of stem cells appearing at the tumor boundary, consistent with recent experiments. The nonlinear coupling between the heterogeneous expressions of growth factors and the heterogeneous distributions of cell populations at different lineage stages tends to create asymmetry in tumor shape that may sufficiently alter otherwise homeostatic feedback so as to favor escape from growth control. This occurs in a setting of invasive fingering, and enhanced aggressiveness after standard therapeutic interventions. We find, however, that combination therapy involving differentiation promoters and radiotherapy is very effective in eradicating such a tumor.
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Affiliation(s)
- H Youssefpour
- Department of Chemical Engineering and Materials Science, University of California, Irvine, USA
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30
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Li S, Qin X, Liu B, Sun L, Zhang X, Li Z, Shan B, You J, Zhou Q. Dickkopf-1 is involved in invasive growth of esophageal cancer cells. J Mol Histol 2011; 42:491-8. [PMID: 21909757 DOI: 10.1007/s10735-011-9347-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Accepted: 07/29/2011] [Indexed: 12/19/2022]
Abstract
Dickkopf-1 (DKK1) is an inhibitor of Wnt/β-catenin signaling pathway. High levels of DKK1 protein were found in a series of cancers. However, the role of DKK1 in the progression of esophageal carcinoma is not fully understood. In the present study, RT-PCR and Western blot were used to detect the expression of DKK1 in esophageal carcinoma tissues, matched adjacent normal esophageal tissues, and esophageal carcinoma cell lines. Our results showed that the expression of DKK1 was upregulated on both mRNA and protein levels in esophageal carcinoma tissues compared with the adjacent normal esophageal tissues, meanwhile, in four esophageal carcinoma cell lines analyzed, expression of DKK1 was detected with different levels. Immunohistochemistry and immunofluoresence revealed that the distribution of DKK1 was mainly in the cytoplasm in both carcinoma tissues and cell lines. To further explore the biological effects of DKK1 on proliferation, cell cycle and invasion capability, we constructed the eukaryotic expression vector pCMV-Tab-2b-DKK1 which can effectively overexpress DKK1. Subsequently, we observed that exogenous expression of DKK1 in EC9706 cell line resulted in an increased rate of proliferation, and S stage and G2/M stage ratio whereas G0/G1 ratio was decreased. In order to evaluate the invasion capability Boyden chamber was analyzed which implied that overexpression of DKK1 resulted in an increase in the invasion ability in EC9706 cell line. Taken together, the study indicates that DKK1 might be a key regulator in the progression of esophageal carcinoma and a potential therapeutic target in esophageal carcinoma.
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Affiliation(s)
- Shujun Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University, General Hospital, Tianjin, China
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Gu YM, Ma YH, Zhao WG, Chen J. Dickkopf3 overexpression inhibits pancreatic cancer cell growth in vitro. World J Gastroenterol 2011; 17:3810-7. [PMID: 21987623 PMCID: PMC3181442 DOI: 10.3748/wjg.v17.i33.3810] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Revised: 04/13/2011] [Accepted: 04/20/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the role of dickkopf3 (Dkk3) in human pancreatic cancer cell growth.
METHODS: Dkk3 mRNA and protein expression in human pancreatic cancer cell lines were detected by real-time reverse transcription polymerase chain reaction (real-time RT-PCR), Western blotting and immunofluorescence. Methylation of the Dkk3 promoter sequence was examined by methylation-specific polymerase chain reaction (MSP) and Dkk3 mRNA expression was determined by real-time RT-PCR after 5-aza-2’-deoxycytidine (5-aza-dC) treatment. The effects of Dkk3 on cancer cell proliferation and in vitro sensitivity to gemcitabine were investigated by CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) after transfecting the Dkk3 expression plasmid into human pancreatic cancer cells. The expression of β-catenin, phosphorylated extracellular signal-regulated protein kinases (pERK) and extracellular signal-regulated protein kinases (ERK) was also examined by real-time RT-PCR and Western blotting after upregulating Dkk3 expression in human pancreatic cancer cells.
RESULTS: The results show that the expression levels of both Dkk3 mRNA and protein were low in all pancreatic cancer cell lines tested. The Dkk3 promoter sequence was methylated in the MIA PaCa-2 and AsPC-1 cell lines, which showed reduced Dkk3 expression. These two cell lines, which initially had a methylated Dkk3 promoter, showed increased Dkk3 mRNA expression that was dependent upon the dosage and timing of the DNA demethylating agent, 5-aza-dC, treatment (P < 0.05 or P < 0.01). When Dkk3 expression was upregulated following the transfection of a Dkk3 expression plasmid into MIA PaCa-2 cells, the ability of cells to proliferate decreased (P < 0.01), and the expression of β-catenin and pERK was downregulated (P < 0.01). Sensitivity to gemcitabine was enhanced in Dkk3 expression plasmid-transfected cells.
CONCLUSION: Our findings, for the first time, implicate Dkk3 as a tumor suppressor in human pancreatic cancer, through the downregulation of β-catenin expression via the ERK-mediated pathway.
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GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. PLoS One 2011; 6:e22129. [PMID: 21811562 PMCID: PMC3139620 DOI: 10.1371/journal.pone.0022129] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 06/16/2011] [Indexed: 12/31/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.
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Morris JP, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 2010; 10:683-95. [PMID: 20814421 PMCID: PMC4085546 DOI: 10.1038/nrc2899] [Citation(s) in RCA: 451] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by near-universal mutations in KRAS and frequent deregulation of crucial embryonic signalling pathways, including the Hedgehog (Hh) and Wnt-β-catenin cascades. The creation of mouse models that closely resemble the human disease has provided a platform to better understand when and in which cell types these pathways are misregulated during PDAC development. Here we examine the central part that KRAS plays in the biology of PDAC, and how the timing and location of Hh and Wnt-β-catenin signalling dictate the specification and oncogenic properties of PDAC.
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Affiliation(s)
- John P Morris
- Diabetes Center, University of California, San Francisco, 513 Parnassus Ave, San Francisco, California 94143, USA
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Glaw JT, Skalak TC, Peirce SM. Inhibition of canonical Wnt signaling increases microvascular hemorrhaging and venular remodeling in adult rats. Microcirculation 2010; 17:348-57. [PMID: 20618692 PMCID: PMC2904644 DOI: 10.1111/j.1549-8719.2010.00036.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The canonical Wnt signaling pathway, heavily studied in development and cancer, has recently been implicated in microvascular growth with the use of developmental and in vitro models. To date, however, no study exists showing the effects of perturbing the canonical Wnt pathway in a complete microvascular network undergoing physiological remodeling in vivo. Our objective was to investigate the effects of canonical Wnt inhibition on the microvascular remodeling of adult rats. METHODS Canonical Wnt inhibitor DKK-1, Wnt inhibitor sFRP-1, BSA or saline was superfused onto the exteriorized mesenteric windows of 300 g adult female Sprague-Dawley rats for 20 minutes. Three days following surgery, mesenteric windows were imaged intravitally and harvested for immunofluorescence staining with smooth muscle alpha-actin and BRDU. RESULTS We observed prominent differences in the response of the mesenteric microvasculature amongst the various treatment groups. Significant increases in hemorrhage area, vascular density, and draining vessel diameter were observed in windows treated with Wnt inhibitors as compared to control-treated windows. Additionally, confocal imaging analysis showed significant increases in proliferating cells as well as evidence of proliferating smooth muscle cells along venules. CONCLUSIONS Together, our results suggest that canonical Wnt inhibition plays an important role in microvascular remodeling, specifically venular remodeling.
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Affiliation(s)
- Jason T Glaw
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA
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