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Wang H, Zhang L, Hu C, Li H, Jiang M. Wnt signaling and tumors (Review). Mol Clin Oncol 2024; 21:45. [PMID: 38798312 PMCID: PMC11117032 DOI: 10.3892/mco.2024.2743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in-depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.
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Affiliation(s)
- Huaishi Wang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Lihai Zhang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Chao Hu
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Hui Li
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Mingyan Jiang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
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Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol 2024; 17:46. [PMID: 38886806 PMCID: PMC11184729 DOI: 10.1186/s13045-024-01563-4] [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: 03/03/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
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Affiliation(s)
- Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Zirui Gao
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yige Bao
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Li Chen
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuhe Huang
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyan Liu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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3
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Sun L, Xing J, Zhou X, Song X, Gao S. Wnt/β-catenin signalling, epithelial-mesenchymal transition and crosslink signalling in colorectal cancer cells. Biomed Pharmacother 2024; 175:116685. [PMID: 38710151 DOI: 10.1016/j.biopha.2024.116685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024] Open
Abstract
Colorectal cancer (CRC), with its significant incidence and metastatic rates, profoundly affects human health. A common oncogenic event in CRC is the aberrant activation of the Wnt/β-catenin signalling pathway, which drives both the initiation and progression of the disease. Persistent Wnt/β-catenin signalling facilitates the epithelial-mesenchymal transition (EMT), which accelerates CRC invasion and metastasis. This review provides a summary of recent molecular studies on the role of the Wnt/β-catenin signalling axis in regulating EMT in CRC cells, which triggers metastatic pathogenesis. We present a comprehensive examination of the EMT process and its transcriptional controllers, with an emphasis on the crucial functions of β-catenin, EMT transcription factors (EMT-TFs). We also review recent evidences showing that hyperactive Wnt/β-catenin signalling triggers EMT and metastatic phenotypes in CRC via "Destruction complex" of β-catenin mechanisms. Potential therapeutic and challenges approache to suppress EMT and prevent CRC cells metastasis by targeting Wnt/β-catenin signalling are also discussed. These include direct β-catenin inhibitors and novel targets of the Wnt pathway, and finally highlight novel potential combinational treatment options based on the inhibition of the Wnt pathway.
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Affiliation(s)
- Luanbiao Sun
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Jianpeng Xing
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Xuanpeng Zhou
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China
| | - Xinyuan Song
- The Chinese University of Hong Kong, New Territories 999077, Hong Kong Special Administrative Region of China
| | - Shuohui Gao
- China-Japan Union Hospital of Jilin University, Changchun, Jilin 130000, PR China.
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de Brot S, Cobb J, Alibhai AA, Jackson-Oxley J, Haque M, Patke R, Harris AE, Woodcock CL, Lothion-Roy J, Varun D, Thompson R, Gomes C, Kubale V, Dunning MD, Jeyapalan JN, Mongan NP, Rutland CS. Immunohistochemical Investigation into Protein Expression Patterns of FOXO4, IRF8 and LEF1 in Canine Osteosarcoma. Cancers (Basel) 2024; 16:1945. [PMID: 38792023 PMCID: PMC11120020 DOI: 10.3390/cancers16101945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/16/2024] [Accepted: 05/18/2024] [Indexed: 05/26/2024] Open
Abstract
Osteosarcoma (OSA) is the most common type of primary bone malignancy in people and dogs. Our previous molecular comparisons of canine OSA against healthy bone resulted in the identification of differentially expressed protein-expressing genes (forkhead box protein O4 (FOXO4), interferon regulatory factor 8 (IRF8), and lymphoid enhancer binding factor 1 (LEF1)). Immunohistochemistry (IHC) and H-scoring provided semi-quantitative assessment of nuclear and cytoplasmic staining alongside qualitative data to contextualise staining (n = 26 patients). FOXO4 was expressed predominantly in the cytoplasm with significantly lower nuclear H-scores. IRF8 H-scores ranged from 0 to 3 throughout the cohort in the nucleus and cytoplasm. LEF1 was expressed in all patients with significantly lower cytoplasmic staining compared to nuclear. No sex or anatomical location differences were observed. While reduced levels of FOXO4 might indicate malignancy, the weak or absent protein expression limits its primary use as diagnostic tumour marker. IRF8 and LEF1 have more potential for prognostic and diagnostic uses and facilitate further understanding of their roles within their respective molecular pathways, including Wnt/beta-catenin/LEF1 signalling and differential regulation of tumour suppressor genes. Deeper understanding of the mechanisms involved in OSA are essential contributions towards the development of novel diagnostic, prognostic, and treatment options in human and veterinary medicine contexts.
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Affiliation(s)
- Simone de Brot
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Comparative Pathology Platform of the University of Bern (COMPATH), Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland
| | - Jack Cobb
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Aziza A. Alibhai
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Jorja Jackson-Oxley
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Maria Haque
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Rodhan Patke
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Anna E. Harris
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Corinne L. Woodcock
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Jennifer Lothion-Roy
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Dhruvika Varun
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Rachel Thompson
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Claudia Gomes
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
| | - Valentina Kubale
- Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - Mark D. Dunning
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Willows Veterinary Centre and Referral Service, Solihull B90 4NH, UK
| | - Jennie N. Jeyapalan
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Faculty of Medicine and Health Science, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
| | - Nigel P. Mongan
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Willows Veterinary Centre and Referral Service, Solihull B90 4NH, UK
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10075, USA
| | - Catrin S. Rutland
- School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham NG7 2RD, UK; (S.d.B.); (J.C.); (A.A.A.); (J.J.-O.); (M.H.); (R.P.); (A.E.H.); (C.L.W.); (J.L.-R.); (D.V.); (R.T.); (C.G.); (M.D.D.); (J.N.J.)
- Faculty of Medicine and Health Science, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
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Yalcin BH, Macas J, Wiercinska E, Harter PN, Fawaz M, Schmachtel T, Ghiro I, Bieniek E, Kosanovic D, Thom S, Fruttiger M, Taketo MM, Schermuly RT, Rieger MA, Plate KH, Bonig H, Liebner S. Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System. Cells 2023; 12:2765. [PMID: 38067194 PMCID: PMC10706863 DOI: 10.3390/cells12232765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 11/20/2023] [Accepted: 11/29/2023] [Indexed: 12/18/2023] Open
Abstract
The bone marrow (BM) hematopoietic system (HS) gives rise to blood cells originating from hematopoietic stem cells (HSCs), including megakaryocytes (MKs) and red blood cells (erythrocytes; RBCs). Many steps of the cell-fate decision remain to be elucidated, being important for cancer treatment. To explore the role of Wnt/β-catenin for MK and RBC differentiation, we activated β-catenin signaling in platelet-derived growth factor b (Pdgfb)-expressing cells of the HS using a Cre-lox approach (Ctnnb1BM-GOF). FACS analysis revealed that Pdgfb is mainly expressed by megakaryocytic progenitors (MKPs), MKs and platelets. Recombination resulted in a lethal phenotype in mutants (Ctnnb1BM-GOFwt/fl, Ctnnb1BM-GOFfl/fl) 3 weeks after tamoxifen injection, showing an increase in MKs in the BM and spleen, but no pronounced anemia despite reduced erythrocyte counts. BM transplantation (BMT) of Ctnnb1BM-GOF BM into lethally irradiated wildtype recipients (BMT-Ctnnb1BM-GOF) confirmed the megakaryocytic, but not the lethal phenotype. CFU-MK assays in vitro with BM cells of Ctnnb1BM-GOF mice supported MK skewing at the expense of erythroid colonies. Molecularly, the runt-related transcription factor 1 (RUNX1) mRNA, known to suppress erythropoiesis, was upregulated in Ctnnb1BM-GOF BM cells. In conclusion, β-catenin activation plays a key role in cell-fate decision favoring MK development at the expense of erythroid production.
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Affiliation(s)
- Burak H. Yalcin
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
| | - Jadranka Macas
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
| | - Eliza Wiercinska
- Institute for Transfusion Medicine and Immunohaematology, and DRK-Blutspendedienst BaWüHe, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
| | - Patrick N. Harter
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
| | - Malak Fawaz
- Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (M.A.R.)
| | - Tessa Schmachtel
- Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (M.A.R.)
| | - Ilaria Ghiro
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
| | - Ewa Bieniek
- German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany; (E.B.); (D.K.)
| | - Djuro Kosanovic
- German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany; (E.B.); (D.K.)
| | - Sonja Thom
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
| | | | - Makoto M. Taketo
- Kyoto University Hospital-iACT Graduate School of Medicine, Kyoto University, Kyoto 06-8501, Japan
| | - Ralph T. Schermuly
- German Center for Lung Research (DZL), Department of Internal Medicine, Excellence Cluster Cardio-Pulmonary Institute (CPI), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany; (E.B.); (D.K.)
| | - Michael A. Rieger
- Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (M.A.R.)
- German Cancer Consortium (DKTK) at the German Cancer Research Center, 69120 Heidelberg, Germany
- Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Partner Site Frankfurt, 60590 Frankfurt am Main, Germany
| | - Karl H. Plate
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
- Frankfurt Cancer Institute (FCI), 60596 Frankfurt am Main, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
| | - Halvard Bonig
- Institute for Transfusion Medicine and Immunohaematology, and DRK-Blutspendedienst BaWüHe, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany
- Department of Medicine/Division of Hematology, University of Washington, Seattle, WA 98195, USA
| | - Stefan Liebner
- Institute of Neurology (Edinger Institute), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany (J.M.); (I.G.); (K.H.P.)
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Partner Site Frankfurt, 60590 Frankfurt am Main, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany
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Yin X, Kim K, Suetsugu H, Bang SY, Wen L, Koido M, Ha E, Liu L, Sakamoto Y, Jo S, Leng RX, Otomo N, Kwon YC, Sheng Y, Sugano N, Hwang MY, Li W, Mukai M, Yoon K, Cai M, Ishigaki K, Chung WT, Huang H, Takahashi D, Lee SS, Wang M, Karino K, Shim SC, Zheng X, Miyamura T, Kang YM, Ye D, Nakamura J, Suh CH, Tang Y, Motomura G, Park YB, Ding H, Kuroda T, Choe JY, Li C, Niiro H, Park Y, Shen C, Miyamoto T, Ahn GY, Fei W, Takeuchi T, Shin JM, Li K, Kawaguchi Y, Lee YK, Wang YF, Amano K, Park DJ, Yang W, Tada Y, Lau YL, Yamaji K, Zhu Z, Shimizu M, Atsumi T, Suzuki A, Sumida T, Okada Y, Matsuda K, Matsuo K, Kochi Y, Yamamoto K, Ohmura K, Kim TH, Yang S, Yamamoto T, Kim BJ, Shen N, Ikegawa S, Lee HS, Zhang X, Terao C, Cui Y, Bae SC. Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study. Ann Rheum Dis 2022; 81:1273-1280. [PMID: 35609976 PMCID: PMC9380500 DOI: 10.1136/annrheumdis-2022-222345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 05/11/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.
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Affiliation(s)
- Xianyong Yin
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, People's Republic of China
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, People's Republic of China
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
- Human Phenome Institute, Fudan University, Shanghai, People's Republic of China
| | - Kwangwoo Kim
- Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea
| | - Hiroyuki Suetsugu
- Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan
- Laboratory for Statistical and Translational Genetics Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - So-Young Bang
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Leilei Wen
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Masaru Koido
- Laboratory for Statistical and Translational Genetics Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eunji Ha
- Department of Biology and Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, Korea
| | - Lu Liu
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Yuma Sakamoto
- Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan
- Koga Hospital 21, Kurume, Japan
| | - Sungsin Jo
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Rui-Xue Leng
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People's Republic of China
| | - Nao Otomo
- Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan
- Laboratory for Statistical and Translational Genetics Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Young-Chang Kwon
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Yujun Sheng
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Nobuhiko Sugano
- Department of Orthopaedic Medical Engineering, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Mi Yeong Hwang
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju-si, South Korea
| | - Weiran Li
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Masaya Mukai
- Department of Rheumatology & Clinical Immunology, Sapporo City General Hospital, Hokkaido, Japan
| | - Kyungheon Yoon
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju-si, South Korea
| | - Minglong Cai
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Kazuyoshi Ishigaki
- Laboratory for Statistical and Translational Genetics Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Center for Data Sciences, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Won Tae Chung
- Department of Internal Medicine, Dong-A University Hospital, Busan, South Korea
| | - He Huang
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Daisuke Takahashi
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Shin-Seok Lee
- Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju, South Korea
| | - Mengwei Wang
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Kohei Karino
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido, Japan
| | - Seung-Cheol Shim
- Division of Rheumatology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, South Korea
| | - Xiaodong Zheng
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Tomoya Miyamura
- Department of Internal Medicine and Rheumatology, National Hospital Organization, Kyushu Medical Center, Fukuoka, Japan
| | - Young Mo Kang
- Division of Rheumatology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, South Korea
| | - Dongqing Ye
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People's Republic of China
| | - Junichi Nakamura
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Chang-Hee Suh
- Department of Rheumatology, Ajou University School of Medicine, Suwon, South Korea
| | - Yuanjia Tang
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Goro Motomura
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yong-Beom Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | - Huihua Ding
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine (SJTUSM), Shanghai, People's Republic of China
| | - Takeshi Kuroda
- Niigata University Health Administration Center, Niigata, Japan
| | - Jung-Yoon Choe
- Department of Rheumatology, Catholic University of Daegu School of Medicine, Daegu, South Korea
| | - Chengxu Li
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Hiroaki Niiro
- Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Youngho Park
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Changbing Shen
- Department of Dermatology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People's Republic of China
- Shenzhen Key Laboratory for Translational Medicine of Dermatology, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong, People's Republic of China
| | - Takeshi Miyamoto
- Department of Orthopaedic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Ga-Young Ahn
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Wenmin Fei
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jung-Min Shin
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Keke Li
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Yasushi Kawaguchi
- Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yeon-Kyung Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Yong-Fei Wang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Koichi Amano
- Department of Rheumatology & Clinical Immunology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Dae Jin Park
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
| | - Wanling Yang
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Yoshifumi Tada
- Department of Rheumatology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yu Lung Lau
- Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Ken Yamaji
- Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
| | - Zhengwei Zhu
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Masato Shimizu
- Hokkaido Medical Center for Rheumatic Diseases, Sapporo, Japan
| | - Takashi Atsumi
- Department of Orthopaedic Surgery, Showa University School of Medicine, Tokyo, Japan
| | - Akari Suzuki
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Takayuki Sumida
- Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Koichi Matsuda
- Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
- Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuta Kochi
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuhiko Yamamoto
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Koichiro Ohmura
- Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tae-Hwan Kim
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Sen Yang
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
| | - Takuaki Yamamoto
- Department of Orthopaedic Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Bong-Jo Kim
- Division of Genome Science, Department of Precision Medicine, National Institute of Health, Cheongju-si, South Korea
| | - Nan Shen
- Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine (SJTUSM), Shanghai, People's Republic of China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, People's Republic of China
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Medical Sciences, Tokyo, Japan
| | - Hye-Soon Lee
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
| | - Xuejun Zhang
- Department of Dermatology and Institute of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, People's Republic of China
- Key Lab of Dermatology, Ministry of Education (Anhui Medical University), Hefei, Anhui, People's Republic of China
- Department of Dermatology, Institute of Dermatology, Huashan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan
- Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yong Cui
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, People's Republic of China
| | - Sang-Cheol Bae
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea
- Hanyang University Institute for Rheumatology Research, Seoul, South Korea
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7
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Sun C, Liu Q, Shah M, Che Q, Zhang G, Zhu T, Zhou J, Rong X, Li D. Talaverrucin A, Heterodimeric Oxaphenalenone from Antarctica Sponge-Derived Fungus Talaromyces sp. HDN151403, Inhibits Wnt/β-Catenin Signaling Pathway. Org Lett 2022; 24:3993-3997. [PMID: 35616425 DOI: 10.1021/acs.orglett.2c01394] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The Wnt/β-catenin signaling pathway is an evolutionarily conserved signaling cascade involved in a broad range of biological roles. Dysregulation of the Wnt/β-catenin pathway is implicated in congenital malformations and various kinds of cancers. We discovered a novel Wnt/β-catenin inhibitor, talaverrucin A (1), featuring an unprecedented 6/6/6/5/5/5/6 fused ring system, from an Antarctica sponge-derived fungus Talaromyces sp. HDN151403. Talaverrucin A exhibits inhibitory activity on the Wnt/β-catenin pathway in both zebrafish embryos in vivo and cultured mammalian cells in vitro, providing a naturally inspired small molecule therapeutic lead to target the Wnt/β-catenin pathway.
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Affiliation(s)
- Chunxiao Sun
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China
| | - Qianwen Liu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China
| | - Mudassir Shah
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China
| | - Qian Che
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China
| | - Guojian Zhang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266071, China.,Marine Biomedical Research Institute of Qingdao, Qingdao 266101, China
| | - Tianjiao Zhu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China
| | - Jianfeng Zhou
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266071, China
| | - Xiaozhi Rong
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266071, China
| | - Dehai Li
- School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China.,Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology, Qingdao 266071, China
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8
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Morris A, Hoyle R, Pagare PP, Uz Zaman S, Ma Z, Li J, Zhang Y. Exploration of Naphthoquinone Analogs in Targeting the TCF-DNA Interaction to Inhibit the Wnt/β-catenin Signaling Pathway. Bioorg Chem 2022; 124:105812. [DOI: 10.1016/j.bioorg.2022.105812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/02/2022]
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Targeting β-catenin in acute myeloid leukaemia: past, present, and future perspectives. Biosci Rep 2022; 42:231097. [PMID: 35352805 PMCID: PMC9069440 DOI: 10.1042/bsr20211841] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/14/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
Acute myeloid leukaemia (AML) is an aggressive disease of the bone marrow with a poor prognosis. Evidence suggests long established chemotherapeutic regimens used to treat AML are reaching the limits of their efficacy, necessitating the urgent development of novel targeted therapies. Canonical Wnt signalling is an evolutionary conserved cascade heavily implicated in normal developmental and disease processes in humans. For over 15 years its been known that the central mediator of this pathway, β-catenin, is dysregulated in AML promoting the emergence, maintenance, and drug resistance of leukaemia stem cells. Yet, despite this knowledge, and subsequent studies demonstrating the therapeutic potential of targeting Wnt activity in haematological cancers, β-catenin inhibitors have not yet reached the clinic. The aim of this review is to summarise the current understanding regarding the role and mechanistic dysregulation of β-catenin in AML, and assess the therapeutic merit of pharmacologically targeting this molecule, drawing on lessons from other disease contexts.
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10
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Abstract
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
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Affiliation(s)
- Chuanrui Xu
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhong Xu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Diego F. Calvisi
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, UCSF, San Francisco, California, USA
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11
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Alshahrani A, Skarratt KK, Robledo KP, Hassanvand M, Tang B, Fuller SJ. Differential Levels of mRNAs in Normal B Lymphocytes, Monoclonal B Lymphocytosis and Chronic Lymphocytic Leukemia Cells from the Same Family Identify Susceptibility Genes. Oncol Ther 2021; 9:621-634. [PMID: 34622420 PMCID: PMC8593151 DOI: 10.1007/s40487-021-00172-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/23/2021] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION People with a family history of chronic lymphocytic leukemia (F-CLL) have an increased risk of monoclonal B lymphocytosis (F-MBL), which is found in up to 18% of first-degree relatives of patients compared to 5% of the total population. This may indicate that the presence of an F-MBL in the relative of a F-CLL patient is due to genetic susceptibility. In this study, we hypothesized that progressive changes in gene expression result in malignant transformation of B lymphocytes to F-MBL, and subsequent alterations in gene expression occur before overt F-CLL develops. The aim of this study of affected and unaffected individuals from a family with multiple CLL cases was to compare mRNA expression levels in control B-lymphocytes, pre-malignant F-MBL and malignant F-CLL cells. METHODS To identify inherited changes in gene expression, a high-resolution DNA microarray was used to identify differentially abundant mRNAs in age-matched cases of F-MBL (n = 4), F-CLL (n = 2) and unaffected family relatives (F-Controls, n = 3) within one family. These were then compared to non-kindred controls (NK-Controls, n = 3) and sporadic CLL (S-CLL) cases (n = 6). RESULTS Seven differentially abundant mRNAs were identified against similar genetic backgrounds of the family: GRASP and AC016745.3 were decreased in F-MBL and further decreased in F-CLL compared to F-Controls, whereas C11orf80 and METTL8 were progressively increased. PARP3 was increased in F-MBL compared to F-Controls but was decreased in F-CLL compared to F-MBL. Compared to F-Controls, levels of ROR1 and LEF1 were similarly increased in F-MBL and F-CLL. For six of the genes, there were no differences in mRNA levels between S-CLL and F-CLL; however PARP3 was higher in S-CLL. CONCLUSION These results are consistent with the hypothesis that changes in expression of specific genes contribute to transformation from normal lymphocytes to MBL and CLL.
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Affiliation(s)
- Abdullah Alshahrani
- Department of Medicine, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia
- College of Applied Medical Sciences, King Khalid University, Guraiger, Abha, 62529, Kingdom of Saudi Arabia
| | - Kristen K Skarratt
- Department of Medicine, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia
| | - Kristy P Robledo
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, 2006, Australia
| | - Maryam Hassanvand
- Department of Medicine, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia
| | - Benjamin Tang
- Department of Medicine, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia
| | - Stephen J Fuller
- Department of Medicine, Sydney Medical School Nepean, Nepean Hospital, University of Sydney, Penrith, NSW, 2750, Australia.
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12
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G3BP1 promotes human breast cancer cell proliferation through coordinating with GSK-3β and stabilizing β-catenin. Acta Pharmacol Sin 2021; 42:1900-1912. [PMID: 33536604 PMCID: PMC8563869 DOI: 10.1038/s41401-020-00598-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 12/13/2020] [Indexed: 01/30/2023]
Abstract
Ras-GTPase activating SH3 domain-binding protein 1 (G3BP1) is a multifunctional binding protein involved in the development of a variety of human cancers. However, the role of G3BP1 in breast cancer progression remains largely unknown. In this study, we report that G3BP1 is upregulated and correlated with poor prognosis in breast cancer. Overexpression of G3BP1 promotes breast cancer cell proliferation by stimulating β-catenin signaling, which upregulates a number of proliferation-related genes. We further show that G3BP1 improves the stability of β-catenin by inhibiting its ubiquitin-proteasome degradation rather than affecting the transcription of β-catenin. Mechanistically, elevated G3BP1 interacts with and inactivates GSK-3β to suppress β-catenin phosphorylation and degradation. Disturbing the G3BP1-GSK-3β interaction accelerates the degradation of β-catenin, impairing the proliferative capacity of breast cancer cells. Our study demonstrates that the regulatory mechanism of the G3BP1/GSK-3β/β-catenin axis may be a potential therapeutic target for breast cancer.
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Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther 2021; 6:307. [PMID: 34456337 PMCID: PMC8403677 DOI: 10.1038/s41392-021-00701-5] [Citation(s) in RCA: 357] [Impact Index Per Article: 89.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 06/19/2021] [Accepted: 06/28/2021] [Indexed: 02/07/2023] Open
Abstract
Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.
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Affiliation(s)
- Fanyuan Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Changhao Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Feifei Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Yanqin Zuo
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Yitian Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Lin Yao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Chenzhou Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Chenglin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China
| | - Ling Ye
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
- Department of Endodontics, West China Stomatology Hospital, Sichuan University, Chengdu, China.
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14
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Li X, Chen W, Yang C, Huang Y, Jia J, Xu R, Guan S, Ma R, Yang H, Xie L. IGHG1 upregulation promoted gastric cancer malignancy via AKT/GSK-3β/β-Catenin pathway. Cancer Cell Int 2021; 21:397. [PMID: 34315496 PMCID: PMC8314571 DOI: 10.1186/s12935-021-02098-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/15/2021] [Indexed: 11/24/2022] Open
Abstract
Background Despite current advances in gastric cancer treatment, disease metastasis and chemo-resistance remain as major hurdles against better overall prognosis. Previous studies indicated that IGHG1 as well as -Catenin serve as important regulators of tumor cellular malignancy. Therefore, understanding detailed molecular mechanism and identifying druggable target will be of great potentials in future therapeutic development. Methods Surgical tissues and gastric cancer cell lines were retrieved to evaluate IGHG1 expression for patients with or without lymph node/distal organ metastasis. Functional assays including CCK8 assay, Edu assay, sphere formation assay and transwell assay, wound healing assay, etc. were subsequently performed to evaluate the impact of IGHG1/-catenin axis on tumor cell proliferation, migration and chemo-resistance. Results Gastric cancer tissues and tumor cell lines demonstrated significantly higher level of IGHG1. Functional study further demonstrated that IGHG1 promoted proliferative and migration as well as chemo-resistance of gastric cancer tumor cells. Further experiments indicated that IGHG1 activated AKT/GSK-3/-Catenin axis, which played crucial role in regulation of proliferative and chemo-resistance of gastric cancer cells. Conclusion This study provided novel evidences that IGHG1 acted as oncogene by promotion of gastric cancer cellular proliferation, migration and chemo-resistance. Our research further suggested that IGHG1/AKT/GSK-3β/β-Catenin axis acted as novel pathway which regulated gastric cancer cellular malignant behavior. Our research might inspire future therapy development to promote overall prognosis of gastric cancer patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02098-1.
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Affiliation(s)
- Xinyu Li
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China
| | - Wen Chen
- Department of Traditional Chinese Medicine Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, 362000, Fujian Province, China
| | - Chunkang Yang
- Department of Gastrointestinal Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, 420 Fuma Road, Jin'an District, Fuzhou City, 350005, Fujian Province, China.
| | - Yisen Huang
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China
| | - Jing Jia
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China
| | - Rongyu Xu
- Department of Thoracic Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China.
| | - Shen Guan
- Department of Gastrointestinal Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, 420 Fuma Road, Jin'an District, Fuzhou City, 350005, Fujian Province, China
| | - Ruijun Ma
- Department of General Surgery, Tongxin County People's Hospital, Ningxia Hui Autonomous Region, Wuzhong City, 751300, Tongxin County, China
| | - Haitao Yang
- Department of General Surgery, Wuzhong People's Hospital, Ningxia Hui Autonomous Region, Wuzhong City, 751000, China
| | - Lifeng Xie
- Department of Gastrointestinal Surgery, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou City, 362002, Fujian Province, China
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Zhang G, Miao F, Liu K, Wu J, Xu J. Downregulation of LEF1 Impairs Myeloma Cell Growth Through Modulating CYLD/NF-κB Signaling. Technol Cancer Res Treat 2021; 20:15330338211034270. [PMID: 34269120 PMCID: PMC8287265 DOI: 10.1177/15330338211034270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Aberrant expression of lymphoid enhancer-binding factor-1 (LEF1) has been identified in various hematological malignancies including multiple myeloma (MM). However, the exact role of LEF1 in MM remains largely unknown. Here, we showed that knockdown of LEF1 could apparently impair the proliferation, induce apoptosis and promote the ROS production in MM cell lines, suggesting that LEF1 might be involved in maintaining MM cell growth and survival. Moreover, we observed that the mRNA level of the deubiquitinase cylindromatosis (CYLD), a well-recognized tumor suppressor in MM, was significantly increased following LEF1 depletion in myeloma cells. Further study showed that LEF1 could directly associate with the promoter of CYLD gene and thus repress its transcription in MM cells. Intriguingly, LEF1 depletion-mediated CYLD upregulation was sufficient to negatively modulate NF-κB signaling pathway in MM cells. Moreover, the decrease in NF-κB activity following LEF1 knockdown could be largely rescued when CYLD was silenced in MM cells. Taken together, our study provided the compelling evidence to show that LEF1 may augment the proliferation and survival of MM cells through direct repression of CYLD transcription and subsequent activation of NF-κB signaling pathway, corroborating that LEF1 may become a potential therapeutic target against MM.
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Affiliation(s)
- Guihua Zhang
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Faan Miao
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Kaige Liu
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jinyan Wu
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jinge Xu
- Department of Hematology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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16
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Abstract
Resident progenitor and/or stem cell populations in the adult adrenal cortex enable cortical cells to undergo homeostatic renewal and regeneration after injury. Renewal occurs predominantly in the outer layers of the adrenal gland but newly formed cells undergo centripetal migration, differentiation and lineage conversion in the process of forming the different functional steroidogenic zones. Over the past 10 years, advances in the genetic characterization of adrenal diseases and studies of mouse models with altered adrenal phenotypes have helped to elucidate the molecular pathways that regulate adrenal tissue renewal, several of which are fine-tuned via complex paracrine and endocrine influences. Moreover, the adrenal gland is a sexually dimorphic organ, and testicular androgens have inhibitory effects on cell proliferation and progenitor cell recruitment in the adrenal cortex. This Review integrates these advances, including the emerging role of sex hormones, into existing knowledge on adrenocortical cell renewal. An in-depth understanding of these mechanisms is expected to contribute to the development of novel therapies for severe endocrine diseases, for which current treatments are unsatisfactory.
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Affiliation(s)
- Rodanthi Lyraki
- Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose, Nice, France
| | - Andreas Schedl
- Université Côte d'Azur, INSERM, CNRS, Institut de Biologie Valrose, Nice, France.
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Ramos YAL, Souza OF, Novo MCT, Guimarães CFC, Popi AF. Quercetin shortened survival of radio-resistant B-1 cells in vitro and in vivo by restoring miR15a/16 expression. Oncotarget 2021; 12:355-365. [PMID: 33659046 PMCID: PMC7899548 DOI: 10.18632/oncotarget.27883] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 09/10/2020] [Indexed: 11/25/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a malignancy disease characterized by the expansion of CD5+ B-1 cells. The NZB mouse model of CLL shows similarities to human CLL, has age-associated increase in malignant B-1 clones and decreased expression of miR-15a/16. It was demonstrated that systemic lentiviral delivery of miR-15a/16 ameliorates disease manifestations in this mouse model. Nowadays, new therapeutic approaches have been focus on miRNA in cancer cells. Natural compounds like quercetin can modulate these miRNAs, consequently, suppress oncogenes or stimulate tumor suppressor genes by altering miRNA expressions. Here we investigate the effects of quercetin on miRNA15a/16 expression by radio-resistant B-1 cells. It has been described that a small percentage of B-1 cell survives to irradiation in vitro, and these cells show similarities to B-CLL cells. In these cells, the level of miR15a/16 is diminished and Bcl-2 is overexpressed. Quercetin treatment restore both, miR15a/16 and Bcl-2, to normal levels. Furthermore, transference of radioresistant B-1 cells to NOD/SCID mice causes an expansion of this population and also a migration to the liver. However, after quercetin treatment, even radioresistant B-1 cells are not able to expand or disseminate in vivo, and the levels of miR15a/16 and Bcl-2 are also normalized. Our data support the hypothesis that quercetin is an important adjuvant molecule that acts on miRNA15a/16 level and leads cells more permissive to apoptosis. This work could help to design new approaches to therapy in CLL patients.
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Affiliation(s)
- Yasmim Alefe Leuzzi Ramos
- Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
| | - Olivia Fonseca Souza
- Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
| | - Marilia Campos Tavares Novo
- Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
| | - Caroline Ferreira Cunha Guimarães
- Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
| | - Ana Flavia Popi
- Laboratory of Ontogeny of Lymphocytes, Discipline of Immunology, Departament of Microbiology, Immunology and Parasitology, Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil
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18
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Guo C, Gao YY, Ju QQ, Zhang CX, Gong M, Li ZL. HELQ and EGR3 expression correlate with IGHV mutation status and prognosis in chronic lymphocytic leukemia. J Transl Med 2021; 19:42. [PMID: 33485349 PMCID: PMC7825181 DOI: 10.1186/s12967-021-02708-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 01/16/2021] [Indexed: 11/16/2022] Open
Abstract
Background IGHV mutation status is a crucial prognostic biomarker for CLL. In the present study, we investigated the transcriptomic signatures associating with IGHV mutation status and CLL prognosis. Methods The co-expression modules and hub genes correlating with IGHV status, were identified using the GSE28654, by ‘WGCNA’ package and R software (version 4.0.2). The over-representation analysis was performed to reveal enriched cell pathways for genes of correlating modules. Then 9 external cohorts were used to validate the correlation of hub genes expression with IGHV status or clinical features (treatment response, transformation to Richter syndrome, etc.). Moreover, to elucidate the significance of hub genes on disease course and prognosis of CLL patients, the Kaplan–Meier analysis for the OS and TTFT of were performed between subgroups dichotomized by the median expression value of individual hub genes. Results 2 co-expression modules and 9 hub genes ((FCRL1/FCRL2/HELQ/EGR3LPL/LDOC1/ZNF667/SOWAHC/SEPTIN10) correlating with IGHV status were identified by WGCNA, and validated by external datasets. The modules were found to be enriched in NF-kappaB, HIF-1 and other important pathways, involving cell proliferation and apoptosis. The expression of hub genes was revealed to be significantly different, not only between CLL and normal B cell, but also between various types of lymphoid neoplasms. HELQ expression was found to be related with response of immunochemotherapy treatment significantly (p = 0.0413), while HELQ and ZNF667 were expressed differently between stable CLL and Richter syndrome patients (p < 0.0001 and p = 0.0278, respectively). By survival analysis of subgroups, EGR3 expression was indicated to be significantly associated with TTFT by 2 independent cohorts (GSE39671, p = 0.0311; GSE22762, p = 0.0135). While the expression of HELQ and EGR3 was found to be associated with OS (p = 0.0291 and 0.0114 respectively).The Kras, Hedgehog and IL6-JAK-STAT3 pathways were found to be associating with the expression of hub genes, resulting from GSEA. Conclusions The expression of HELQ and EGR3 were correlated with IGHV mutation status in CLL patients. Additionally, the expression of HELQ/EGR3 were prognostic markers for CLL associating with targetable cell signaling pathways.
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Affiliation(s)
- Chao Guo
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China
| | - Ya-Yue Gao
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China
| | - Qian-Qian Ju
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China
| | - Chun-Xia Zhang
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China
| | - Ming Gong
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China
| | - Zhen-Ling Li
- Department of Hematology, China-Japan Friendship Hospital, Yinghua East Street, Beijing, 100029, China.
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19
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20
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Danek P, Kardosova M, Janeckova L, Karkoulia E, Vanickova K, Fabisik M, Lozano-Asencio C, Benoukraf T, Tirado-Magallanes R, Zhou Q, Burocziova M, Rahmatova S, Pytlik R, Brdicka T, Tenen DG, Korinek V, Alberich-Jorda M. β-Catenin-TCF/LEF signaling promotes steady-state and emergency granulopoiesis via G-CSF receptor upregulation. Blood 2020; 136:2574-2587. [PMID: 32822472 PMCID: PMC7714095 DOI: 10.1182/blood.2019004664] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 08/09/2020] [Indexed: 12/11/2022] Open
Abstract
The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.
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Affiliation(s)
- Petr Danek
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Faculty of Science, Charles University, Prague, Czech Republic
| | - Miroslava Kardosova
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
| | | | - Elena Karkoulia
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Karolina Vanickova
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Faculty of Science, Charles University, Prague, Czech Republic
| | - Matej Fabisik
- Department of Leukocyte Cell Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Carlos Lozano-Asencio
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Touati Benoukraf
- Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| | | | - Qiling Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Monika Burocziova
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Sarka Rahmatova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic; and
| | - Robert Pytlik
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic; and
| | - Tomas Brdicka
- Department of Leukocyte Cell Signaling, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Daniel G Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA
| | | | - Meritxell Alberich-Jorda
- Department of Hemato-oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Childhood Leukemia Investigation Prague, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
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21
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Cardona-Echeverry A, Prada-Arismendy J. Deciphering the role of Wnt signaling in acute myeloid leukemia prognosis: how alterations in DNA methylation come into play in patients' prognosis. J Cancer Res Clin Oncol 2020; 146:3097-3109. [PMID: 32980885 DOI: 10.1007/s00432-020-03407-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 09/21/2020] [Indexed: 10/23/2022]
Abstract
Acute myeloid leukemia (AML) is a malignant clonal disorder affecting myeloid differentiation through mechanisms that include epigenetic dysregulation. Abnormal changes in DNA methylation and gene expression profiles of pathways involved in hematopoietic development, such as Wnt/β-catenin, contribute to the transformation, development, and maintenance of leukemic cells. This review summarizes the alterations of Wnt signaling-related genes at the epigenetic and transcriptional level and their implications for AML prognosis. Among the implications of epigenetic alterations in AML, methylation of Wnt antagonists is related to poor prognosis, whereas their upregulation has been associated with a better clinical outcome. Furthermore, Wnt target genes c-Myc and LEF-1 present distinct implications. LEF-1 expression positively influences the patient overall survival. c-Myc upregulation has been associated with treatment resistance in AML, although c-Myc expression is not exclusively dependent of Wnt signaling. Understanding the signaling abnormalities could help us to further understand leukemogenesis, improve the current risk stratification for AML patients, and even serve to propose novel therapeutic targets.
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Affiliation(s)
- Andrés Cardona-Echeverry
- Grupo de Investigación e innovación Biomédica-GI2B, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano-ITM, 050034, Medellín, Colombia
| | - Jeanette Prada-Arismendy
- Grupo de Investigación e innovación Biomédica-GI2B, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnológico Metropolitano-ITM, 050034, Medellín, Colombia.
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22
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Chen Y, Fu Z, Li D, Yue Y, Liu X. Optimizations of a novel fluorescence polarization-based high-throughput screening assay for β-catenin/LEF1 interaction inhibitors. Anal Biochem 2020; 612:113966. [PMID: 32956692 DOI: 10.1016/j.ab.2020.113966] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/21/2020] [Accepted: 09/15/2020] [Indexed: 01/20/2023]
Abstract
Aberrant activation of the Wnt/β-catenin signaling pathway is prominent in the development and metastasis of non-small cell lung cancer (NSCLC). Highly effective inhibition of this pathway highlights a therapeutic avenue against NSCLC. Moreover, β-catenin/LEF1 interaction regulates β-catenin nuclear transport as well as the transcriptions of the key oncogenes in Wnt/β-catenin signaling pathway. Therefore, interruption of this interaction would be a promising therapeutic strategy for NSCLC metastasis. To date, no economical and rapid high-throughput screening (HTS) assay has been reported for the discovery of β-catenin/LEF1 interaction inhibitors. In this study, we developed a novel fluorescence polarization (FP)-based HTS assay to identify β-catenin/LEF1 interaction inhibitors. The FITC-LEF1 sequence, incubation time, temperature, and DMSO resistance were optimized, and then a high Z' factor of 0.77 was achieved. A pilot screening of a natural product library via this established FP screening assay identified sanguinarine analogues as potential β-catenin/LEF1 interaction inhibitors. GST pull-down and surface plasmon resonance (SPR) assay demonstrated that β-catenin/LEF1 interaction is a potential anticancer target of sanguinarine in vitro. This newly developed FP screening assay will be vital for the rapid discovery of novel Wnt inhibitors targeting β-catenin/LEF1 interaction.
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Affiliation(s)
- Yunyu Chen
- Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu, 241002, China
| | - Zhenghao Fu
- Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu, 241002, China
| | - Dongsheng Li
- Department of Medicinal Chemistry, Shanghai Synergy Pharmaceutical Sciences Co., Ltd., Shanghai, 201203, China
| | - Yuhuan Yue
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, 130122, China.
| | - Xiaoping Liu
- Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu, 241002, China.
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23
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Feder K, Edmaier-Schröger K, Rawat VPS, Kirsten N, Metzeler K, Kraus JM, Döhner K, Döhner H, Kestler HA, Feuring-Buske M, Buske C. Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis. Leukemia 2019; 34:1027-1037. [DOI: 10.1038/s41375-019-0635-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/06/2019] [Indexed: 12/12/2022]
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24
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Barth E, Srivastava A, Stojiljkovic M, Frahm C, Axer H, Witte OW, Marz M. Conserved aging-related signatures of senescence and inflammation in different tissues and species. Aging (Albany NY) 2019; 11:8556-8572. [PMID: 31606727 PMCID: PMC6814591 DOI: 10.18632/aging.102345] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 09/27/2019] [Indexed: 12/14/2022]
Abstract
Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual’s life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.
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Affiliation(s)
- Emanuel Barth
- Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany.,FLI Leibniz Institute for Age Research, Jena, Germany
| | - Akash Srivastava
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Milan Stojiljkovic
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Christiane Frahm
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Hubertus Axer
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Otto W Witte
- Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany
| | - Manja Marz
- Bioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, Jena, Germany.,FLI Leibniz Institute for Age Research, Jena, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
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25
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Ghosh N, Hossain U, Mandal A, Sil PC. The Wnt signaling pathway: a potential therapeutic target against cancer. Ann N Y Acad Sci 2019; 1443:54-74. [PMID: 31017675 DOI: 10.1111/nyas.14027] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/05/2018] [Accepted: 01/18/2019] [Indexed: 02/06/2023]
Abstract
The role of the evolutionarily conserved Wnt signaling pathway is well documented in several cellular processes, such as cell proliferation, differentiation, cell motility, and maintenance of the stem cell niche. The very first indication that aberrant Wnt signaling can cause carcinogenesis came from a finding that the mutation of the adenomatous polyposis coli gene (APC) predisposes a person to colorectal carcinoma. Later, with progressing research it became clear that abnormal activation or mutation of the genes related to this pathway could drive tumorigenesis. Here, we review recent advances in research regarding Wnt signaling regulation and its role in several cancer subtypes. Additionally, the utility of Wnt pathway-targeted cancer therapy intervention is also highlighted, with an overview of current approaches to target the Wnt pathway in oncogenesis and the future scopes and challenges associated with them.
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Affiliation(s)
- Noyel Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Uday Hossain
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Ankita Mandal
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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26
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Morgan RG, Ridsdale J, Payne M, Heesom KJ, Wilson MC, Davidson A, Greenhough A, Davies S, Williams AC, Blair A, Waterman ML, Tonks A, Darley RL. LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells. Haematologica 2019; 104:1365-1377. [PMID: 30630973 PMCID: PMC6601079 DOI: 10.3324/haematol.2018.202846] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 01/03/2019] [Indexed: 12/24/2022] Open
Abstract
Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia (AML) patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin, we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β- catenin level in human myeloid leukemia.
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Affiliation(s)
- Rhys G Morgan
- School of Life Sciences, University of Sussex, Brighton, UK .,School of Cellular and Molecular Medicine, University of Bristol, UK
| | - Jenna Ridsdale
- Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, UK
| | - Megan Payne
- School of Life Sciences, University of Sussex, Brighton, UK
| | | | | | | | | | - Sara Davies
- Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, UK
| | - Ann C Williams
- School of Life Sciences, University of Sussex, Brighton, UK
| | - Allison Blair
- School of Life Sciences, University of Sussex, Brighton, UK
| | - Marian L Waterman
- Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA
| | - Alex Tonks
- Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, UK
| | - Richard L Darley
- Department of Haematology, Division of Cancer and Genetics, School of Medicine, Cardiff University, UK
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Li Z, Liu S, Lou J, Mulholland M, Zhang W. LGR4 protects hepatocytes from injury in mouse. Am J Physiol Gastrointest Liver Physiol 2019; 316:G123-G131. [PMID: 30406697 PMCID: PMC6383381 DOI: 10.1152/ajpgi.00056.2018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Leucine-rich repeat G protein-coupled receptors (LGRs) and their endogenous ligands R-spondin1-4 (Rspo) are critical in embryonic development and in maintenance of stem cells. The functions of the Rspo-LGR system in differentiated cells remain uncharacterized. In this study, the expression profiles of LGRs and Rspos were characterized in mature hepatocytes. A liver-specific knockout of LGR4 in mouse was generated and used to study hepatic ischemia/reperfusion-induced injury (HIRI) as well as lipopolysaccharide/ D- galactosamine (LPS/D-Gal)-induced liver injury. We have demonstrated that, in adult liver, LGR4 is expressed in hepatocytes and responds to Rspo1 with internalization. Rspo1 is responsive to various nutritional states and to mTOR signaling. Activation of LGR4 by Rspo1 significantly reduced tumor necrosis factor-α (TNFα)-induced cell death, and levels of NF-κB-p65 and caspase-3 in cultured hepatocytes. Knockdown of hepatic LGR4 rendered hepatocytes more vulnerable to TNFα-induced damage in cultured primary cells and in the setting of HIRI and LPS/D-Gal-induced liver injury. Rspo1 potentiated both basal and Wnt3a-induced stabilization of β-catenin. Disruption of β-catenin signaling reversed the protective effects of Rspo1 on TNFα-induced hepatocyte toxicity. LGR4 knockdown increased nuclear translocation of NF-κB-p65 in response to acute injury. Overexpression of IKKβ attenuated the protective effects of Rspo1 on TNFα-induced cell death. In conclusion, the Rspo1-LGR4 system represents a novel pathway for cytoprotection and modulation of stress-induced tissue damage. NEW & NOTEWORTHY Functional LGR4 is present in mature hepatocytes. R-spodin1 protects hepatocytes from tumor necrosis factor-α-induced cell death. Liver-specific knockdown of LGR4 renders liver more susceptible to acute injury. LGR4 protects hepatocytes from injury by inhibition of NF-κB signaling.
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Affiliation(s)
- Ziru Li
- 1Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Shiying Liu
- 2Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
| | - Jianing Lou
- 3Department of Stomatology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Michael Mulholland
- 1Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Weizhen Zhang
- 1Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan,2Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
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28
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Mangolini M, Götte F, Moore A, Ammon T, Oelsner M, Lutzny-Geier G, Klein-Hitpass L, Williamson JC, Lehner PJ, Dürig J, Möllmann M, Rásó-Barnett L, Hughes K, Santoro A, Méndez-Ferrer S, Oostendorp RAJ, Zimber-Strobl U, Peschel C, Hodson DJ, Schmidt-Supprian M, Ringshausen I. Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia. Nat Commun 2018; 9:3839. [PMID: 30242258 PMCID: PMC6155045 DOI: 10.1038/s41467-018-06069-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 07/31/2018] [Indexed: 01/05/2023] Open
Abstract
The Wnt signalling pathway, one of the core de-regulated pathways in chronic lymphocytic leukaemia (CLL), is activated in only a subset of patients through somatic mutations. Here we describe alternative, microenvironment-dependent mechanisms of Wnt activation in malignant B cells. We show that tumour cells specifically induce Notch2 activity in mesenchymal stromal cells (MSCs) required for the transcription of the complement factor C1q. MSC-derived C1q in turn inhibits Gsk3-β mediated degradation of β-catenin in CLL cells. Additionally, stromal Notch2 activity regulates N-cadherin expression in CLL cells, which interacts with and further stabilises β-catenin. Together, these stroma Notch2-dependent mechanisms induce strong activation of canonical Wnt signalling in CLL cells. Pharmacological inhibition of the Wnt pathway impairs microenvironment-mediated survival of tumour cells. Similarly, inhibition of Notch signalling diminishes survival of stroma-protected CLL cells in vitro and disease engraftment in vivo. Notch2 activation in the microenvironment is a pre-requisite for the activation of canonical Wnt signalling in tumour cells.
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Affiliation(s)
- Maurizio Mangolini
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK
| | - Frederik Götte
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
| | - Andrew Moore
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK
| | - Tim Ammon
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
| | - Madlen Oelsner
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
| | - Gloria Lutzny-Geier
- Department of Internal Medicine 5, Haematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, 91054, Germany
| | - Ludger Klein-Hitpass
- Institute of Cell Biology, Faculty of Medicine, University of Duisburg-Essen, Essen, 45122, Germany
| | - James C Williamson
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, CB2 0XY, UK
| | - Paul J Lehner
- Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, CB2 0XY, UK
| | - Jan Dürig
- Department of Hematology, University Hospital Essen,, University of Duisburg-Essen, Essen, 45122, Germany
| | - Michael Möllmann
- Department of Hematology, University Hospital Essen,, University of Duisburg-Essen, Essen, 45122, Germany
| | - Lívia Rásó-Barnett
- Haematopathology and Oncology Diagnostic Service (HODS), Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
| | - Katherine Hughes
- Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK
| | - Antonella Santoro
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK
| | - Simón Méndez-Ferrer
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK
- NHS Blood and Transplant, Cambridge, CB2 0PT, UK
| | - Robert A J Oostendorp
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
| | | | - Christian Peschel
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
- German Cancer Consortium, DKFZ, Heidelberg, 69120, Germany
| | - Daniel J Hodson
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK
| | - Marc Schmidt-Supprian
- Department of Hematology and Medical Oncology, Klinikum rechts der Isar der Technischen Universität München, Munich, 81675, Germany
- German Cancer Consortium, DKFZ, Heidelberg, 69120, Germany
| | - Ingo Ringshausen
- Wellcome Trust/ MRC Cambridge Stem Cell Institute & Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK.
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29
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Huang X, Zhong L, Hendriks J, Post JN, Karperien M. The Effects of the WNT-Signaling Modulators BIO and PKF118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells. Int J Mol Sci 2018; 19:ijms19020561. [PMID: 29438298 PMCID: PMC5855783 DOI: 10.3390/ijms19020561] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 01/29/2018] [Accepted: 02/02/2018] [Indexed: 01/22/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells, mainly from bone marrow, and an ideal source of cells in bone and cartilage tissue engineering. A study of the chondrogenic differentiation of MSCs is of particular interest for MSCs-based cartilage regeneration. In this study, we aimed to optimize the conditions for the chrondogenic differentiation of MSCs by regulating WNT signaling using the small molecule WNT inhibitor PKF118-310 and activator BIO. Human mesenchymal stem cells (hMSCs) were isolated from bone marrow aspirates and cultured in hMSCs proliferation medium. Pellet culture was subsequently established for three-dimensional chondrogenic differentiation of 5 weeks. WNT signaling was increased by the small molecule glycogen synthase kinase-3 inhibitor 6-bromoindirubin-3-oxim (BIO) and decreased by the WNT inhibitor PKF118-310 (PKF). The effects of BIO and PKF on the chondrogenesis of hMSCs was examined by real-time PCR, histological methods, and ELISA. We found that activation of canonical WNT-signaling by BIO significantly downregulated the expression of cartilage-specific genes SOX9, COL2A1, and ACAN, and matrix metalloproteinase genes MMP1/3/9/13, but increased ADAMTS 4/5. Inhibition of WNT signaling by PKF increased the expression of SOX9, COL2A1, ACAN, and MMP9, but decreased MMP13 and ADAMTS4/5. In addition, a high level of WNT signaling induced the expression of hypertrophic markers COL10A1, ALPL, and RUNX2, the dedifferentiation marker COL1A1, and glycolysis genes GULT1 and PGK1. Deposition of glycosaminoglycan (GAG) and collagen type II in the pellet matrix was significantly lost in the BIO-treated group and increased in the PKF-treated group. The protein level of COL10A1 was also highly induced in the BIO group. Interestingly, BIO decreased the number of apoptotic cells while PKF significantly induced apoptosis during chondrogenesis. The natural WNT antagonist DKK1 and the protein level of MMP1 in the pellet culture medium were decreased after PKF treatment. All of these chondrogenic effects appeared to be mediated through the canonical WNT signaling pathway, since the target gene Axin2 and other WNT members, such as TCF4 and β-catenin, were upregulated by BIO and downregulated by PKF, respectively, and BIO induced nuclear translocation of β-catenin while PKF inhibited β-catenin translocation into the nucleus. We concluded that addition of BIO to a chondrogenic medium of hMSCs resulted in a loss of cartilage formation, while PKF induced chondrogenic differentiation and cartilage matrix deposition and inhibited hypertrophic differentiation. However, BIO promoted cell survival by inhibiting apoptosis while PKF induced cell apoptosis. This result indicates that either an overexpression or overinhibition of WNT signaling to some extent causes harmful effects on chondrogenic differentiation. Cartilage tissue engineering could benefit from the adjustment of the critical level of WNT signaling during chondrogenesis of hMSC.
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Affiliation(s)
- Xiaobin Huang
- Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
| | - Leilei Zhong
- Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
| | - Jan Hendriks
- Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
| | - Janine N Post
- Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
| | - Marcel Karperien
- Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500 AE, The Netherlands.
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30
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Keutgen XM, Kumar S, Gara S, Boufraqech M, Agarwal S, Hruban RH, Nilubol N, Quezado M, Finney R, Cam M, Kebebew E. Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype. Cancer 2018; 124:636-647. [PMID: 29149451 PMCID: PMC5780230 DOI: 10.1002/cncr.31057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 07/19/2017] [Accepted: 08/24/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. METHODS Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. RESULTS Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet-derived growth factor receptor β (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. CONCLUSIONS Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. © 2017 American Cancer Society.
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Affiliation(s)
- Xavier M. Keutgen
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, Illinois
| | - Suresh Kumar
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sudheer Gara
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Myriem Boufraqech
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sunita Agarwal
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Ralph H. Hruban
- The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Naris Nilubol
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Martha Quezado
- Department of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Richard Finney
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Maggie Cam
- Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Electron Kebebew
- Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
- Department of Surgery, The George Washington University, School of Medicine and Health Sciences, Washington, District of Columbia
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31
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Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev 2018; 62:50-60. [PMID: 29169144 PMCID: PMC5745276 DOI: 10.1016/j.ctrv.2017.11.002] [Citation(s) in RCA: 742] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/01/2017] [Accepted: 11/03/2017] [Indexed: 12/17/2022]
Abstract
The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.
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Affiliation(s)
- Nithya Krishnamurthy
- Center for Personalized Cancer Therapy, UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
| | - Razelle Kurzrock
- Center for Personalized Cancer Therapy, UCSD Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Division of Hematology-Oncology, University of California San Diego, La Jolla, CA, USA
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32
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Wu W, Zhu H, Fu Y, Shen W, Miao K, Hong M, Xu W, Fan L, Young KH, Liu P, Li J. High LEF1 expression predicts adverse prognosis in chronic lymphocytic leukemia and may be targeted by ethacrynic acid. Oncotarget 2017; 7:21631-43. [PMID: 26950276 PMCID: PMC5008311 DOI: 10.18632/oncotarget.7795] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 02/05/2016] [Indexed: 01/07/2023] Open
Abstract
Aberrant activation of lymphoid enhancer-binding factor-1 (LEF1) has been identified in several cancers, including chronic lymphocytic leukemia (CLL). As a key transcription factor of the Wnt/β-catenin pathway, LEF1 helps to regulate important genes involved in tumor cell death mechanisms. In this study, we determined LEF1 gene expression levels in CLL (n = 197) and monoclonal B-cell lymphocytosis (MBL) (n = 6) patients through real-time RT-PCR. LEF1 was significantly up-regulated in both MBL and CLL patients compared with normal B cells. Treatment-free survival (TFS) time and overall survival (OS) time were much longer in CLL patients with low LEF1 expression than in those with high LEF1 levels. Furthermore, Wnt inhibitor ethacrynic acid (EA) induced both apoptosis and necroptosis in primary CLL cells. EA also enhanced the cytotoxicity of both fludarabine and cyclophosphamide against CLL cells in vitro. Finally, we demonstrated that EA functions by inhibiting the recruitment of LEF1 to DNA promoters and restoring cylindromatosis (CYLD) expression in CLL cells. Our results showed, for the first time, that high LEF1 expression is associated with poor survival for CLL patients. Combined with other chemotherapeutic drugs, EA may be a promising therapeutic agent for CLL.
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Affiliation(s)
- Wei Wu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Huayuan Zhu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Yuan Fu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Wenyi Shen
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Kourong Miao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Min Hong
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Wei Xu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Lei Fan
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
| | - Ken H Young
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Peng Liu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.,Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jianyong Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China
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33
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Janovská P, Bryja V. Wnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomas. Br J Pharmacol 2017; 174:4701-4715. [PMID: 28703283 PMCID: PMC5727250 DOI: 10.1111/bph.13949] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/19/2017] [Accepted: 06/29/2017] [Indexed: 12/31/2022] Open
Abstract
In this review, we discuss the intricate roles of the Wnt signalling network in the development and progression of mature B-cell-derived haematological malignancies, with a focus on chronic lymphocytic leukaemia (CLL) and related B-cell lymphomas. We review the current literature and highlight the differences between the β-catenin-dependent and -independent branches of Wnt signalling. Special attention is paid to the role of the non-canonical Wnt/planar cell polarity (PCP) pathway, mediated by the Wnt-5-receptor tyrosine kinase-like orphan receptor (ROR1)-Dishevelled signalling axis in CLL. This is mainly because the Wnt/PCP co-receptor ROR1 was found to be overexpressed in CLL and the Wnt/PCP pathway contributes to numerous aspects of CLL pathogenesis. We also discuss the possibilities of therapeutically targeting the Wnt signalling pathways as an approach to disrupt the crucial interaction between malignant cells and their micro-environment. We also advocate the need for research in this direction for other lymphomas, namely, diffuse large B-cell lymphoma, Hodgkin lymphoma, mantle cell lymphoma, Burkitt lymphoma and follicular lymphoma where the Wnt signalling pathway probably plays a similar role. 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)
- Pavlína Janovská
- Institute of Experimental Biology, Faculty of ScienceMasaryk UniversityBrnoCzech Republic
| | - Vítězslav Bryja
- Institute of Experimental Biology, Faculty of ScienceMasaryk UniversityBrnoCzech Republic
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Abstract
The canonical Wnt/β-catenin signaling pathway, an important modulator of progenitor cell proliferation and differentiation, is highly regulated for the maintenance of critical biological homeostasis. Decades of studies in cancer genetics and genomics have demonstrated that multiple genes encoding key proteins in this signaling pathway serve as targets for recurrent mutational alterations. Among these proteins, β-catenin and adenomatosis polyposis coli (APC) are two key nodes. β-catenin contributes in transporting extracellular signals for nuclear programming. Mutations of the CTNNB1 gene that encodes β-catenin occur in a wide spectrum of cancers. These mutations alter the spatial characteristics of the β-catenin protein, leading to drastic reprogramming of the nuclear transcriptional network. Among the outcomes of this reprogramming are increased cell proliferation, enhanced immunosuppression, and disruption of metabolic regulation. Herein we review the current understanding of CTNNB1 mutations, their roles in tumorigenesis and discuss their possible therapeutic implications for cancer.
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35
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Eritja N, Yeramian A, Chen BJ, Llobet-Navas D, Ortega E, Colas E, Abal M, Dolcet X, Reventos J, Matias-Guiu X. Endometrial Carcinoma: Specific Targeted Pathways. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 943:149-207. [PMID: 27910068 DOI: 10.1007/978-3-319-43139-0_6] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy in the western world with more than 280,000 cases per year worldwide. Prognosis for EC at early stages, when primary surgical resection is the most common initial treatment, is excellent. Five-year survival rate is around 70 %.Several molecular alterations have been described in the different types of EC. They occur in genes involved in important signaling pathways. In this chapter, we will review the most relevant altered pathways in EC, including PI3K/AKT/mTOR, RAS-RAF-MEK-ERK, Tyrosine kinase, WNT/β-Catenin, cell cycle, and TGF-β signaling pathways. At the end of the chapter, the most significant clinical trials will be briefly discussed.This information is important to identify specific targets for therapy.
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Affiliation(s)
- Nuria Eritja
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
| | - Andree Yeramian
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
| | - Bo-Juen Chen
- New York Genome Center, New York, NY, 10013, USA
| | - David Llobet-Navas
- Institute of Genetic Medicine, Newcastle University, Newcastle-Upon-Tyne, NE1 3BZ, UK
| | - Eugenia Ortega
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
| | - Eva Colas
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- Research Unit in Biomedicine and Translational and Pediatric Oncology, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Miguel Abal
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Xavier Dolcet
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
| | - Jaume Reventos
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain
- Research Unit in Biomedicine and Translational and Pediatric Oncology, Vall d'Hebron Research Institute, Barcelona, Spain
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain.
- GEICEN Research Group, Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Av Rovira Roure, 80, 25198, Lleida, Spain.
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Nayak A, Siddharth S, Das S, Nayak D, Sethy C, Kundu CN. Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β. Toxicol Appl Pharmacol 2017; 330:53-64. [DOI: 10.1016/j.taap.2017.07.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/10/2017] [Accepted: 07/13/2017] [Indexed: 01/07/2023]
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Franiak-Pietryga I, Maciejewski H, Ziemba B, Appelhans D, Voit B, Robak T, Jander M, Treliński J, Bryszewska M, Borowiec M. Blockage of Wnt/β-Catenin Signaling by Nanoparticles Reduces Survival and Proliferation of CLL Cells In Vitro-Preliminary Study. Macromol Biosci 2017; 17. [DOI: 10.1002/mabi.201700130] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/19/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Ida Franiak-Pietryga
- Department of Clinical and Laboratory Genetics; Medical University of Lodz; Pomorska Str. 251 92-213 Lodz Poland
- Laboratory of Clinical and Transplant Immunology and Genetics; Copernicus Memorial Hospital; Pabianicka Str. 62 93-513 Lodz Poland
- GeneaMed LTD; Kopcinskiego Str. 16/18/904 90-232 Lodz Poland
| | - Henryk Maciejewski
- Department of Computer Engineering; Wroclaw University of Technology; Janiszewskiego Str. 11/17 50-372 Wroclaw Poland
| | - Barbara Ziemba
- Department of Clinical and Laboratory Genetics; Medical University of Lodz; Pomorska Str. 251 92-213 Lodz Poland
| | - Dietmar Appelhans
- Leibniz Institute of Polymer Research Dresden; Hohe Str. 6 D-01069 Dresden Germany
| | - Brigitte Voit
- Leibniz Institute of Polymer Research Dresden; Hohe Str. 6 D-01069 Dresden Germany
| | - Tadeusz Robak
- Department of Hematology; Medical University of Lodz; Copernicus Memorial Hospital; Pabianicka Str. 62 93-513 Lodz Poland
| | | | - Jacek Treliński
- Department of Hematology; Medical University of Lodz; Copernicus Memorial Hospital; Pabianicka Str. 62 93-513 Lodz Poland
| | - Maria Bryszewska
- Department of General Biophysics; Faculty of Biology and Environmental Protection; University of Lodz; Pomorska Str. 141/143 90-236 Lodz Poland
| | - Maciej Borowiec
- Department of Clinical and Laboratory Genetics; Medical University of Lodz; Pomorska Str. 251 92-213 Lodz Poland
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Rodriguez-Blanco J, Pednekar L, Penas C, Li B, Martin V, Long J, Lee E, Weiss WA, Rodriguez C, Mehrdad N, Nguyen DM, Ayad NG, Rai P, Capobianco AJ, Robbins DJ. Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. Oncogene 2017; 36:6306-6314. [PMID: 28714964 DOI: 10.1038/onc.2017.232] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 06/02/2017] [Accepted: 06/05/2017] [Indexed: 12/24/2022]
Abstract
The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.
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Affiliation(s)
- J Rodriguez-Blanco
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - L Pednekar
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - C Penas
- Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - B Li
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - V Martin
- Morphology and Cell Biology Department, University of Oviedo, Asturias, Spain
| | - J Long
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - E Lee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - W A Weiss
- Department of Neurobiology, University of California, San Francisco, CA, USA
| | - C Rodriguez
- Morphology and Cell Biology Department, University of Oviedo, Asturias, Spain
| | - N Mehrdad
- Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - D M Nguyen
- Division of Cardiothoracic Surgery, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - N G Ayad
- Center for Therapeutic Innovation, Department of Psychiatry and Behavioral Sciences, University of Miami, Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - P Rai
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.,Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - A J Capobianco
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - D J Robbins
- Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.,Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
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39
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Maffei R, Fiorcari S, Martinelli S, Benatti S, Bulgarelli J, Rizzotto L, Debbia G, Santachiara R, Rigolin GM, Forconi F, Rossi D, Laurenti L, Palumbo GA, Vallisa D, Cuneo A, Gaidano G, Luppi M, Marasca R. Increased SHISA3 expression characterizes chronic lymphocytic leukemia patients sensitive to lenalidomide. Leuk Lymphoma 2017. [PMID: 28639485 DOI: 10.1080/10428194.2017.1339872] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Lenalidomide is a therapeutically effective drug in chronic lymphocytic leukemia (CLL). Twenty-seven CLL patients were treated with lenalidomide in a phase II clinical trial. Ten patients were grouped as responders (R) and 6 as nonresponders (NR). We evaluated T lymphocytes, NK, monocytes and dendritic cells at baseline and after treatment. A gene expression analysis was performed on 16 CLL samples collected before treatment. The levels of immune cells or immune-related cytokines are not different between R and NR patients. However, CLL patients sensitive to lenalidomide clearly show a peculiar gene expression profile in leukemic cells. The most up-regulated gene (fold change = +23 in R vs. NR) is Wnt inhibitor SHISA homolog 3 (SHISA3). SHISA3highCLL are characterized by a restrained activation of Wnt signaling and sensibility to lenalidomide-induced apoptosis. In conclusion, SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent.
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Affiliation(s)
- Rossana Maffei
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Stefania Fiorcari
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Silvia Martinelli
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Stefania Benatti
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Jenny Bulgarelli
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy.,b Immunotherapy Unit , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola , Italy
| | - Lara Rizzotto
- c Division of Hematology Department of Biomedical Sciences , Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara , Ferrara , Italy
| | - Giulia Debbia
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Rita Santachiara
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Gian Matteo Rigolin
- c Division of Hematology Department of Biomedical Sciences , Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara , Ferrara , Italy
| | - Francesco Forconi
- d Cancer Sciences Unit, CRUK Clinical Centre , University of Southampton , Southampton , UK.,e Division of Hematology, Department of Medicine, Surgery and Neuroscience , University of Siena , Siena , Italy
| | - Davide Rossi
- f Department of Hematology , Oncology Institute of Southern Switzerland and Institute of Oncology Research , Bellinzona , Switzerland.,g Division of Hematology, Department of Translational Medicine , University of Eastern Piedmont , Novara , Italy
| | - Luca Laurenti
- h Department of Hematology , Catholic University of the Sacred Hearth , Rome , Italy
| | - Giuseppe A Palumbo
- i Division of Hematology , AOU "Policlinico- V. Emanuele" , Catania , Italy
| | - Daniele Vallisa
- j Department of Medical Oncology and Hematology , Hospital of Piacenza , Piacenza , Italy
| | - Antonio Cuneo
- c Division of Hematology Department of Biomedical Sciences , Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara , Ferrara , Italy
| | - Gianluca Gaidano
- g Division of Hematology, Department of Translational Medicine , University of Eastern Piedmont , Novara , Italy
| | - Mario Luppi
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
| | - Roberto Marasca
- a Division of Hematology, Department of Medical and Surgical Sciences , University of Modena and Reggio Emilia , Modena , Italy
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Martinez-Font E, Felipe-Abrio I, Calabuig-Fariñas S, Ramos R, Terrasa J, Vögler O, Alemany R, Martín-Broto J, Obrador-Hevia A. Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells. Mol Cancer Ther 2017; 16:1166-1176. [DOI: 10.1158/1535-7163.mct-16-0585] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 10/13/2016] [Accepted: 03/02/2017] [Indexed: 12/29/2022]
Abstract
Abstract
Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vitro antitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-310 with doxorubicin resulted in enhanced reduction of cell viability, suggesting that Wnt inhibition could be a new combination regime in these patients. Our findings support the usefulness of Wnt inhibitors as new therapeutic strategies for the prevalent STS. Mol Cancer Ther; 16(6); 1166–76. ©2017 AACR.
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Affiliation(s)
- Esther Martinez-Font
- 1Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain
| | - Irene Felipe-Abrio
- 2Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
| | - Silvia Calabuig-Fariñas
- 3Molecular Oncology Laboratory, Fundación de Investigación, Hospital General Universitario de Valencia, Valencia, Spain
- 4Department of Pathology, Universitat de Valencia, Valencia, Spain
| | - Rafael Ramos
- 5Department of Pathology, Hospital Universitari Son Espases, Palma de Mallorca, Spain
| | - Josefa Terrasa
- 1Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain
- 6Department of Oncology, Hospital Universitari Son Espases, Palma de Mallorca, Spain
| | - Oliver Vögler
- 1Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain
- 7Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Spain
| | - Regina Alemany
- 1Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain
- 7Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Spain
| | - Javier Martín-Broto
- 2Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
- 8Department of Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Antònia Obrador-Hevia
- 1Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain
- 6Department of Oncology, Hospital Universitari Son Espases, Palma de Mallorca, Spain
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Aberrant Wnt Signaling in Leukemia. Cancers (Basel) 2016; 8:cancers8090078. [PMID: 27571104 PMCID: PMC5040980 DOI: 10.3390/cancers8090078] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 07/25/2016] [Accepted: 08/22/2016] [Indexed: 12/21/2022] Open
Abstract
The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment.
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42
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Ghamlouch H, Darwiche W, Hodroge A, Ouled-Haddou H, Dupont S, Singh AR, Guignant C, Trudel S, Royer B, Gubler B, Marolleau JP. Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells. Oncotarget 2016; 6:18484-503. [PMID: 26050196 PMCID: PMC4621905 DOI: 10.18632/oncotarget.3941] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 04/28/2015] [Indexed: 11/25/2022] Open
Abstract
Recent research has shown that chronic lymphocytic leukemia (CLL) B-cells display a strong tendency to differentiate into antibody-secreting cells (ASCs) and thus may be amenable to differentiation therapy. However, the effect of this differentiation on factors associated with CLL pathogenesis has not been reported. In the present study, purified CLL B-cells were stimulated to differentiate into ASCs by phorbol myristate acetate or CpG oligodeoxynucleotide, in combination with CD40 ligand and cytokines in a two-step, seven-day culture system. We investigated (i) changes in the immunophenotypic, molecular, functional, morphological features associated with terminal differentiation into ASCs, (ii) the expression of factors involved in CLL pathogenesis, and (iii) the expression of pro- and anti-apoptotic proteins in the differentiated cells. Our results show that differentiated CLL B-cells are able to display the transcriptional program of ASCs. Differentiation leads to depletion of the malignant program and deregulation of the apoptosis/survival balance. Analysis of apoptosis and the cell cycle showed that differentiation is associated with low cell viability and a low rate of cell cycle entry. Our findings shed new light on the potential for differentiation therapy as a part of treatment strategies for CLL.
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Affiliation(s)
- Hussein Ghamlouch
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Immunology, Amiens University Medical Center, Amiens, France.,Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France
| | - Walaa Darwiche
- PériTox, Périnatalité & Risques Toxiques, UMR-I 01 Unité mixte INERIS, Amiens, France
| | - Ahmed Hodroge
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France
| | | | - Sébastien Dupont
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France
| | | | - Caroline Guignant
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Immunology, Amiens University Medical Center, Amiens, France
| | - Stéphanie Trudel
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Molecular Oncobiology, Amiens University Medical Center, Amiens, France
| | - Bruno Royer
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France
| | - Brigitte Gubler
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Immunology, Amiens University Medical Center, Amiens, France.,Department of Molecular Oncobiology, Amiens University Medical Center, Amiens, France
| | - Jean-Pierre Marolleau
- EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France.,Department of Clinical Hematology and Cell Therapy, Amiens University Medical Center, Amiens, France
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Li PP, Lu K, Geng LY, Zhou XX, Li XY, Wang X. Bruton's tyrosine kinase inhibitor restrains Wnt signaling in chronic lymphocytic leukemia. Mol Med Rep 2016; 13:4934-8. [PMID: 27082823 DOI: 10.3892/mmr.2016.5111] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 03/29/2016] [Indexed: 11/06/2022] Open
Abstract
The B-cell receptor (BCR) signaling pathway serves an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and has been identified as a novel and effective therapeutic target of CLL, with particular focus its kinase factor, BTK. Previous studies have focused on combining the BTK inhibitor with additional chemotherapeutic agents to improve the prognosis of patients with CLL. Further investigation into the mechanism of the BTK inhibitor would promote an understanding of the pathogenesis of CLL. The current study investigated the association between ibrutinib and the Wnt signaling pathway, additionally focussing upon one of its regulators, metadherin (MTDH), which has been identified to be overexpressed in CLL and is considered a promoter of the Wnt pathway. The experiments in the current study were performed in the MEC-1 CLL cell line. Results indicated that MTDH, β-catenin and lymphoid-enhancing factor-1 were inhibited subsequent to ibrutinib treatment. The results indicate that in CLL, ibrutinib is likely to possess an inhibitory role in Wnt signaling.
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Affiliation(s)
- Pei-Pei Li
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Kang Lu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Ling-Yun Geng
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xiang-Xiang Zhou
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xin-Yu Li
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway. Life Sci 2016; 151:23-29. [PMID: 26944438 DOI: 10.1016/j.lfs.2016.02.098] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 02/24/2016] [Accepted: 02/29/2016] [Indexed: 11/22/2022]
Abstract
AIM Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. MAIN METHODS The expressions of β-catenin and related molecules of Wnt/β-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of β-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. KEY FINDINGS We found that SKI II decreased the expression of β-catenin and the downstream molecules of β-catenin signal pathway and promotes the β-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered β-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of β-catenin and downstream molecules of β-catenin signal pathway. SIGNIFICANCE SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated β-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.
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45
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Chen SR, Qiu HC, Hu Y, Wang Y, Wang YT. Herbal Medicine Offered as an Initiative Therapeutic Option for the Management of Hepatocellular Carcinoma. Phytother Res 2016; 30:863-77. [PMID: 26879574 DOI: 10.1002/ptr.5594] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 12/28/2015] [Accepted: 01/22/2016] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common malignant cancer and is the third leading cause of death worldwide. Effective treatment of this disease is limited by the complicated molecular mechanism underlying HCC pathogenesis. Thus, therapeutic options for HCC management are urgently needed. Targeting the Wnt/β-catenin, Hedgehog, Notch, and Hippo-YAP signaling pathways in cancer stem cell development has been extensively investigated as an alternative treatment. Herbal medicine has emerged as an initiative therapeutic option for HCC management because of its multi-level, multi-target, and coordinated intervention effects. In this article, we summarized the recent progress and clinical benefits of targeting the above mentioned signaling pathways and using natural products such as herbal medicine formulas to treat HCC. Proving the clinical success of herbal medicine is expected to deepen the knowledge on herbal medicine efficiency and hasten the adoption of new therapies. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Shao-Ru Chen
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, SAR, China
| | - Hong-Cong Qiu
- Guangxi Institute of Traditional Medical and Pharmaceutical Sciences and Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Nanning, 530022, China
| | - Yang Hu
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, SAR, China
| | - Ying Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, SAR, China
| | - Yi-Tao Wang
- State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, SAR, China
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Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol 2016; 22:823-832. [PMID: 26811628 PMCID: PMC4716080 DOI: 10.3748/wjg.v22.i2.823] [Citation(s) in RCA: 241] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/05/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.
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Yao QM, Li PP, Liang SM, Lu K, Zhu XJ, Liu YX, Zhang F, Yuan T, Wang X. Methylprednisolone suppresses the Wnt signaling pathway in chronic lymphocytic leukemia cell line MEC-1 regulated by LEF-1 expression. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:7921-7928. [PMID: 26339357 PMCID: PMC4555685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 06/23/2015] [Indexed: 06/05/2023]
Abstract
High dose methylprednisolone (HDMP) has been an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia (CLL), while little is known about the exact mechanisms implicated in glucocorticoid-induced cell death. To explore the mechanism of glucocorticoid-induced cell death, we investigated the effect of HDMP on canonical Wnt signaling which emerged as a key pathway implicated in the pathogenesis of CLL. In this study, the human CLL cell line MEC-1 was incubated with various concentrations of methylprednisolone. Cell proliferation activity was detected by CCK8 assay, the apoptotic effect was evaluated by TUNEL assay. Western blot was used to detect active-caspase 3, and the key proteins in Wnt signaling pathway (LEF-1, β-catenin). RT-PCR was performed to assess the mRNA levels of β-catenin, LEF-1, c-myc and cyclin D1. We observed that high concentration of methylprednisolone could suppress the proliferation activity of MEC-1 cells, promote the relative expression of active-caspase 3, and induce apoptotic cell death. Furthermore, methylprednisolone could inhibit LEF-1 protein expression, consequently down-regulate mRNA levels of c-myc and cyclin D1, but could not affect the transcription level of β-catenin and LEF-1 mRNA. The results of this study indicate that methylprednisolone can suppress Wnt signaling pathway by down-regulating LEF-1 protein expression, indicating a novel mechanism for HDMP therapy in CLL.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Caspase 3/metabolism
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cyclin D1/genetics
- Cyclin D1/metabolism
- Dose-Response Relationship, Drug
- Gene Expression Regulation, Neoplastic
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Lymphoid Enhancer-Binding Factor 1/genetics
- Lymphoid Enhancer-Binding Factor 1/metabolism
- Methylprednisolone/pharmacology
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- RNA, Messenger/metabolism
- Time Factors
- Up-Regulation
- Wnt Signaling Pathway/drug effects
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Affiliation(s)
- Qing-Min Yao
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Pei-Pei Li
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Shu-Mei Liang
- Department of Gynaecology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Kang Lu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Xiao-Juan Zhu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Yan-Xia Liu
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Feng Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Ting Yuan
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong UniversityJinan, Shandong, China
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48
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Understanding multicellular function and disease with human tissue-specific networks. Nat Genet 2015; 47:569-76. [PMID: 25915600 PMCID: PMC4828725 DOI: 10.1038/ng.3259] [Citation(s) in RCA: 586] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/06/2015] [Indexed: 12/17/2022]
Abstract
Tissue and cell-type identity lie at the core of human physiology and disease. Understanding the genetic underpinnings of complex tissues and individual cell lineages is crucial for developing improved diagnostics and therapeutics. We present genome-wide functional interaction networks for 144 human tissues and cell types developed using a data-driven Bayesian methodology that integrates thousands of diverse experiments spanning tissue and disease states. Tissue-specific networks predict lineage-specific responses to perturbation, reveal genes’ changing functional roles across tissues, and illuminate disease-disease relationships. We introduce NetWAS, which combines genes with nominally significant GWAS p-values and tissue-specific networks to identify disease-gene associations more accurately than GWAS alone. Our webserver, GIANT, provides an interface to human tissue networks through multi-gene queries, network visualization, analysis tools including NetWAS, and downloadable networks. GIANT enables systematic exploration of the landscape of interacting genes that shape specialized cellular functions across more than one hundred human tissues and cell types.
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Ashihara E, Takada T, Maekawa T. Targeting the canonical Wnt/β-catenin pathway in hematological malignancies. Cancer Sci 2015; 106:665-671. [PMID: 25788321 PMCID: PMC4471797 DOI: 10.1111/cas.12655] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 02/26/2015] [Accepted: 03/04/2015] [Indexed: 12/14/2022] Open
Abstract
The canonical Wnt/β-catenin pathway plays an important role in different developmental processes through the regulation of stem cell functions. In the activation of the canonical Wnt/β-catenin pathway, β-catenin protein is imported into the nucleus and activates transcription of target genes including cyclin D1 and c-myc. Aberrant activation of the Wnt/β-catenin pathway contributes to carcinogenesis and malignant behaviors, and Wnt signaling is essential for the maintenance of cancer stem cells. The canonical Wnt/β-catenin pathway has been investigated extensively as a target in cancer treatment and several specific inhibitors of this signaling pathway have been identified through high-throughput screening. In this review, the significance of the canonical Wnt/β-catenin pathway in hematological carcinogenesis and screening methods for specific inhibitors are discussed.
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Affiliation(s)
- Eishi Ashihara
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tetsuya Takada
- Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Taira Maekawa
- Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan
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Menter T, Dirnhofer S, Tzankov A. LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol 2015; 68:473-8. [PMID: 25713417 DOI: 10.1136/jclinpath-2015-202862] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 02/05/2015] [Indexed: 11/03/2022]
Abstract
AIMS Chronic lymphocytic B cell leukaemia (CLL)/small lymphocytic B cell lymphoma (SLL) has proven to be not a uniform entity but to consist of various disease subtypes. CLL might also pose diagnostic challenges by demonstrating an uncommon immunohistochemical profile. Recently, the role of lymphocyte enhancer-binding factor 1 (LEF1) in CLL was elucidated being highly expressed and seeming to have a prognostic value. Our aim was to test the applicability of LEF1 as marker for CLL in a diagnostic setting. METHODS We investigated LEF1 expression in lymphomas by immunohistochemistry on tissue microarrays containing several lymphoma entities (altogether 720 cases, including 61 CLL cases). We also separated CLL cases by zeta-chain-associated protein kinase 70 (ZAP70) and CD38 stainings and fluorescence in situ hybridisation analyses for TP53 deletions and trisomy 12 into respective groups and correlated data with LEF1 expression. RESULTS The area under the receiver operating characteristic curve for LEF1 as a diagnostic marker for CLL was 0.815 (95% CI 0.742 to 0.888). The relevant diagnostic cut-off value for LEF1 positivity determined by the Youden's index was 10% (specificity 92%, sensitivity 70%). The majority of CLL cases (70%) expressed LEF1. Eighteen per cent of (transformed) diffuse large B cell lymphoma cases also expressed LEF1. In most other lymphoma entities, LEF1 was negative. There was a positive correlation of LEF1 staining with ZAP70 expression (Spearman's rho: 0.438, p<0.001), but not with CD38 expression, TP53 deletions or trisomy 12. CONCLUSIONS LEF1 is a useful marker in the differential diagnosis of CLL in difficult cases. It shows a high specificity (92%) and a reasonable sensitivity (70%) for this entity.
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Affiliation(s)
- Thomas Menter
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Stephan Dirnhofer
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Alexandar Tzankov
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
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