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Wang Y, Bendre SV, Krauklis SA, Steelman AJ, Nelson ER. Role of Protein Regulators of Cholesterol Homeostasis in Immune Modulation and Cancer Pathophysiology. Endocrinology 2025; 166:bqaf031. [PMID: 39951497 PMCID: PMC11878532 DOI: 10.1210/endocr/bqaf031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/30/2025] [Accepted: 02/12/2025] [Indexed: 02/16/2025]
Abstract
Cholesterol metabolism and homeostasis have emerged as important factors governing various aspects of cancer biology. Clinical associations between circulating cholesterol and poor prognosis or use of cholesterol-lowering medication and improved prognosis have been noted for several different solid tumors. Mechanistically, cholesterol has many different direct and indirect effects on cancer cells themselves but is also critically involved in shaping the function of other cells of the tumor microenvironment, especially immune cells. There are 2 major feedback loops regulating cholesterol homeostasis. Here we highlight the major proteins involved in the so-called oxysterol-bile acid feedback loop and discuss how each has been implicated in cancer biology. We focus on roles within the immune system with implications for cancer. Given that many of these proteins are enzymes or nuclear receptors, both of which are amenable to small molecule intervention, we posit that this axis may represent a promising area for therapeutic intervention.
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Affiliation(s)
- Yu Wang
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Shruti V Bendre
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
| | - Steven A Krauklis
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Andrew J Steelman
- Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Erik R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology- Anticancer Discovery from Pets to People (ERN) and Regenerative Biology & Tissue Engineering (AJS), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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Haratipour Z, Foutch D, Blind RD. A novel heuristic of rigid docking scores positively correlates with full-length nuclear receptor LRH-1 regulation. Comput Struct Biotechnol J 2024; 23:3065-3080. [PMID: 39185441 PMCID: PMC11342790 DOI: 10.1016/j.csbj.2024.07.021] [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: 06/14/2024] [Revised: 07/26/2024] [Accepted: 07/26/2024] [Indexed: 08/27/2024] Open
Abstract
The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) is a ligand-regulated transcription factor and validated drug target for several human diseases. LRH-1 activation is regulated by small molecule ligands, which bind to the ligand binding domain (LBD) within the full-length LRH-1. We recently identified 57 compounds that bind LRH-1, and unexpectedly found these compounds regulated either the isolated LBD, or the full-length LRH-1 in cells, with little overlap. Here, we correlated compound binding energy from a single rigid-body scoring function with full-length LRH-1 activity in cells. Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "ΔΔG". Initial regressions, correlations and contingency analyses all suggest compounds with high ΔΔG values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 separate crystal structures of LRH-1 to obtain averaged ΔΔG values for each compound, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low ΔΔG values, identifying a structural relationship between ΔΔG and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest rigid-body computational docking can be used to quickly calculate ΔΔG, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose ΔΔG as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for resource-intense secondary screening.
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Affiliation(s)
- Zeinab Haratipour
- Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Nashville, TN 37232, USA
- Austin Peay State University, Department of Chemistry
| | - David Foutch
- Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Nashville, TN 37232, USA
| | - Raymond D. Blind
- Vanderbilt University Medical Center, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Nashville, TN 37232, USA
- Vanderbilt University School of Medicine, Departments of Biochemistry and Pharmacology, Nashville, TN 37232, USA
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Wu T, Lu ZF, Yu HN, Wu XS, Liu Y, Xu Y. Liver receptor homolog-1: structures, related diseases, and drug discovery. Acta Pharmacol Sin 2024; 45:1571-1581. [PMID: 38632319 PMCID: PMC11272790 DOI: 10.1038/s41401-024-01276-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 03/24/2024] [Indexed: 04/19/2024]
Abstract
Liver receptor homolog-1 (LRH-1), a member of the nuclear receptor superfamily, is a ligand-regulated transcription factor that plays crucial roles in metabolism, development, and immunity. Despite being classified as an 'orphan' receptor due to the ongoing debate surrounding its endogenous ligands, recent researches have demonstrated that LRH-1 can be modulated by various synthetic ligands. This highlights the potential of LRH-1 as an attractive drug target for the treatment of inflammation, metabolic disorders, and cancer. In this review, we provide an overview of the structural basis, functional activities, associated diseases, and advancements in therapeutic ligand research targeting LRH-1.
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Affiliation(s)
- Tong Wu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China
| | - Zhi-Fang Lu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China
| | - Hao-Nan Yu
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China
| | - Xi-Shan Wu
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China
| | - Yang Liu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Yong Xu
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- State Key Laboratory of Respiratory Disease, China-New Zealand Joint Laboratory of Biomedicine and Health, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangzhou Medical University, Guangzhou, China.
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4
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Chapagain P, Haratipour Z, Malabanan MM, Choi WJ, Blind RD. Bilirubin is a new ligand for nuclear receptor Liver Receptor Homolog-1. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.05.592606. [PMID: 38853895 PMCID: PMC11160564 DOI: 10.1101/2024.05.05.592606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2 ) binds to phospholipids that regulate important LRH-1 functions in the liver. A recent compound screen unexpectedly identified bilirubin, the product of liver heme metabolism, as a possible ligand for LRH-1. Here, we show unconjugated bilirubin directly binds LRH-1 with apparent K d =9.3uM, altering LRH-1 interaction with all transcriptional coregulator peptides tested. Bilirubin decreased LRH-1 protease sensitivity, consistent with MD simulations predicting bilirubin stably binds LRH-1 within the canonical ligand binding site. Bilirubin activated a luciferase reporter specific for LRH-1, dependent on co-expression with the bilirubin membrane transporter SLCO1B1 , but bilirubin failed to activate ligand-binding genetic mutants of LRH-1. Gene profiling in HepG2 cells shows bilirubin selectively regulated transcripts from endogenous LRH-1 ChIP-seq target genes, which was significantly attenuated by either genetic knockdown of LRH-1, or by a specific chemical competitor of LRH-1. Gene set enrichment suggests bilirubin and LRH-1 share roles in cholesterol metabolism and lipid efflux, thus we propose a new role for LRH-1 in directly sensing intracellular levels of bilirubin.
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Zheng Q, Tang J, Aicher A, Bou Kheir T, Sabanovic B, Ananthanarayanan P, Reina C, Chen M, Gu JM, He B, Alcala S, Behrens D, Lawlo RT, Scarpa A, Hidalgo M, Sainz B, Sancho P, Heeschen C. Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity. J Exp Clin Cancer Res 2023; 42:323. [PMID: 38012687 PMCID: PMC10683265 DOI: 10.1186/s13046-023-02883-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/02/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs. METHODS We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers. RESULTS Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment. CONCLUSIONS The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes. A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com ).
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Affiliation(s)
- Quan Zheng
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajia Tang
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Alexandra Aicher
- Precision Immunotherapy, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Immunology Research and Development Center, China Medical University, Taichung, Taiwan
| | - Tony Bou Kheir
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Berina Sabanovic
- Pancreatic Cancer Heterogeneity Lab, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy
| | - Preeta Ananthanarayanan
- Pancreatic Cancer Heterogeneity Lab, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy
| | - Chiara Reina
- Pancreatic Cancer Heterogeneity Lab, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy
| | - Minchun Chen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Min Gu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Sonia Alcala
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Chronic Diseases and Cancer Area 3 Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain
| | - Diana Behrens
- Experimental Pharmacology and Oncology Berlin-Buch GmbH, Berlin, Germany
| | - Rita T Lawlo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net, Applied Research On Cancer Centre, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net, Applied Research On Cancer Centre, University of Verona, Verona, Italy
| | - Manuel Hidalgo
- Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Bruno Sainz
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Chronic Diseases and Cancer Area 3 Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain
| | - Patricia Sancho
- IIS Aragon, Hospital Universitario Miguel Servet, 50009, Saragossa, Spain.
| | - Christopher Heeschen
- Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Pancreatic Cancer Heterogeneity Lab, Candiolo Cancer Institute - FPO - IRCCS, Candiolo, Turin, Italy.
- Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
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6
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Azevedo-Pouly A, Hale MA, Swift GH, Hoang CQ, Deering TG, Xue J, Wilkie TM, Murtaugh LC, MacDonald RJ. Key transcriptional effectors of the pancreatic acinar phenotype and oncogenic transformation. PLoS One 2023; 18:e0291512. [PMID: 37796967 PMCID: PMC10553828 DOI: 10.1371/journal.pone.0291512] [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: 04/19/2023] [Accepted: 08/30/2023] [Indexed: 10/07/2023] Open
Abstract
Proper maintenance of mature cellular phenotypes is essential for stable physiology, suppression of disease states, and resistance to oncogenic transformation. We describe the transcriptional regulatory roles of four key DNA-binding transcription factors (Ptf1a, Nr5a2, Foxa2 and Gata4) that sit at the top of a regulatory hierarchy controlling all aspects of a highly differentiated cell-type-the mature pancreatic acinar cell (PAC). Selective inactivation of Ptf1a, Nr5a2, Foxa2 and Gata4 individually in mouse adult PACs rapidly altered the transcriptome and differentiation status of PACs. The changes most emphatically included transcription of the genes for the secretory digestive enzymes (which conscript more than 90% of acinar cell protein synthesis), a potent anabolic metabolism that provides the energy and materials for protein synthesis, suppressed and properly balanced cellular replication, and susceptibility to transformation by oncogenic KrasG12D. The simultaneous inactivation of Foxa2 and Gata4 caused a greater-than-additive disruption of gene expression and uncovered their collaboration to maintain Ptf1a expression and control PAC replication. A measure of PAC dedifferentiation ranked the effects of the conditional knockouts as Foxa2+Gata4 > Ptf1a > Nr5a2 > Foxa2 > Gata4. Whereas the loss of Ptf1a or Nr5a2 greatly accelerated Kras-mediated transformation of mature acinar cells in vivo, the absence of Foxa2, Gata4, or Foxa2+Gata4 together blocked transformation completely, despite extensive dedifferentiation. A lack of correlation between PAC dedifferentiation and sensitivity to oncogenic KrasG12D negates the simple proposition that the level of differentiation determines acinar cell resistance to transformation.
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Affiliation(s)
- Ana Azevedo-Pouly
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Michael A. Hale
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Galvin H. Swift
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Chinh Q. Hoang
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Tye G. Deering
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jumin Xue
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Thomas M. Wilkie
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - L. Charles Murtaugh
- Department of Human Genetics, University of Utah, Salt Lake City, Utah, United States of America
| | - Raymond J. MacDonald
- Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
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Topham JT, Tsang ES, Karasinska JM, Metcalfe A, Ali H, Kalloger SE, Csizmok V, Williamson LM, Titmuss E, Nielsen K, Negri GL, Spencer Miko SE, Jang GH, Denroche RE, Wong HL, O'Kane GM, Moore RA, Mungall AJ, Loree JM, Notta F, Wilson JM, Bathe OF, Tang PA, Goodwin R, Morin GB, Knox JJ, Gallinger S, Laskin J, Marra MA, Jones SJM, Schaeffer DF, Renouf DJ. Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma. Nat Commun 2022; 13:5941. [PMID: 36209277 PMCID: PMC9547977 DOI: 10.1038/s41467-022-33718-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 09/29/2022] [Indexed: 11/15/2022] Open
Abstract
Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events. KRAS wildtype metastatic pancreatic ductal adenocarcinoma (mPDAC) could represent a distinct molecular entity from other PDACs. Here, the authors analyse KRAS wildtype mPDAC tumours using genomics and transcriptomics and find molecular similarities with cholangiocarcinomas.
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Affiliation(s)
| | - Erica S Tsang
- Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | | | | | - Hassan Ali
- Pancreas Centre BC, Vancouver, BC, Canada
| | - Steve E Kalloger
- Pancreas Centre BC, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada
| | - Veronika Csizmok
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Laura M Williamson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Emma Titmuss
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Karina Nielsen
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Gian Luca Negri
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | | | - Gun Ho Jang
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | | | - Hui-Li Wong
- Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada
| | | | - Richard A Moore
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Andrew J Mungall
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | | | - Faiyaz Notta
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Julie M Wilson
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Oliver F Bathe
- Departments of Surgery and Oncology, Cummings School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Patricia A Tang
- Departments of Surgery and Oncology, Cummings School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Rachel Goodwin
- The Ottawa Hospital Cancer Centre, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Gregg B Morin
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Jennifer J Knox
- University Health Network, University of Toronto, Toronto, ON, Canada
| | - Steven Gallinger
- Ontario Institute for Cancer Research, Toronto, ON, Canada.,University Health Network, University of Toronto, Toronto, ON, Canada
| | - Janessa Laskin
- Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada.,Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada
| | - Steven J M Jones
- Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - David F Schaeffer
- Pancreas Centre BC, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada.,Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, BC, Canada
| | - Daniel J Renouf
- Pancreas Centre BC, Vancouver, BC, Canada. .,Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada. .,Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
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8
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Cato ML, Cornelison JL, Spurlin RM, Courouble VV, Patel AB, Flynn AR, Johnson AM, Okafor CD, Frank F, D’Agostino EH, Griffin PR, Jui NT, Ortlund EA. Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket. J Med Chem 2022; 65:6888-6902. [PMID: 35503419 PMCID: PMC10026694 DOI: 10.1021/acs.jmedchem.2c00235] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.
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Affiliation(s)
- Michael L. Cato
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | | | | | | | - Anamika B. Patel
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Autumn R. Flynn
- Department of Chemistry, Emory University, Atlanta, Georgia 30322
| | | | - C. Denise Okafor
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Filipp Frank
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Emma H. D’Agostino
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | | | - Nathan T. Jui
- Department of Chemistry, Emory University, Atlanta, Georgia 30322
| | - Eric A. Ortlund
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
- Corresponding Author:
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9
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Pouraghajan K, Mahdiuni H, Ghobadi S, Khodarahmi R. LRH-1 (liver receptor homolog-1) derived affinity peptide ligand to inhibit interactions between β-catenin and LRH-1 in pancreatic cancer cells: from computational design to experimental validation. J Biomol Struct Dyn 2022; 40:3082-3097. [PMID: 33183172 DOI: 10.1080/07391102.2020.1845241] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/28/2020] [Indexed: 10/23/2022]
Abstract
Poor prognosis, rapid progression and the lack of an effective treatment make pancreatic cancer one of the most lethal malignancies. Recent studies point to a role for liver receptor homolog-1 (LRH-1) in pathogenesis of pancreatic cancer and suggest prevention of the β-catenin/LRH-1 complex formation as a potential strategy for inhibition of the pancreas cancer cells progression. In the current investigation, we have followed a biomimetic strategy and designed an affinity peptide with sequence DEMEEPQQTE to inhibit formation of the β-catenin/LRH-1 complex. Quantitative real-time PCR experiments on the AsPC-1 pancreatic metastatic cells showed that the peptide has an inhibitory effect on the Wnt signaling proliferation line by reducing the expression levels of the CCND1, CCNE1, and MYC genes. Furthermore, the increased expression level of BAX gene showed that AsPC-1 cells were directed to the apoptosis pathway. At last, POU5F1, KLF4, and CD44 gene expression levels suggested that the peptide has an inhibitory effect on the stemness feature of the AsPC-1 cells. Here, we introduced a novel peptide inhibitor targeting an important protein-protein interaction, the β-catenin/LRH-1 complex, which may provide highly promising starting points for subsequent drug design. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Khadijeh Pouraghajan
- Bioinformatics Laboratory, Department of Biology, School of Sciences, Razi University, Kermanshah, Iran
| | - Hamid Mahdiuni
- Bioinformatics Laboratory, Department of Biology, School of Sciences, Razi University, Kermanshah, Iran
| | - Sirous Ghobadi
- Bioinformatics Laboratory, Department of Biology, School of Sciences, Razi University, Kermanshah, Iran
| | - Reza Khodarahmi
- Medical Biology Research Center (MBRC), Kermanshah University of Medical Sciences, Kermanshah, Iran
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10
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Sandhu N, Rana S, Meena K. Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases. Mol Biol Rep 2021; 48:8155-8170. [PMID: 34643922 DOI: 10.1007/s11033-021-06784-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/22/2021] [Indexed: 10/20/2022]
Abstract
Nuclear receptors are the regulatory molecules that mediate cellular signals as they interact with specific DNA sequences. NR5A2 is a member of NR5A subfamily having four members (Nr5a1-Nr5a4). NR5A2 shows involvement in diverse biological processes like reverse cholesterol transport, embryonic stem cell pluripotency, steroidogenesis, development and differentiation of embryo, and adult homeostasis. NR5A2 haploinsufficiency has been seen associated with chronic pancreatitis, pancreatic and gastrointestinal cancer. There is a close relationship between the progression of pancreatic cancer from chronic pancreatitis, NR5A2 serving a common link. NR5A2 activity is regulated by intracellular phospholipids, transcriptional coregulators and post-translational modifications. The specific ligand of NR5A2 is unknown hence called an orphan receptor, but specific phospholipids such as dilauroyl phosphatidylcholine and diundecanoyl phosphatidylcholine act as a ligand and they are established drug targets in various diseases. This review will focus on the NR5A2 structure, regulation of its activity, and role in biological processes and diseases. In future, need more emphasis on discovering small molecule agonists and antagonist, which act as a drug target for therapeutic applications.
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Affiliation(s)
- Nikita Sandhu
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Rishikesh, Rishikesh, Uttarakhand, India
| | - Satyavati Rana
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Rishikesh, Rishikesh, Uttarakhand, India
| | - Kiran Meena
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Rishikesh, Rishikesh, Uttarakhand, India.
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11
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Tan X, Zhang L, Li T, Zhan J, Qiao K, Wu H, Sun S, Huang M, Zhang F, Zhang M, Li C, Li R, Pan H. Lgr4 Regulates Oviductal Epithelial Secretion Through the WNT Signaling Pathway. Front Cell Dev Biol 2021; 9:666303. [PMID: 34631693 PMCID: PMC8497904 DOI: 10.3389/fcell.2021.666303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022] Open
Abstract
The WNT signaling pathway plays a crucial role in oviduct/fallopian development. However, the specific physiological processes regulated by the WNT pathway in the fallopian/oviduct function remain obscure. Benefiting from the Lgr4 knockout mouse model, we report the regulation of oviduct epithelial secretion by LGR4. Specifically, the loss of Lgr4 altered the mouse oviduct size and weight, severely reduced the number of oviductal epithelial cells, and ultimately impaired the epithelial secretion. These alterations were mediated by a failure of CTNNB1 protein accumulation in the oviductal epithelial cytoplasm, by the modulation of WNT pathways, and subsequently by a profound change of the gene expression profile of epithelial cells. In addition, selective activation of the WNT pathway triggered the expression of steroidogenic genes, like Cyp11a1 and 3β-Hsd1, through the activation of the transcriptional factor NR5A2 in an oviduct primary cell culture system. As demonstrated, the LGR4 protein modulates a WNT-NR5A2 signaling cascade facilitating epithelial secretory cell maturation and steroidogenesis to safeguard oviduct development and function in mice.
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Affiliation(s)
- Xue Tan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Lingling Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Tianqi Li
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Jianmin Zhan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Kun Qiao
- Center for Reproductive Medicine, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Haili Wu
- Shanghai Endangered Species Conservation and Research Centre, Shanghai Zoo, Shanghai, China
| | - Shenfei Sun
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Meina Huang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Fangxi Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Meixing Zhang
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Changwei Li
- Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases With Integrated Chinese-Western Medicine, Ruijin Hospital, Shanghai Institute of Traumatology and Orthopedics, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Runsheng Li
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
| | - Hongjie Pan
- National Health Commission (NHC) Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, School of Pharmacy, Fudan University, Shanghai, China
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12
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Aney KJ, Nissim S. More than acinar identity? A novel cystic phenotype suggests broader roles for NR5A2 in pancreatic cancer †. J Pathol 2021; 254:1-4. [PMID: 33448017 PMCID: PMC8439571 DOI: 10.1002/path.5619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/05/2021] [Accepted: 01/10/2021] [Indexed: 11/10/2022]
Abstract
The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains dismal. Multiple genome-wide association studies (GWAS) have implicated the nuclear receptor NR5A2 in modulating PDAC risk, but mechanisms for this association are not understood. NR5A2 is a transcription factor that maintains acinar cell identity, and heterozygous loss of Nr5a2 in mice accelerates oncogenic Kras-driven formation of pancreatic intraepithelial neoplasia (PanIN), a PDAC precursor derived from acinar cells. In a recent issue of The Journal of Pathology, Cobo et al characterize a novel mouse model that uses Ptf1a:Cre to drive oncogenic Kras as well as heterozygous Nr5a2 inactivation. In addition to the expected PanIN lesions, these mice exhibited a surprising phenotype: large pancreatic cystic lesions which have not been previously reported. Comparing expression of oncogenic Kras and heterozygous Nr5a2 in various mouse models reveals several possible explanations for these cystic lesions. Importantly, these differences across mouse models suggest that NR5A2 may contribute to PDAC precursors in ways beyond its previously characterized acinar cell-autonomous role. These observations highlight that pathways implicated by GWAS may have roles in unexpected cell types, and an understanding of these roles will be critical to guide new preventive and treatment strategies for PDAC. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Katherine J Aney
- Harvard–MIT Health Sciences and Technology, Harvard
Medical School, Boston, MA, USA
| | - Sahar Nissim
- Harvard–MIT Health Sciences and Technology, Harvard
Medical School, Boston, MA, USA
- Divisions of Gastroenterology and Genetics, Brigham and
Womenʼs Hospital, Boston, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
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13
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Zerlotin R, Arconzo M, Piccinin E, Moschetta A. Another One Bites the Gut: Nuclear Receptor LRH-1 in Intestinal Regeneration and Cancer. Cancers (Basel) 2021; 13:cancers13040896. [PMID: 33672730 PMCID: PMC7924345 DOI: 10.3390/cancers13040896] [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: 12/23/2020] [Revised: 01/25/2021] [Accepted: 02/16/2021] [Indexed: 11/16/2022] Open
Abstract
The process of self-renewal in normal intestinal epithelium is characterized by a fine balance between proliferation, differentiation, migration, and cell death. When even one of these aspects escapes the normal control, cellular proliferation and differentiation are impaired, with consequent onset of tumorigenesis. In humans, colorectal cancer (CRC) is the main pathological manifestation of this derangement. Nowadays, CRC is the world's fourth most deadly cancer with a limited survival after treatment. Several conditions can predispose to CRC development, including dietary habits and pre-existing inflammatory bowel diseases. Given their extraordinary ability to interact with DNA, it is widely known that nuclear receptors play a key role in the regulation of intestinal epithelium, orchestrating the expression of a series of genes involved in developmental and homeostatic pathways. In particular, the nuclear receptor Liver Receptor Homolog-1 (LRH-1), highly expressed in the stem cells localized in the crypts, promotes intestine cell proliferation and renewal in both direct and indirect DNA-binding manner. Furthermore, LRH-1 is extensively correlated with diverse intestinal inflammatory pathways. These evidence shed a light in the dynamic intestinal microenvironment in which increased regenerative epithelial cell turnover, mutagenic insults, and chronic DNA damages triggered by factors within an inflammatory cell-rich microenvironment act synergistically to favor cancer onset and progression.
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Affiliation(s)
- Roberta Zerlotin
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (R.Z.); (M.A.); (E.P.)
| | - Maria Arconzo
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (R.Z.); (M.A.); (E.P.)
| | - Elena Piccinin
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (R.Z.); (M.A.); (E.P.)
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (R.Z.); (M.A.); (E.P.)
- INBB, National Institute for Biostructures and Biosystems, 00136 Rome, Italy
- National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy
- Correspondence: ; Tel.: +39-080-559-3262
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14
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Qi J, Pan L, Yu Z, Ni W. The lncRNA RP3-439F8.1 promotes GBM cell proliferation and progression by sponging miR-139-5p to upregulate NR5A2. Pathol Res Pract 2021; 223:153319. [PMID: 33991848 DOI: 10.1016/j.prp.2020.153319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2, LRH-1) is an oncogene in a wide range of cancer types. Bioinformatics analysis on glioblastoma multiforme (GBM) tumors has revealed that the miR-139-5p-NR5A2 axis may be putatively regulated by the long non-coding RNA (lncRNA) RP3-439F8.1. This led us to hypothesize the existence of a RP3-439F8.1-miR-139-5p-NR5A2 regulatory axis in GBM cells. METHODS Gene expression analysis was performed in GBM tumor samples and normal controls from our hospital, the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) cohort, and the Gene Expression Omnibus (GEO) database (GSE7696). Cell proliferation, apoptosis, Matrigel Transwell, colony formation, and cell cycle assays were performed in T98 G and U251 cells in vitro. An orthotopic U251 xenograft murine model was employed to test the effects of RP3-439F8.1 knockdown in vivo. RESULTS NR5A2 was upregulated in the three independent GBM tumor cohorts. In vitro, NR5A2 overexpression enhanced GBM cell proliferation, colony formation, invasiveness, and G0-G1 cell cycle phase shift via co-activating β-catenin/TCF4 signaling, with no apparent effect upon apoptosis. In contrast, RP3-439F8.1 knockdown produced the opposite effects. RP3-439F8.1 knockdown reduced tumor progression in vivo, increasing overall survival in model mice. Further in vitro experiments revealed that RP3-439F8.1 acts as a competing endogenous RNA (ceRNA) to regulate NR5A2 by sponging the microRNA miR-139-5p. These findings were clinically validated by a positive correlation between RP3-439F8.1 and NR5A2 and a negative correlation between RP3-439F8.1 and miR-139-5p in GBM tumors. CONCLUSIONS Our study supports a tumorigenic role for RP3-439F8.1 in GBM through the RP3-439F8.1/miR-139-5p/NR5A2 axis.
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Affiliation(s)
- Junhui Qi
- Department of Neurosurgery, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Lei Pan
- Department of Rehabilitation Medicine, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Zeran Yu
- Department of Neurosurgery, the Second People's Hospital of Yunnan Province, Kunming, China
| | - Wei Ni
- Department of Neurosurgery, Yunnan Cancer Hospital, Kunming, China.
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15
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Zhou J, Wang Y, Wu D, Wang S, Chen Z, Xiang S, Chan FL. Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer. Oncogene 2021; 40:2625-2634. [PMID: 33750894 PMCID: PMC8049868 DOI: 10.1038/s41388-021-01737-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 01/31/2023]
Abstract
Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2), steroidogenic factor 1 (SF-1, AD4BP, NR5A1) and estrogen-related receptor α (ERRα, NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.
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Affiliation(s)
- Jianfu Zhou
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China ,grid.411866.c0000 0000 8848 7685The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China ,grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Yuliang Wang
- grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Dinglan Wu
- grid.488521.2Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Shusheng Wang
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhiqiang Chen
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Songtao Xiang
- grid.411866.c0000 0000 8848 7685Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Franky Leung Chan
- grid.10784.3a0000 0004 1937 0482School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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16
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He T, Shen H, Wang S, Wang Y, He Z, Zhu L, Du X, Wang D, Li J, Zhong S, Huang W, Yang H. MicroRNA-3613-5p Promotes Lung Adenocarcinoma Cell Proliferation through a RELA and AKT/MAPK Positive Feedback Loop. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:572-583. [PMID: 33230458 PMCID: PMC7562961 DOI: 10.1016/j.omtn.2020.09.024] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/21/2020] [Indexed: 12/24/2022]
Abstract
Aberrant activation of nuclear factor κB (NF-κB)/RELA is often found in lung adenocarcinoma (LUAD). In this study, we determined that microRNA-3613-5p (miR-3613-5p) plays a crucial role in RELA-mediated post-transcriptional regulation of LUAD cell proliferation. Expression of miR-3613-5p in clinical LUAD specimens is associated with poor prognosis in LUAD. Upregulation of miR-3613-5p promotes LUAD cell proliferation in vitro and in vivo. Our results suggested a mechanism whereby miR-3613-5p expression is induced by RELA through its direct interaction with JUN, thereby stimulating the AKT/mitogen-activated protein kinase (MAPK) pathway by directly targeting NR5A2. In addition, we also found that phosphorylation of AKT1 and MAPK3/1 co-transactivates RELA, thus constituting a RELA/JUN/miR-3613-5p/NR5A2/AKT1/MAPK3/1 positive feedback loop, leading to persistent NF-κB activation. Our findings also revealed that miR-3613-5p plays an oncogenic role in LUAD by promoting cell proliferation and acting as a key regulator of the positive feedback loop underlying the link between the NF-κB/RELA and AKT/MAPK pathways.
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Affiliation(s)
- Tao He
- Department of Biology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Hongyou Shen
- Emergency Department, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510310, P.R. China
| | - Shuangmiao Wang
- Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, Guangdong 524023, P.R. China
| | - Yanfang Wang
- National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhiwei He
- School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Litong Zhu
- Department of Gynecology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen, Guangdong 518028, P.R. China
| | - Xinyue Du
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Dan Wang
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Jiao Li
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
| | - Shizhen Zhong
- National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Wenhua Huang
- National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
- Guangdong Medical University, Zhanjiang, Guangdong 524002, P.R. China
| | - Huiling Yang
- School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
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Michalek S, Brunner T. Nuclear-mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog-1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer. IUBMB Life 2020; 73:592-610. [PMID: 32931651 DOI: 10.1002/iub.2386] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 08/26/2020] [Indexed: 12/15/2022]
Abstract
Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor with widespread activities in the regulation of development, stemness, metabolism, steroidogenesis, and proliferation. Many of the LRH-1-regulated processes target the mitochondria and associated activities. While under physiological conditions, a balanced LRH-1 expression and regulation contribute to the maintenance of a physiological equilibrium, deregulation of LRH-1 has been associated with inflammation and cancer. In this review, we discuss the role and mechanism(s) of how LRH-1 regulates metabolic processes, cell survival, and cancer in a nuclear-mitochondrial crosstalk, and evaluate its potential as a pharmacological target.
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Affiliation(s)
- Svenja Michalek
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Thomas Brunner
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
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18
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Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis. Cell Death Dis 2020; 11:154. [PMID: 32111818 PMCID: PMC7048823 DOI: 10.1038/s41419-020-2348-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 12/31/2022]
Abstract
Liver receptor homolog-1 (LRH-1, Nr5a2) is an orphan nuclear receptor mainly expressed in tissues of endodermal origin, where its physiological role has been extensively studied. LRH-1 has been implicated in liver cell differentiation and proliferation, as well as glucose, lipid, and bile acid metabolism. In addition, increasing evidence highlights its role in immunoregulatory processes via glucocorticoid synthesis in the intestinal epithelium. Although the direct function of LRH-1 in immune cells is fairly elucidated, a role of LRH-1 in the regulation of macrophage differentiation has been recently reported. In this study, we aimed to investigate the role of LRH-1 in the regulation of pro-inflammatory cytokine production in macrophages. Our data demonstrate that pharmacological inhibition, along with LRH-1 knockdown, significantly reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines in the macrophage line RAW 264.7 cells, as well as in primary murine macrophages. This inhibitory effect was found to be independent of defects of LRH-1-regulated cell proliferation or toxic effects of the LRH-1 inhibitors. In contrast, LRH-1 inhibition reduced the mitochondrial ATP production and metabolism of macrophages through downregulation of the LRH-1 targets glucokinase and glutminase-2, and thus impairing the LPS-induced macrophage activation. Interestingly, in vivo pharmacological inhibition of LRH-1 also resulted in reduced tumor necrosis factor (TNF) production and associated decreased liver damage in a macrophage- and TNF-dependent mouse model of hepatitis. Noteworthy, despite hepatocytes expressing high levels of LRH-1, pharmacological inhibition of LRH-1 per se did not cause any obvious liver damage. Therefore, this study proposes LRH-1 as an emerging therapeutic target in the treatment of inflammatory disorders, especially where macrophages and cytokines critically decide the extent of inflammation.
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19
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Lai HT, Chiang CT, Tseng WK, Chao TC, Su Y. GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH-1 expression. Mol Oncol 2020; 14:1327-1347. [PMID: 32037723 PMCID: PMC7266275 DOI: 10.1002/1878-0261.12647] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/09/2020] [Accepted: 02/07/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells play critical roles in tumor initiation, progression, and relapse. Since we previously found that GATA6 promotes the stemness in HCT‐116 and HT‐29 human colorectal cancer (CRC) cells, we aimed to identify the downstream mediator(s) of the stemness‐stimulating effect of GATA6 herein. LRH‐1 was found as a direct target of GATA6 and its upregulation promoted the stemness in both HCT‐116 and HT‐29 cells. Subsequently, hypoxia‐inducible factor‐1α (HIF‐1α) was identified as a direct target of LRH‐1 and its expression level and activity were significantly elevated in the LRH‐1‐overexpressing clones established from the aforementioned two CRC lines. Accordingly, the expression levels of several HIF‐1α targets were also markedly increased, resulting in a stronger glycolysis associated with dramatic elevations of the lactate levels in these cells. Strikingly, higher mitochondrial activities were also found in these clones which might be attributed to the increase of PGC‐1α stimulated by the lactate uptaken through the upregulated MCT‐1. Finally, significant increases in the self‐renewal ability, intracellular radical oxygen species levels and mitochondrial mass were detected in the CD133+/CD44+ subpopulations isolated from CRC cells regardless of their LRH‐1 expression levels. Together, our results suggest a novel metabolic symbiosis between different colorectal cancer stem cell subpopulations critical for maintaining their mutual stemness.
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Affiliation(s)
- Hung-Tzu Lai
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Chin-Ting Chiang
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Wen-Ko Tseng
- Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C.,Colorectal Surgery Department, Chung-Gung Memorial Hospital, Keelung Branch, Taiwan, R.O.C
| | - Ta-Chung Chao
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan, R.O.C.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, R.O.C
| | - Yeu Su
- Institute of Biopharmaceutical Sciences, School of Pharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan, R.O.C
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20
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Xu L, Chen Z, Shao K, Wang Y, Cui L, Guo N. Rational discovery of novel type-III FTF antagonists to competitively suppress TIF-2 coactivation in liver cancer. J Recept Signal Transduct Res 2019; 39:304-311. [PMID: 31755335 DOI: 10.1080/10799893.2019.1690513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Linlin Xu
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Zhongming Chen
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Keke Shao
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Yungang Wang
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Leilei Cui
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
| | - Naizhou Guo
- Department of Laboratory Medicine, The First People’s Hospital of Yancheng City, the Fourth Affiliated Hospital of Nantong University, Yancheng, China
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21
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Seitz C, Huang J, Geiselhöringer AL, Galbani-Bianchi P, Michalek S, Phan TS, Reinhold C, Dietrich L, Schmidt C, Corazza N, Delgado ME, Schnalzger T, Schoonjans K, Brunner T. The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions. SCIENCE ADVANCES 2019; 5:eaav9732. [PMID: 31328159 PMCID: PMC6636985 DOI: 10.1126/sciadv.aav9732] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 06/12/2019] [Indexed: 06/10/2023]
Abstract
LRH-1 (liver receptor homolog-1/NR5a2) is an orphan nuclear receptor, which regulates glucose and lipid metabolism, as well as intestinal inflammation via the transcriptional control of intestinal glucocorticoid synthesis. Predominantly expressed in epithelial cells, its expression and role in immune cells are presently enigmatic. LRH-1 was found to be induced in immature and mature T lymphocytes upon stimulation. T cell-specific deletion of LRH-1 causes a drastic loss of mature peripheral T cells. LRH-1-depleted CD4+ T cells exert strongly reduced activation-induced proliferation in vitro and in vivo and fail to mount immune responses against model antigens and to induce experimental intestinal inflammation. Similarly, LRH-1-deficient cytotoxic CD8+ T cells fail to control viral infections. This study describes a novel and critical role of LRH-1 in T cell maturation, functions, and immopathologies and proposes LRH-1 as an emerging pharmacological target in the treatment of T cell-mediated inflammatory diseases.
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Affiliation(s)
- Carina Seitz
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Juan Huang
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
- Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Sichuan, P.R. China
| | - Anna-Lena Geiselhöringer
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | | | - Svenja Michalek
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Truong San Phan
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Cindy Reinhold
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Lea Dietrich
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Christian Schmidt
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Nadia Corazza
- Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland
| | - M. Eugenia Delgado
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Theresa Schnalzger
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Thomas Brunner
- Division of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
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22
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Ahmed A, Schmidt C, Brunner T. Extra-Adrenal Glucocorticoid Synthesis in the Intestinal Mucosa: Between Immune Homeostasis and Immune Escape. Front Immunol 2019; 10:1438. [PMID: 31316505 PMCID: PMC6611402 DOI: 10.3389/fimmu.2019.01438] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/07/2019] [Indexed: 12/12/2022] Open
Abstract
Glucocorticoids (GCs) are steroid hormones predominantly produced in the adrenal glands in response to physiological cues and stress. Adrenal GCs mediate potent anti-inflammatory and immunosuppressive functions. Accumulating evidence in the past two decades has demonstrated other extra-adrenal organs and tissues capable of synthesizing GCs. This review discusses the role and regulation of GC synthesis in the intestinal epithelium in the regulation of normal immune homeostasis, inflammatory diseases of the intestinal mucosa, and the development of intestinal tumors.
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Affiliation(s)
- Asma Ahmed
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
- Department of Pharmacology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Christian Schmidt
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - Thomas Brunner
- Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany
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23
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A new class of protein biomarkers based on subcellular distribution: application to a mouse liver cancer model. Sci Rep 2019; 9:6913. [PMID: 31061415 PMCID: PMC6502816 DOI: 10.1038/s41598-019-43091-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/15/2019] [Indexed: 12/18/2022] Open
Abstract
To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in association with other proteins to form modules localized in particular subcellular compartments in specialized cell types and tissues. Sub-cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells. Here, we describe a strategy for tissue-biomarker detection based on a mitochondrial fold enrichment (mtFE) score, which is sensitive to protein abundance changes as well as changes in subcellular distribution between mitochondria and cytosol. The mtFE score integrates protein abundance data from total cellular lysates and mitochondria-enriched fractions, and provides novel information for the classification of cancer samples that is not necessarily apparent from conventional abundance measurements alone. We apply this new strategy to a panel of wild-type and mutant mice with a liver-specific gene deletion of Liver receptor homolog 1 (Lrh-1hep−/−), with both lines containing control individuals as well as individuals with liver cancer induced by diethylnitrosamine (DEN). Lrh-1 gene deletion attenuates cancer cell metabolism in hepatocytes through mitochondrial glutamine processing. We show that proteome changes based on mtFE scores outperform protein abundance measurements in discriminating DEN-induced liver cancer from healthy liver tissue, and are uniquely robust against genetic perturbation. We validate the capacity of selected proteins with informative mtFE scores to indicate hepatic malignant changes in two independent mouse models of hepatocellular carcinoma (HCC), thus demonstrating the robustness of this new approach to biomarker research. Overall, the method provides a novel, sensitive approach to cancer biomarker discovery that considers contextual information of tested proteins.
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24
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Liu L, Li Y, Pan B, Zhang T, Wei D, Zhu Y, Guo Y. Nr5a2 promotes tumor growth and metastasis of gastric cancer AGS cells by Wnt/beta-catenin signaling. Onco Targets Ther 2019; 12:2891-2902. [PMID: 31114234 PMCID: PMC6489909 DOI: 10.2147/ott.s201228] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/19/2019] [Indexed: 12/14/2022] Open
Abstract
Purpose: Nr5a2 (nuclear receptor subfamily 5 group A member 2, also known as LRH-1), which belongs to the NR5A (Ftz-F1) subfamily of nuclear receptors, is a key regulator in stem cell pluripotency and the development of several types of cancer. However, the data are controversial. Since Nr5a2 plays different roles in multiple types of cancer and the function of Nr5a2 in gastric cancer (GC) has not been revealed, we studied the role and molecular mechanism of Nr5a2 in GC. Methods: In this study, we have investigated the effect of Nr5a2 on tumor growth and metastasis by in vivo and in vitro models. Results: The results showed that knockdown of Nr5a2 could inhibit cell proliferation via arresting the cell cycle in the G2/M phase and suppress cell mobility through preventing the epithelial-mesenchymal transition (EMT) process in AGS cells. In addition, knockdown of Nr5a2 could suppress tumorigenesis and metastasis of AGS cells in vivo. We also demonstrated that knockdown of Nr5a2 inhibited cellular proliferation and mobility by suppressing the Wnt/beta-catenin signaling pathway. Conclusion: Nr5a2 may act as an oncogene in GC development. The EMT process and the Wnt/beta-catenin signaling pathway play an important role in the Nr5a2 induced GC development.
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Affiliation(s)
- Lei Liu
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
| | - Yan Li
- Department of General Surgery, No. 42 Hospital of PLA, Leshan, Sichuan, People's Republic of China
| | - Biran Pan
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
| | - Tongtong Zhang
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
| | - Danfeng Wei
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
| | - Yifang Zhu
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
| | - Yuanbiao Guo
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan, People's Republic of China.,The Affiliated Hospital of Southwest Jiaotong University, Chengdu, Sichuan, People's Republic of China.,The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, People's Republic of China
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25
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Meinsohn MC, Smith OE, Bertolin K, Murphy BD. The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction. Physiol Rev 2019; 99:1249-1279. [DOI: 10.1152/physrev.00019.2018] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Nuclear receptors are intracellular proteins that act as transcription factors. Proteins with classic nuclear receptor domain structure lacking identified signaling ligands are designated orphan nuclear receptors. Two of these, steroidogenic factor-1 (NR5A1, also known as SF-1) and liver receptor homolog-1 (NR5A2, also known as LRH-1), bind to the same DNA sequences, with different and nonoverlapping effects on targets. Endogenous regulation of both is achieved predominantly by cofactor interactions. SF-1 is expressed primarily in steroidogenic tissues, LRH-1 in tissues of endodermal origin and the gonads. Both receptors modulate cholesterol homeostasis, steroidogenesis, tissue-specific cell proliferation, and stem cell pluripotency. LRH-1 is essential for development beyond gastrulation and SF-1 for genesis of the adrenal, sexual differentiation, and Leydig cell function. Ovary-specific depletion of SF-1 disrupts follicle development, while LRH-1 depletion prevents ovulation, cumulus expansion, and luteinization. Uterine depletion of LRH-1 compromises decidualization and pregnancy. In humans, SF-1 is present in endometriotic tissue, where it regulates estrogen synthesis. SF-1 is underexpressed in ovarian cancer cells and overexpressed in Leydig cell tumors. In breast cancer cells, proliferation, migration and invasion, and chemotherapy resistance are regulated by LRH-1. In conclusion, the NR5A orphan nuclear receptors are nonredundant factors that are crucial regulators of a panoply of biological processes, across multiple reproductive tissues.
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Affiliation(s)
- Marie-Charlotte Meinsohn
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Olivia E. Smith
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Kalyne Bertolin
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
| | - Bruce D. Murphy
- Centre de Recherche en Reproduction et Fertilité, Université de Montréal, St-Hyacinthe, Québec, Canada
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26
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Regulation of liver receptor homologue-1 by DDB2 E3 ligase activity is critical for hepatic glucose metabolism. Sci Rep 2019; 9:5304. [PMID: 30923324 PMCID: PMC6438966 DOI: 10.1038/s41598-019-41411-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 02/07/2019] [Indexed: 02/07/2023] Open
Abstract
Liver receptor homologue-1 (LRH-1) plays a critical role in hepatic metabolism and disease. Here we show that LRH-1 protein stability is regulated by the cullin 4 (CUL4) E3 ubiquitin ligase complex. We found that DNA damage-binding protein 2 (DDB2) directly interacts with LRH-1 and functions as a substrate recognition component of CUL4-DDB1 to promote LRH-1 ubiquitination and proteasomal degradation. In human hepatoma (HepG2) cells, we observed that protein levels of endogenous LRH-1 are increased by insulin without a change in mRNA levels of LRH-1. However, overexpression of DDB2 impaired the insulin-stimulated increase in LRH-1 levels. In addition, DDB2 overexpression decreased LRH-1 transcriptional activation and expression of target genes, such as glucokinase, whereas knockdown of DDB2 increased the expression of glucokinase. Finally, we demonstrated that DDB2 knockdown increases glucose uptake and intracellular levels of glucose-6-phosphate in HepG2 cells. Our study reveals a novel regulatory mechanism of LRH-1 activity and suggests a role for DDB2 in hepatic glucose metabolism.
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27
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Ye T, Li J, Sun Z, Liu Y, Kong L, Zhou S, Tang J, Wang J, Xing HR. Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog. Cancer Med 2019; 8:1232-1245. [PMID: 30740909 PMCID: PMC6434341 DOI: 10.1002/cam4.1992] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/05/2018] [Accepted: 01/04/2019] [Indexed: 12/30/2022] Open
Abstract
Lung cancer has the highest mortality rate due to late diagnosis and high incidence of metastasis. Cancer stem cells (CSCs) are a subgroup of cancer cells with self‐renewal capability similar to that of normal stem cells (NSCs). While CSCs may play an important role in cancer progression, mechanisms underlying CSC self‐renewal and the relationship between self‐renewal of the NSCs and CSCs remain elusive. The orphan nuclear receptor Nr5a2 is a transcriptional factor, and a regulator of stemness of embryonic stem cells and induced pluripotent stem cells. However, whether Nr5a2 regulates the self‐renewal of lung CSCs is unknown. Here, we showed the diagnostic and prognostic values of elevated Nr5a2 expression in human lung cancer. We generated the mouse LLC‐SD lung carcinoma CSC cellular model in which Nr5a2 expression was enhanced. Using the LLC‐SD model, through transient and stable siRNA interference of Nr5a2 expression, we provided convincing evidence for a regulatory role of Nr5a2 in the maintenance of lung CSC self‐renewal and stem cell properties in vitro. Further, using the syngeneic and orthotopic lung transplantation model, we elucidated augmented cancer biological properties associated with Nr5a2 promotion of LLC‐SD self‐renewal. More importantly, we revealed that Nr5a2’s regulatory role in promoting LLC‐SD self‐renewal is mediated by transcriptional activation of its direct target Nanog. Taken together, in this study, we have provided convincing evidence in vitro and in vivo demonstrating that Nr5a2 can induce lung CSC properties and promote tumorigenesis and progression through transcriptional up‐regulation of Nanog.
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Affiliation(s)
- Ting Ye
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Jingyuan Li
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Zhiwei Sun
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Yongli Liu
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Liangsheng Kong
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Shixia Zhou
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Junlin Tang
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Jianyu Wang
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - H Rosie Xing
- Laboratory of Translational Cancer Stem Cell Research, Institute of Life Sciences, Chongqing Medical University, Chongqing, China.,College of Biomedical Engineering, State Key Laboratory of Ultrasound Engineering in Medicine, Chongqing Medical University, Chongqing, China
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28
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Liu Y, Xing Y, Wang H, Yan S, Wang X, Cai L. LRH1 as a promising prognostic biomarker and predictor of metastasis in patients with non-small cell lung cancer. Thorac Cancer 2018; 9:1725-1732. [PMID: 30273983 PMCID: PMC6275822 DOI: 10.1111/1759-7714.12887] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/04/2018] [Accepted: 09/06/2018] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND LRH1, which promotes the malignant transformation of carcinoma, has recently been documented in several types of malignancies. However, LRH1 has not been assessed as a potential clinical biomarker in any cancer. METHODS LRH1 expression was tested in fresh-frozen tissue samples with quantitative real-time PCR and Western blot analysis. Surgically resected tumor tissues were collected from 156 non-small cell lung cancer (NSCLC) patients: 75 with adenocarcinoma and 81 with squamous cell carcinoma. Subsequently, the immunohistochemical expression of LRH1 was examined, and its clinical significance was evaluated. RESULTS LRH1 overexpression was observed in NSCLC carcinoma tissues compared to adjacent normal lung tissues. LRH1 expression was correlated with poorer differentiation (P = 0.023), pathological tumor classification (P < 0.001), advanced pathological tumor node metastasis stage (P = 0.017), adenocarcinoma subtype (P = 0.031), and positive lymph node metastasis (P < 0.001). Multivariate analysis demonstrated that LRH1 expression status was an independent prognostic factor for overall (hazard ratio 1.372, 95% confidence interval 1.225-1.617; P = 0.003) and disease-free survival (hazard ratio 1.497, 95% confidence interval 1.059-2.115; P = 0.011) in patients who suffered from resectable NSCLC. CONCLUSION The results of our study indicate that LRH1 predicts NSCLC progression, metastasis, and a dismal prognosis, emphasizing its promising role as a novel target in NSCLC therapies.
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Affiliation(s)
- Yuechao Liu
- The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Ying Xing
- The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Hongmei Wang
- Department of PathologyHarbin Medical University Cancer HospitalHarbinChina
| | - Shi Yan
- The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Xinzhu Wang
- The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Li Cai
- The Fourth Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
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29
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Macchini M, Chiaravalli M, Zanon S, Peretti U, Mazza E, Gianni L, Reni M. Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. Cancer Treat Rev 2018; 72:1-6. [PMID: 30414985 DOI: 10.1016/j.ctrv.2018.10.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/27/2018] [Indexed: 12/27/2022]
Abstract
By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.
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Affiliation(s)
- Marina Macchini
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Marta Chiaravalli
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Silvia Zanon
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Umberto Peretti
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Elena Mazza
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Luca Gianni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
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30
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Xiao L, Wang Y, Liang W, Liu L, Pan N, Deng H, Li L, Zou C, Chan FL, Zhou Y. LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21. Cancer Manag Res 2018; 10:2389-2400. [PMID: 30122988 PMCID: PMC6078084 DOI: 10.2147/cmar.s162887] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background To explore potential therapeutic target is one of the areas of great interest in both clinical and basic hepatocellular carcinoma (HCC) studies. Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is proved to play a positive role in several cancers including breast cancer, pancreatic cancer and intestinal cancer in recent years. However, the exact role of LRH-1 in the development and progression of HCC is not fully elucidated. Methods The LRH-1 expression level in HCC clinical samples was examined by immunohis-tochemistry (IHC). Stable LRH-1-suppressed HepG2 clones (HepG2LRH-1/-) were generated by transcription activator-like effector nucleases (TALENs) and both in vitro and in vivo experiments were conducted. Results We confirmed that LRH-1 showed an increased expression pattern in HCC clinical samples. Our in vitro and in vivo results indicated that suppression of LRH-1 in HepG2 significantly attenuated its proliferation rate and tumorigenic capacity. Gene expression microarray analysis indicated that LRH-1mostly regulated gene expression involved in cell cycle. In addition, our gain-of-function experiments indicated that ectopic expression of LRH-1 dramatically induced the mRNA and protein levels of c-myc and cyclin E1, while attenuating the expression of p21. Conclusion Our results suggest that LRH-1 might be a potential therapeutic target for clinical HCC treatment.
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Affiliation(s)
- Lijia Xiao
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China, .,Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical University, Shenzhen, China
| | - Yuliang Wang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,
| | - Weicheng Liang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,
| | - Liping Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China
| | - Nannan Pan
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China,
| | - Huimin Deng
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China,
| | - Luqian Li
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China,
| | - Chang Zou
- Clinical Medicine Research Center, Shenzhen Public Service Platform of Precision Medicine and Molecular Diagnosis on Tumor, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China
| | - Franky Leung Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China,
| | - Yiwen Zhou
- Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China,
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Jiang X, Yang Z. Multiple biological functions of transcription factor 21 in the development of various cancers. Onco Targets Ther 2018; 11:3533-3539. [PMID: 29950858 PMCID: PMC6016277 DOI: 10.2147/ott.s164033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Transcription factor 21 (TCF21) is a basic helix–loop–helix transcription factor that binds to DNA and regulates cell differentiation and cell fate specification through mesenchymal–epithelial transition during development. The TCF21 gene is epigenetically inactivated in many types of human cancers and exerts a wide variety of functions, including the regulation of epithelial–mesenchymal transition, invasion, metastasis, cell cycle, and autophagy. This review focuses on research progress in relation to the roles of TCF21 in tumor development. We systematically consider multiple pathological functions of TCF21 in various cancers, revealing the molecular bases of its diverse biological roles and providing new directions for future research.
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Affiliation(s)
- Xiaodi Jiang
- Department of Infectious Disease, The Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhi Yang
- Department of Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, China
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32
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Wu C, Feng J, Li L, Wu Y, Xie H, Yin Y, Ye J, Li Z. Liver receptor homologue 1, a novel prognostic marker in colon cancer patients. Oncol Lett 2018; 16:2833-2838. [PMID: 30127869 PMCID: PMC6096149 DOI: 10.3892/ol.2018.8988] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 04/13/2018] [Indexed: 01/31/2023] Open
Abstract
Liver receptor homologue 1 (LRH-1) is an orphan nuclear receptor that is highly expressed in a variety of cancer tissues, promotes tumor cell proliferation and metastasis, and is involved in the tumor cell cycle and apoptosis. The aim of the present study was to assess the association between the expression of LRH-1 and the prognosis of patients with colon cancer. Immunohistochemistry was used to detect the expression of LRH1 in 128 cases of colon cancer and adjacent tissues. The 5-year survival rate was obtained from telephone follow-up data, outpatient review and through access to medical records. Positive expression of LRH-1 was found in 108/128 colon cancer samples, compared with 17/128 normal tissues. Statistical analysis showed that positive LRH-1 expression was significantly associated with clinical pathological stage, depth of invasion and lymph node metastasis. The overall survival (OS) rate of patients with positive LRH-1 expression was significantly lower than that of patients with low expression. Multivariate analysis showed that LRH-1 expression could be used as an independent predictor of OS. In conclusion, the present findings suggest that LRH-1 may serve an important role in the development and progression of colon cancer, with potential value as a prognostic molecular marker that could be used to assist in the diagnosis and evaluation of colon cancer. LRH-1 may become a target for novel therapies for patients with colon cancer.
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Affiliation(s)
- Cong Wu
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Jin Feng
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Ling Li
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Yugang Wu
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Haibin Xie
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Yong Yin
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Jing Ye
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
| | - Zhong Li
- Department of General Surgery, The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, P.R. China
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33
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Chen Q, Yuan H, Shi GD, Wu Y, Liu DF, Lin YT, Chen L, Ge WL, Jiang K, Miao Y. Association between NR5A2 and the risk of pancreatic cancer, especially among Caucasians: a meta-analysis of case-control studies. Onco Targets Ther 2018; 11:2709-2723. [PMID: 29785120 PMCID: PMC5953269 DOI: 10.2147/ott.s157759] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Previous studies have reported that nuclear receptor subfamily 5, group A, member 2 (NR5A2) polymorphisms (rs3790843 G>A, rs3790844 T>C, rs12029406 C>T) are associated with the risk of pancreatic cancer. However, the results of epidemiological investigations are still controversial. In order to explore its potential attributing factors, we pooled the updated literatures to evaluate the association between NR5A2 polymorphism and the risk of pancreatic cancer in this meta-analysis. Materials and methods Databases such as PubMed, Google Scholar and China National Knowledge Infrastructure were searched for eligible articles following strict inclusion and exclusion criteria (updated to November 18, 2017). Odds ratios (ORs) and 95% CIs were computed to assess the intensity of association. In addition, heterogeneity, sensitivity analysis and publication bias were explored. All statistical analyses were conducted by STATA 14.0. Results Our results showed that the rs3790843 (GA vs GG: OR=0.86, CI=0.76–0.98, P=0.992; GA+AA vs GG: OR=0.83, CI=0.73–0.94, P=0.950; A vs G: OR=0.85, CI=0.78–0.93, P=0.802), rs3790844 (CC vs TT: OR=0.65, CI=0.54–0.78, P=0.617; CC vs TT+CT: OR=0.73, CI=0.62–0.85, P=0.742; C vs T: OR=0.78, CI=0.73–0.84, P=0.555) and rs12029406 (TT vs CC: OR=0.73, CI=0.61–0.89, P=0.483; TT vs CC+CT: OR=0.78, CI=0.66–0.92, P=0.648; T vs C: OR=0.87, CI=0.79–0.95, P=0.837) polymorphisms were associated statistically with the risk of pancreatic cancer. Furthermore, the results of subgroup analysis showed that rs3790843 and rs3790844 polymorphisms were especially related to the risk of pancreatic cancer in Caucasian population. Conclusion Our results revealed that NR5A2 may have a protective effect on pancreatic cancer. However, more well-designed researches are needed to verify the relationship between NR5A2 polymorphisms and the risk of pancreatic cancer.
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Affiliation(s)
- Qun Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Hao Yuan
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Guo-Dong Shi
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yang Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China.,Division of Pancreatic Surgery, Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians University, Munich, Germany
| | - Dong-Fang Liu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yu-Ting Lin
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Lei Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Wan-Li Ge
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Pancreas Institute, Nanjing Medical University, Nanjing, China
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34
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LRH1 enhances cell resistance to chemotherapy by transcriptionally activating MDC1 expression and attenuating DNA damage in human breast cancer. Oncogene 2018; 37:3243-3259. [DOI: 10.1038/s41388-018-0193-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 01/30/2018] [Accepted: 02/02/2018] [Indexed: 11/08/2022]
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35
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Naqvi AAT, Hasan GM, Hassan MI. Investigating the role of transcription factors of pancreas development in pancreatic cancer. Pancreatology 2018; 18:184-190. [PMID: 29289465 DOI: 10.1016/j.pan.2017.12.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 11/20/2017] [Accepted: 12/22/2017] [Indexed: 02/08/2023]
Abstract
Pancreatic cancer (PC) is the seventh most common cause of cancer-related deaths worldwide that kills more than 300,000 people every year. Prognosis of PC is very poor with a five-year survival rate about 5%. The most common and highly observed type of PC is pancreatic ductal adenocarcinoma (PDAC). It is preceded by the progression of precursor lesions such as Pancreatic Intraepithelial Neoplasia (PanIN), Intraductal Papillary Neoplasm (IPMN) and Mucinous Cystic Neoplasm (MCN). PanIN is the most common among these premalignant lesions. Genes orchestrating the origin and differentiation of cells during organogenesis have the tendency to produce tumor cells in response to activating or inactivating mutations. Based on the following premise, we discuss the role of transcription factors (TFs) of pancreas development and cell fate differentiation in PC. Pancreas/duodenum homeobox protein 1 (PDX1), Pancreas transcription factor 1 subunit alpha (PTF1A), Nuclear receptor subfamily 5 group A member 2 (NR5A2), Hepatocyte nuclear factor 1-alpha (HNF1A) and Hepatocyte nuclear factor 1-beta (HNF1B) play vital role in the development and differentiation of pancreatic precursor cells. Mutated KRAS induces abnormalities in the regular function of these TFs which in turn cause abnormal cell growth and proliferation that leads to cancer. Thus, these TFs are highly susceptible for the origin of PC. Therefore, we propose that these TFs can be treated as therapeutic targets for the development of anticancer drugs.
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Affiliation(s)
- Ahmad Abu Turab Naqvi
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Gulam Mustafa Hasan
- Department of Biochemistry, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Science, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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36
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Xiao L, Wang Y, Xu K, Hu H, Xu Z, Wu D, Wang Z, You W, Ng CF, Yu S, Chan FL. Nuclear Receptor LRH-1 Functions to Promote Castration-Resistant Growth of Prostate Cancer via Its Promotion of Intratumoral Androgen Biosynthesis. Cancer Res 2018; 78:2205-2218. [PMID: 29438990 DOI: 10.1158/0008-5472.can-17-2341] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/27/2017] [Accepted: 02/05/2018] [Indexed: 11/16/2022]
Abstract
Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1-mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205-18. ©2018 AACR.
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Affiliation(s)
- Lijia Xiao
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.,Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Yuliang Wang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Kexin Xu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Hao Hu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Zhenyu Xu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Dinglan Wu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Zhu Wang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Wenxing You
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China
| | - Chi-Fai Ng
- Department of Surgery, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Shan Yu
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
| | - Franky Leung Chan
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
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37
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Cuomo D, Porreca I, Cobellis G, Tarallo R, Nassa G, Falco G, Nardone A, Rizzo F, Mallardo M, Ambrosino C. Carcinogenic risk and Bisphenol A exposure: A focus on molecular aspects in endoderm derived glands. Mol Cell Endocrinol 2017; 457:20-34. [PMID: 28111205 DOI: 10.1016/j.mce.2017.01.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Epidemiological and experimental evidence associates the exposure to Bisphenol A with the increase of cancer risk in several organs, including prostate. BPA targets different pathways involved in carcinogenicity including the Nuclear Receptors (i.e. estrogen and androgen receptors), stress regulated proteins and, finally, epigenetic changes. Here, we analyse BPA-dependent carcinogenesis in endoderm-derived glands, thyroid, liver, pancreas and prostate focusing on cell signalling, DNA damage repair pathways and epigenetic modifications. Mainly, we gather molecular data evidencing harmful effects at doses relevant for human risk (low-doses). Since few molecular data are available, above all for the pancreas, we analysed transcriptomic data generated in our laboratory to suggest possible mechanisms of BPA carcinogenicity in endoderm-derived glands, discussing the role of nuclear receptors and stress/NF-kB pathways. We evidence that an in vitro toxicogenomic approach might suggest mechanisms of toxicity applicable to cells having the same developmental origin. Although we cannot draw firm conclusions, published data summarized in this review suggest that exposure to BPA, primarily during the developmental stages, represents a risk for carcinogenesis of endoderm-derived glands.
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Affiliation(s)
- Danila Cuomo
- IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy; Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy
| | | | - Gilda Cobellis
- Department of Experimental Medicine, Sez. Bozzatti, II University of Naples, 80138 Napoli, Italy
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy; Genomix4Life srl, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, Italy
| | - Geppino Falco
- Department of Biology, University of Naples "Federico II", Napoli, Italy
| | - Antonio Nardone
- Department of Public Health, University of Naples "Federico II", Napoli, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Massimo Mallardo
- Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Napoli, Italy
| | - Concetta Ambrosino
- Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
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38
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Qu R, Hao S, Jin X, Shi G, Yu Q, Tong X, Guo D. MicroRNA-374b reduces the proliferation and invasion of colon cancer cells by regulation of LRH-1/Wnt signaling. Gene 2017; 642:354-361. [PMID: 29128635 DOI: 10.1016/j.gene.2017.11.019] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/28/2017] [Accepted: 11/07/2017] [Indexed: 02/07/2023]
Abstract
Deregulation of microRNA (miRNA) has been suggested as a critical event in colon cancer development and progression. Recent studies have suggested that miR-374b is a novel cancer-related miRNA involved in several cancer types. Thus far, very little is known about the role of miR-374b in colon cancer; therefore, the goal of this study was to investigate the potential role of miR-374b in colon cancer. Here, we showed that miR-374b expression was significantly downregulated in colon cancer tissues and cell lines. Overexpression of miR-374b inhibited the proliferation and invasion of colon cancer cells, while miR-374b suppression promoted colon cancer cell proliferation and invasion. Liver receptor homolog-1 (LRH-1) was identified as a target of miR-374b in colon cancer cells. Both the mRNA and protein expression of LRH-1 were regulated by miR-374b. In addition, an inverse correlation between LRH-1 mRNA and miR-374b expression was evidenced in colon cancer specimens. Notably, overexpression of miR-374b also downregulated the Wnt signaling in colon cancer cells. Furthermore, restoration of LRH-1 expression significantly abolished the antitumor effect of miR-374b in colon cancer cells. These findings suggest that miR-374b inhibits colon cancer cell proliferation and invasion through downregulation of LRH-1 expression. Inhibiting LRH-1 by miR-374b may represent a novel therapeutic strategy for the treatment of colon cancer.
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Affiliation(s)
- Rongfeng Qu
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China
| | - Shuhong Hao
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China
| | - Xianmei Jin
- Department of Pediatric Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Guang Shi
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China
| | - Qiong Yu
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China
| | - Xianshuang Tong
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China
| | - Dongrui Guo
- Department of Hematology and Oncology, The Second Hospital of Jilin University, Changchun, Jilin 130022, China.
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39
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LRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness. Oncotarget 2017; 8:83626-83636. [PMID: 29137369 PMCID: PMC5663541 DOI: 10.18632/oncotarget.18886] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 05/12/2017] [Indexed: 11/25/2022] Open
Abstract
The significance and regulation of liver receptor homologue 1 (LRH-1, NR5A2), a tumour-promoting transcription factor in breast cancer cell lines, is unknown in clinical breast cancers. This study aims to determine LRH-1/NR5A2 expression in breast cancers and relationship with DNA methylation and tumour characteristics. In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036). LRH-1 immunohistochemistry of 329 invasive carcinomas and ductal carcinoma in situ (DCIS) was performed. Densely punctate/coarsely granular nuclear reactivity was significantly associated with high tumour grade (p<0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively). These significant associations of LRH-1 protein expression with tumour phenotype suggest that LRH-1 is an important indicator of tumour biology in breast cancers and may be useful in risk stratification.
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40
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Yuan Q, Cao G, Li J, Zhang Y, Yang W. MicroRNA-136 inhibits colon cancer cell proliferation and invasion through targeting liver receptor homolog-1/Wnt signaling. Gene 2017; 628:48-55. [PMID: 28710032 DOI: 10.1016/j.gene.2017.07.031] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022]
Abstract
An increasing number of studies have reported that microRNAs (miRNAs) are involved in the malignant behavior of colon cancer cells through directly targeting multiple tumor suppressors or oncogenes. The expression and role of miR-136 has been reported in several types of human cancer. However, the role of miR-136 in colon cancer remains unclear. In this study, we aimed to investigate the expression and function of miR-136 in colon cancer and the potential underlying mechanism. Here, we found that miR-136 was decreased in colon cancer cell lines and tissues. Overexpression of miR-136 inhibited the proliferation and invasion in SW480 and HCT116 cell lines while suppression of miR-136 exhibited the opposite effect. Liver receptor homolog-1 (LRH-1) was identified as a direct target gene of miR-136. Notably, miR-136 overexpression suppressed LRH-1 expression as well as Wnt signaling in SW480 and HCT116 cell lines. The miR-136 expression level inversely correlated with LRH-1 mRNA expression in colon cancer specimens. Moreover, overexpression of LRH-1 partially reversed the miR-136-induced antitumor effect in SW480 and HCT116 cell lines. Taken together, these findings suggest that miR-136 functions as a negative regulator in colon cancer progression by targeting LRH-1 and that miR-136 downregulation contributes to high expression of LRH-1 and aberrant activation of Wnt signaling, leaving open the possibility that miR-136 may serve as a potential therapeutic target for colon cancer.
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Affiliation(s)
- Qinggong Yuan
- Department of General Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710004, China
| | - Gang Cao
- Department of General Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710004, China
| | - Junhui Li
- Department of General Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710004, China
| | - Yan Zhang
- Department of General Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710004, China
| | - Wenbin Yang
- Department of General Surgery, The Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an 710004, China.
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41
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Neto M, Naval-Sánchez M, Potier D, Pereira PS, Geerts D, Aerts S, Casares F. Nuclear receptors connect progenitor transcription factors to cell cycle control. Sci Rep 2017; 7:4845. [PMID: 28687780 PMCID: PMC5501803 DOI: 10.1038/s41598-017-04936-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 05/23/2017] [Indexed: 01/31/2023] Open
Abstract
The specification and growth of organs is controlled simultaneously by networks of transcription factors. While the connection between these transcription factors with fate determinants is increasingly clear, how they establish the link with the cell cycle is far less understood. Here we investigate this link in the developing Drosophila eye, where two transcription factors, the MEIS1 homologue hth and the Zn-finger tsh, synergize to stimulate the proliferation of naïve eye progenitors. Experiments combining transcriptomics, open-chromatin profiling, motif analysis and functional assays indicate that these progenitor transcription factors exert a global regulation of the proliferation program. Rather than directly regulating cell cycle genes, they control proliferation through an intermediary layer of nuclear receptors of the ecdysone/estrogen-signaling pathway. This regulatory subnetwork between hth, tsh and nuclear receptors might be conserved from Drosophila to mammals, as we find a significant co-overexpression of their human homologues in specific cancer types.
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Affiliation(s)
- Marta Neto
- CABD, Andalusian Centre for Developmental Biology, CSIC-UPO-JA, 41013, Seville, Spain.,i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | | | - Delphine Potier
- School of Medicine, University of Leuven, box 602 3000, Leuven, Belgium
| | - Paulo S Pereira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal.,IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - Dirk Geerts
- Department of Medical Biology L2-109, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stein Aerts
- School of Medicine, University of Leuven, box 602 3000, Leuven, Belgium.
| | - Fernando Casares
- CABD, Andalusian Centre for Developmental Biology, CSIC-UPO-JA, 41013, Seville, Spain.
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42
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Zhai G, Song J, Shu T, Yan J, Jin X, He J, Yin Z. LRH-1 senses signaling from phosphatidylcholine to regulate the expansion growth of digestive organs via synergy with Wnt/β-catenin signaling in zebrafish. J Genet Genomics 2017. [PMID: 28642062 DOI: 10.1016/j.jgg.2017.03.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor that is critical for the growth and proliferation of cancer cells and other biological processes, including lipid transportation and metabolism, sexual determination and steroidogenesis. However, because homozygous lrh-1-/- mice die in utero, the regulatory mechanisms involved in embryonic development mediated by this receptor are poorly understood. In the present study, we performed transcription activator-like effector nuclease (TALEN)-mediated loss-of-function assays, taking advantage of zebrafish external fertilization, to investigate the function of lrh-1. The digestive organs were affected by lrh-1 depletion as a result of cell-cycle arrest (at the checkpoint of G1 to S phase), but not cell apoptosis. Biochemical analysis revealed that LRH-1 augments the transcriptional activity of β-catenin 1 and 2 via physical interactions. Screening the specific ligand(s) sensed by LRH-1 during organogenesis revealed that phosphatidylcholine (PC), a potential ligand, is the upstream target of LRH-1 during endoderm development. These data provide evidence for the crosstalk between the PC/LRH-1 and Wnt/β-catenin signaling pathways during the expansion growth of endoderm organs.
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Affiliation(s)
- Gang Zhai
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Jia Song
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Tingting Shu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Junjun Yan
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of the Chinese Academy of Sciences, Beijing 100049, China
| | - Xia Jin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Jiangyan He
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Zhan Yin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
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Xu P, Oosterveer MH, Stein S, Demagny H, Ryu D, Moullan N, Wang X, Can E, Zamboni N, Comment A, Auwerx J, Schoonjans K. LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev 2017; 30:1255-60. [PMID: 27298334 PMCID: PMC4911925 DOI: 10.1101/gad.277483.116] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/12/2016] [Indexed: 11/30/2022]
Abstract
Xu et al. identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamine-induced metabolism and signaling to promote hepatocellular carcinogenesis.
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Affiliation(s)
- Pan Xu
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Maaike H Oosterveer
- Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, NL-9700 RB Groningen, The Netherlands
| | - Sokrates Stein
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Hadrien Demagny
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Dongryeol Ryu
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Norman Moullan
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Xu Wang
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Emine Can
- Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Nicola Zamboni
- Department of Biology, Institute for Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zurich, Switzerland
| | - Arnaud Comment
- Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
| | - Kristina Schoonjans
- Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
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44
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Fletterick R. NR5A2 discovering compounds that block tumor growth in PDAC. J Surg Oncol 2017; 116:89-93. [PMID: 28445593 DOI: 10.1002/jso.24639] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 03/22/2017] [Indexed: 11/08/2022]
Abstract
Pancreatic cancers depend on driver molecules, oncogene proteins such as RAS. NR5A2 protein is a transcription factor and either activates or inhibits transcription through actions at hundreds of enhancers. It has unusual properties with effects appearing in multiple signaling networks. NR5A2 is a pluripotency reprogramming factor in the class nuclear receptor. Its controlling hormone is PIP3. Experiments suggest NR5A2 activation drives PDAC and inhibitors blunt cancer cell proliferation.
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Affiliation(s)
- Robert Fletterick
- Department of Biochemistry, School of Medicine, UCSF, San Francisco, California
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45
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Yan L, Qiu J, Yao J. Downregulation of microRNA-30d promotes cell proliferation and invasion by targeting LRH-1 in colorectal carcinoma. Int J Mol Med 2017; 39:1371-1380. [PMID: 28440426 PMCID: PMC5428944 DOI: 10.3892/ijmm.2017.2958] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 04/03/2017] [Indexed: 12/13/2022] Open
Abstract
The aberrant expression of miR-30d has been reported in several types of human malignancies. However, its biological function in colorectal cancer (CRC) remains largely unknown. In this study, we identified that miR-30d was significantly downregulated in CRC tissues compared to that observed in normal controls as detected by RT-qPCR analysis. Downregulation of miR-30d was significantly associated with aggressive clinicopathological parameters including tumor differentiation, invasive depth, TNM stage, lymph node metastasis, distant metastasis, and poor prognosis. Furthermore, functional analysis revealed that overexpression of miR-30d significantly inhibited cell proliferation, caused cell cycle arrest at the G0/G1 phase, suppressed cell migration and invasion, induced cell apoptosis in vitro, and decreased tumor growth in a xenograft mouse model. Bioinformatic analysis and dual-luciferase reporter assay revealed that liver receptor homologue-1 (LRH-1) is a direct target of miR-30d in CRC cells. Rescue assay showed that LRH-1 overexpression could restore the inhibitory effect of miR-30d on CRC cells. In addition, miR-30d overexpression suppressed the activation of key components of the Wnt/β-catenin signaling pathway, β-catenin, c-Myc and cyclin D1, which contributed to the inhibition of CRC development. Thus, our findings suggest that miR-30d functions as a tumor suppressor against CRC development and miR-30d/LRH-1/Wnt signaling may be novel potential targets for CRC treatment.
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Affiliation(s)
- Likun Yan
- Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Jian Qiu
- Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Jianfeng Yao
- Department of General Surgery, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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46
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Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions. Cell Death Dis 2017; 8:e2745. [PMID: 28406481 PMCID: PMC5477591 DOI: 10.1038/cddis.2017.173] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/16/2017] [Accepted: 03/17/2017] [Indexed: 01/25/2023]
Abstract
CD95/Fas ligand (FasL) is a cell death-promoting member of the tumor necrosis factor family with important functions in the regulation of T-cell homeostasis and cytotoxicity. In T cells, FasL expression is tightly regulated on a transcriptional level involving a complex set of different transcription factors. The orphan nuclear receptor liver receptor homolog-1 (LRH-1/NR5a2) is involved in the regulation of development, lipid metabolism and proliferation and is predominantly expressed in epithelial tissues. However, its expression in T lymphocytes has never been reported so far. Based on in silico analysis, we identified potential LRH-1 binding sites within the FASLG promoter. Here, we report that LRH-1 is expressed in primary and secondary lymphatic tissues, as well as in CD4+ and CD8+ T cells. LRH-1 directly binds to its binding sites in the FASLG promoter, and thereby drives FASLG promoter activity. Mutations in the LRH-1 binding sites reduce FASLG promoter activity. Pharmacological inhibition of LRH-1 decreases activation-induced FasL mRNA expression, as well as FasL-mediated activation-induced T-cell apoptosis and T-cell cytotoxicity. In a mouse model of Concanavalin A-induced and FasL-mediated hepatitis pharmacological inhibition of LRH-1 resulted in decreased hepatic FasL expression and a significant reduction of liver damage. In summary, these data show for the first time LRH-1 expression in T cells, its role in FASLG transcription and the potential of pharmacological inhibition of LRH-1 in the treatment of FasL-mediated immunopathologies.
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47
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Larsen HL, Grapin-Botton A. The molecular and morphogenetic basis of pancreas organogenesis. Semin Cell Dev Biol 2017; 66:51-68. [PMID: 28089869 DOI: 10.1016/j.semcdb.2017.01.005] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/06/2017] [Accepted: 01/09/2017] [Indexed: 01/08/2023]
Abstract
The pancreas is an essential endoderm-derived organ that ensures nutrient metabolism via its endocrine and exocrine functions. Here we review the essential processes governing the embryonic and early postnatal development of the pancreas discussing both the mechanisms and molecules controlling progenitor specification, expansion and differentiation. We elaborate on how these processes are orchestrated in space and coordinated with morphogenesis. We draw mainly from experiments conducted in the mouse model but also from investigations in other model organisms, complementing a recent comprehensive review of human pancreas development (Jennings et al., 2015) [1]. The understanding of pancreas development in model organisms provides a framework to interpret how human mutations lead to neonatal diabetes and may contribute to other forms of diabetes and to guide the production of desired pancreatic cell types from pluripotent stem cells for therapeutic purposes.
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Affiliation(s)
- Hjalte List Larsen
- DanStem, University of Copenhagen, 3 B Blegdamsvej, DK-2200 Copenhagen N, Denmark
| | - Anne Grapin-Botton
- DanStem, University of Copenhagen, 3 B Blegdamsvej, DK-2200 Copenhagen N, Denmark.
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48
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Luo Z, Li Y, Zuo M, Liu C, Tian W, Yan D, Wang H, Li D. Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers. Mol Carcinog 2017; 56:1438-1448. [PMID: 27996162 DOI: 10.1002/mc.22604] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 12/02/2016] [Accepted: 12/15/2016] [Indexed: 01/06/2023]
Abstract
NR5A2 (aka LRH-1) has been identified as a pancreatic cancer susceptibility gene with missing biological link. This study aims to demonstrate expression and potential role of NR5A2 in pancreatic cancer. NR5A2 expression was quantified in resected pancreatic ductal adenocarcinomas and the normal adjacent tissues of 134 patients by immunohistochemistry. The intensity and extent of NR5A2 staining was quantified and analyzed in association with overall survival (OS). The impact of NR5A2 knockdown on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers was examined in cancer cells using RT-PCR and Western Blot. NR5A2 was overexpressed in pancreatic tumors, the IHC-staining H score (mean ± SE) was 96.4 ± 8.3 in normal versus 137.9 ± 8.2 in tumor tissues (P < 0.0001). Patients with a higher NR5A2 expression had a median survival time 18.4 months compared to 23.7 months for those with low IHC H scores (P = 0.019). The hazard ratio of death (95% confidence interval) was 1.60 (1.07-2.41) after adjusting for disease stage and tumor grade (P = 0.023). NR5A2 was highly expressed in pancreatic cancer sphere forming cells. NR5A2-inhibition by siRNA was associated with reduced sphere formation and decreased levels of CSCs markers NANOG, OCT4, LIN28B, and NOTCH1. NR5A2 knockdown also resulted in reduced expression of FGB, MMP2, MMP3, MMMP9, SNAIL, and TWIST, increased expression of epithelial markers E-cadherin and β-catenin, and a lower expression of mesenchymal marker Vimentin. Taken together, our findings suggest that NR5A2 could play a role in CSC stemness and EMT in pancreatic cancer, which may contribute to the worse clinical outcome.
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Affiliation(s)
- Zhaofan Luo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yanan Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mingxin Zuo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Chang Liu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Dong Yan
- Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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49
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Li C, Dong J, Han Z, Zhang K. MicroRNA-219-5p Represses the Proliferation, Migration, and Invasion of Gastric Cancer Cells by Targeting the LRH-1/Wnt/β-Catenin Signaling Pathway. Oncol Res 2016; 25:617-627. [PMID: 27983934 PMCID: PMC7841075 DOI: 10.3727/096504016x14768374457986] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) are reportedly involved in gastric cancer development and progression. In particular, miR-219-5p has been reported to be a tumor-associated miRNA in human cancer. However, the role of miR-219-5p in gastric cancer remains unclear. In this study, we investigated for the first time the potential role and underlying mechanism of miR-219-5p in the proliferation, migration, and invasion of human gastric cancer cells. miR-219-5p was found to be markedly decreased in gastric cancer tissues and cell lines compared with adjacent tissues and normal gastric epithelial cells. miR-219-5p mimics or anti-miR-219-5p was transfected into gastric cancer cell lines to overexpress or suppress miR-219-5p expression, respectively. Results showed that miR-219-5p overexpression significantly decreased the proliferation, migration, and invasion of gastric cancer cells. Conversely, miR-219-5p suppression demonstrated a completely opposite effect. Bioinformatics and luciferase reporter assays indicated that miR-219-5p targeted the 3′-untranslated region of the liver receptor homolog-1 (LRH-1), a well-characterized oncogene. Furthermore, miR-219-5p inhibited the mRNA and protein levels of LRH-1. LRH-1 mRNA expression was inversely correlated with miR-219-5p expression in gastric cancer tissues. miR-219-5p overexpression significantly decreased the Wnt/β-catenin signaling pathway in gastric cancer cells. Additionally, LRH-1 restoration can markedly reverse miR-219-5p-mediated tumor suppressive effects. Our study suggests that miR-219-5p regulated the proliferation, migration, and invasion of human gastric cancer cells by suppressing LRH-1. miR-219-5p may be a potential target for gastric cancer therapy.
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Affiliation(s)
- Chunsheng Li
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, P.R. China
| | - Jingrong Dong
- Endoscopic Center, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, P.R. China
| | - Zhenqi Han
- Endoscopic Center, The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, P.R. China
| | - Kai Zhang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China
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50
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Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, Hautman C, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, Kamineni A, Kolonel LN, Kulke MH, Malats N, Olson SH, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Brais L, Bueno-de-Mesquita HB, Basso D, Berndt SI, Boutron-Ruault MC, Bijlsma MF, Brenner H, Burdette L, Campa D, Caporaso NE, Capurso G, Cavestro GM, Cotterchio M, Costello E, Elena J, Boggi U, Gaziano JM, Gazouli M, Giovannucci EL, Goggins M, Gross M, Haiman CA, Hassan M, Helzlsouer KJ, Hu N, Hunter DJ, Iskierka-Jazdzewska E, Jenab M, Kaaks R, Key TJ, Khaw KT, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, Landi MT, Landi S, Marchand LL, Mambrini A, Mannisto S, Milne RL, Neale RE, Oberg AL, Panico S, Patel AV, Peeters PHM, Peters U, Pezzilli R, Porta M, Purdue M, Quiros JR, Riboli E, Rothman N, Scarpa A, Scelo G, Shu XO, Silverman DT, Soucek P, Strobel O, Sund M, Małecka-Panas E, Taylor PR, Tavano F, Travis RC, Thornquist M, Tjønneland A, Tobias GS, et alZhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, Figlioli G, Mocci E, Collins I, Chung CC, Hautman C, Arslan AA, Beane-Freeman L, Bracci PM, Buring J, Duell EJ, Gallinger S, Giles GG, Goodman GE, Goodman PJ, Kamineni A, Kolonel LN, Kulke MH, Malats N, Olson SH, Sesso HD, Visvanathan K, White E, Zheng W, Abnet CC, Albanes D, Andreotti G, Brais L, Bueno-de-Mesquita HB, Basso D, Berndt SI, Boutron-Ruault MC, Bijlsma MF, Brenner H, Burdette L, Campa D, Caporaso NE, Capurso G, Cavestro GM, Cotterchio M, Costello E, Elena J, Boggi U, Gaziano JM, Gazouli M, Giovannucci EL, Goggins M, Gross M, Haiman CA, Hassan M, Helzlsouer KJ, Hu N, Hunter DJ, Iskierka-Jazdzewska E, Jenab M, Kaaks R, Key TJ, Khaw KT, Klein EA, Kogevinas M, Krogh V, Kupcinskas J, Kurtz RC, Landi MT, Landi S, Marchand LL, Mambrini A, Mannisto S, Milne RL, Neale RE, Oberg AL, Panico S, Patel AV, Peeters PHM, Peters U, Pezzilli R, Porta M, Purdue M, Quiros JR, Riboli E, Rothman N, Scarpa A, Scelo G, Shu XO, Silverman DT, Soucek P, Strobel O, Sund M, Małecka-Panas E, Taylor PR, Tavano F, Travis RC, Thornquist M, Tjønneland A, Tobias GS, Trichopoulos D, Vashist Y, Vodicka P, Wactawski-Wende J, Wentzensen N, Yu H, Yu K, Zeleniuch-Jacquotte A, Kooperberg C, Risch HA, Jacobs EJ, Li D, Fuchs C, Hoover R, Hartge P, Chanock SJ, Petersen GM, Stolzenberg-Solomon RS, Wolpin BM, Kraft P, Klein AP, Canzian F, Amundadottir LT. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget 2016; 7:66328-66343. [PMID: 27579533 PMCID: PMC5340084 DOI: 10.18632/oncotarget.11041] [Show More Authors] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/1969] [Accepted: 12/31/1969] [Indexed: 12/20/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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Affiliation(s)
- Mingfeng Zhang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Zhaoming Wang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Ofure Obazee
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jinping Jia
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Erica J. Childs
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jason Hoskins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Gisella Figlioli
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Evelina Mocci
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Irene Collins
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Charles C. Chung
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Christopher Hautman
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Alan A. Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
- New York University Cancer Institute, New York, New York, USA
| | - Laura Beane-Freeman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Paige M. Bracci
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA
| | - Julie Buring
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Eric J. Duell
- Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Graham G. Giles
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Gary E. Goodman
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Phyllis J. Goodman
- Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Aruna Kamineni
- Group Health Research Institute, Seattle, Washington, USA
| | - Laurence N. Kolonel
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
| | - Matthew H. Kulke
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Núria Malats
- Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain
| | - Sara H. Olson
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Howard D. Sesso
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Kala Visvanathan
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Wei Zheng
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Christian C. Abnet
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Gabriella Andreotti
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Lauren Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - H. Bas Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Daniela Basso
- Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Marie-Christine Boutron-Ruault
- Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France
- University Paris Sud, UMRS 1018, F-94805, Villejuif, France
- IGR, F-94805, Villejuif, France
| | - Maarten F. Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Laurie Burdette
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
- Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy
| | - Neil E. Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Gabriele Capurso
- Digestive and Liver Disease Unit, ‘Sapienza’ University of Rome, Rome, Italy
| | - Giulia Martina Cavestro
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Michelle Cotterchio
- Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Eithne Costello
- National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom
| | - Joanne Elena
- Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ugo Boggi
- Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy
| | - J. Michael Gaziano
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Edward L. Giovannucci
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Michael Goggins
- Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA
- Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA
- Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA
| | - Myron Gross
- Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christopher A. Haiman
- Preventive Medicine, University of Southern California, Los Angeles, California, USA
| | - Manal Hassan
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Kathy J. Helzlsouer
- Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David J. Hunter
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Harvard School of Public Health, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | | | - Mazda Jenab
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Timothy J. Key
- Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
| | - Kay-Tee Khaw
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Eric A. Klein
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Manolis Kogevinas
- Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain
- Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain
- National School of Public Health, Athens, Greece
| | - Vittorio Krogh
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Juozas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Robert C. Kurtz
- Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Maria T. Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
| | - Le Loic Marchand
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
| | - Andrea Mambrini
- Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy
| | - Satu Mannisto
- National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland
| | - Roger L. Milne
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia
| | - Rachel E. Neale
- Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ann L. Oberg
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Salvatore Panico
- Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy
| | - Alpa V. Patel
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA
| | - Petra H. M. Peeters
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Raffaele Pezzilli
- Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Miquel Porta
- Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain
- School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Mark Purdue
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - J. Ramón Quiros
- Public Health and Participation Directorate, Asturias, Spain
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Aldo Scarpa
- ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy
| | - Ghislaine Scelo
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Xiao-Ou Shu
- Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Debra T. Silverman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Pavel Soucek
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
| | - Oliver Strobel
- Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Malin Sund
- Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden
| | - Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland
| | - Philip R. Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
| | - Ruth C. Travis
- Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom
| | - Mark Thornquist
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Anne Tjønneland
- Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark
| | - Geoffrey S. Tobias
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Dimitrios Trichopoulos
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
- Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
- Hellenic Health Foundation, Athens, Greece
| | - Yogesh Vashist
- Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Jean Wactawski-Wende
- Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA
| | - Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Herbert Yu
- Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Anne Zeleniuch-Jacquotte
- Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
- New York University Cancer Institute, New York, New York, USA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA
| | - Eric J. Jacobs
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Charles Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
| | - Robert Hoover
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Gloria M. Petersen
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Rachael S. Stolzenberg-Solomon
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Peter Kraft
- Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
| | - Alison P. Klein
- Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Laufey T. Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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