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He Y, Zhou H, Huang X, Qu Y, Wang Y, Pei W, Zhang R, Chen S, You H. Infiltration of LPAR5 + macrophages in osteosarcoma tumor microenvironment predicts better outcomes. Front Immunol 2022; 13:909932. [PMID: 36591220 PMCID: PMC9797602 DOI: 10.3389/fimmu.2022.909932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. Methods Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. Results Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. Conclusion We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.
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Affiliation(s)
- Yi He
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Haiting Zhou
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaojian Huang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yunkun Qu
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yingguang Wang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenbin Pei
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Rui Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Sheng Chen
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongbo You
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Hongbo You,
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Wang S, Chen J, Guo XZ. KAI1/CD82 gene and autotaxin-lysophosphatidic acid axis in gastrointestinal cancers. World J Gastrointest Oncol 2022; 14:1388-1405. [PMID: 36160748 PMCID: PMC9412925 DOI: 10.4251/wjgo.v14.i8.1388] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/06/2022] [Accepted: 07/22/2022] [Indexed: 02/05/2023] Open
Abstract
The KAI1/CD82 gene inhibits the metastasis of most tumors and is remarkably correlated with tumor invasion and prognosis. Cell metabolism dysregulation is an important cause of tumor occurrence, development, and metastasis. As one of the important characteristics of tumors, cell metabolism dysregulation is attracting increasing research attention. Phospholipids are an indispensable substance in the metabolism in various tumor cells. Phospholipid metabolites have become important cell signaling molecules. The pathological role of lysophosphatidic acid (LPA) in tumors was identified in the early 1990s. Currently, LPA inhibitors have entered clinical trials but are not yet used in clinical treatment. Autotaxin (ATX) has lysophospholipase D (lysoPLD) activity and can regulate LPA levels in vivo. The LPA receptor family and ATX/lysoPLD are abnormally expressed in various gastrointestinal tumors. According to our recent pre-experimental results, KAI1/CD82 might inhibit the migration and metastasis of cancer cells by regulating the ATX-LPA axis. However, no relevant research has been reported. Clarifying the mechanism of ATX-LPA in the inhibition of cancer metastasis by KAI1/CD82 will provide an important theoretical basis for targeted cancer therapy. In this paper, the molecular compositions of the KAI1/CD82 gene and the ATX-LPA axis, their physiological functions in tumors, and their roles in gastrointestinal cancers and target therapy are reviewed.
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Affiliation(s)
- Shuo Wang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Jiang Chen
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, Liaoning Province, China
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Tong C, Wang C, Wang Y, Xiao X. TNRC6C-AS1 Promotes Thyroid Cancer Progression by Upregulating LPAR5 via miR-513c-5p. Cancer Manag Res 2021; 13:6141-6155. [PMID: 34393509 PMCID: PMC8354737 DOI: 10.2147/cmar.s312621] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/19/2021] [Indexed: 12/21/2022] Open
Abstract
Background Considering the combined role of long non-coding RNA (lncRNAs)-microRNA (miRNA)-mRNA in tumorigenesis, the purpose of this study was to investigate how TNRC6C-AS1 regulates the expression of lysophosphatidic acid receptor 5 (LPAR5) by modulating miR-513c-5p, thus influencing the progression of thyroid cancer (THCA). Methods qRT-PCR and Western blotting were performed to detect the expression levels of TNRC6C-AS1, miR-513c-5p, and LPAR5 in THCA tissues and cell lines. The viability, proliferation, migration, and invasion were assessed using CCK-8, BrdU, wound healing, and transwell migration assays, respectively. Dual-luciferase reporter assay, RIP assay, and RNA pull-down assay were used to evaluate the relationship between TNRC6C-AS1, miR-513c-5p, and LPAR5. Results TNRC6C-AS1 was highly expressed in THCA tissues, and knockout of TNRC6C-AS1 reduced the viability, proliferation, migration, and invasion of THCA cells. TNRC6C-AS1 competitively adsorbed miR-513c-5p. In addition, the biological function of TNRC6C-AS1 was blocked by knocking down the thyroid cell line TNRC6C-AS1 with miR-513c-5p inhibitor transfection. LPAR5 is the target gene for miR-513c-5p, which has the ability to eliminate the influence of miR-513c-5p on THCA cells. Conclusion The TNRC6C-AS1/miR-513c-5p/LPAR5 axis is a novel signaling pathway that modulates THCA progression and may be a potential target for cancer therapy.
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Affiliation(s)
- Chuanming Tong
- Department of General Surgery, People's Hospital of Dongxihu District, Wuhan, Hubei, 430040, People's Republic of China
| | - Chuan Wang
- Department of General Surgery, People's Hospital of Dongxihu District, Wuhan, Hubei, 430040, People's Republic of China
| | - Yajie Wang
- Department of General Surgery, People's Hospital of Dongxihu District, Wuhan, Hubei, 430040, People's Republic of China
| | - Xiongsheng Xiao
- Department of Thyroid and Breast Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524000, People's Republic of China
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Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials. Cells 2021; 10:cells10071629. [PMID: 34209775 PMCID: PMC8306951 DOI: 10.3390/cells10071629] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.
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Yang B, Su Z, Chen G, Zeng Z, Tan J, Wu G, Zhu S, Lin L. Identification of prognostic biomarkers associated with metastasis and immune infiltration in osteosarcoma. Oncol Lett 2021; 21:180. [PMID: 33574919 PMCID: PMC7816295 DOI: 10.3892/ol.2021.12441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 12/07/2020] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma is the most common primary malignancy of the bones, and is associated with a high rate of metastasis and a poor prognosis. A tight association between the tumor microenvironment (TME) and osteosarcoma metastasis has been established. In the present study, the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm was applied to calculate the immune and stromal scores of patients with osteosarcoma based on data from The Cancer Genome Atlas database. A metagene approach and deconvolution method were used to reveal distinct TME landscapes in patients with osteosarcoma. Bioinformatics analysis was used to identify differentially expressed genes (DEGs) associated with metastasis and immune infiltration in osteosarcoma, and a risk model was constructed using the DEGs with potential prognostic significance. Subsequently, gene set enrichment and Spearman's correlation analyses were used to delineate the biological processes associated with these prognostic biomarkers. Finally, immunohistochemical (IHC) analysis was performed to evaluate the expression levels of immune infiltrates and prognostic biomarkers in clinical osteosarcoma tissues. The results of the ESTIMATE demonstrated that patients with non-metastatic osteosarcoma presented with higher immune/stromal scores and a more favorable prognosis compared with those with metastatic osteosarcoma. The TME landscapes in patients with osteosarcoma suggested that high levels of tumor-infiltrating immune cells (TIICs) may suppress metastasis. Increased numbers of CD56bright natural killer cells, immature B cells, M1 macrophages and neutrophils, and lower levels of M2 macrophages were observed in the non-metastatic tissues compared with those in the metastatic tissues. A total of 69 DEGs were identified to be associated with metastasis and immune infiltration in osteosarcoma. Of these, GATA3, LPAR5, EVI2B, RIAM and CFH exhibited prognostic potential and were highly expressed in non-metastatic osteosarcoma tissues based on the IHC analysis results. These biomarkers were involved in various immune-related biological processes and were positively associated with multiple TIICs and immune signatures. The risk model constructed using these prognostic biomarkers demonstrated high predictive accuracy for the prognosis of osteosarcoma. In conclusion, the present study proposed a five-biomarker prognostic signature for the prediction of metastasis and immune infiltration in patients with osteosarcoma.
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Affiliation(s)
- Bingsheng Yang
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Zexin Su
- Department of Joint Surgery, Huadu District People's Hospital, Southern Medical University, Guangzhou, Guangdong 510800, P.R. China
| | - Guoli Chen
- Department of Orthopaedics, Affiliated Hospital of Putian University, Putian, Fujian 351100, P.R. China
| | - Zhirui Zeng
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou 550009, P.R. China
| | - Jianye Tan
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Guofeng Wu
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Shuang Zhu
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - Lijun Lin
- Department of Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Gundamaraju R, Lu W, Azimi I, Eri R, Sohal SS. Endogenous Anti-Cancer Candidates in GPCR, ER Stress, and EMT. Biomedicines 2020; 8:biomedicines8100402. [PMID: 33050301 PMCID: PMC7601667 DOI: 10.3390/biomedicines8100402] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 10/05/2020] [Accepted: 10/08/2020] [Indexed: 12/12/2022] Open
Abstract
The majority of cellular responses to external stimuli are mediated by receptors such as G protein-coupled receptors (GPCRs) and systems including endoplasmic reticulum stress (ER stress). Since GPCR signalling is pivotal in numerous malignancies, they are widely targeted by a number of clinical drugs. Cancer cells often negatively modulate GPCRs in order to survive, proliferate and to disseminate. Similarly, numerous branches of the unfolded protein response (UPR) act as pro-survival mediators and are involved in promoting cancer progression via mechanisms such as epithelial to mesenchymal transition (EMT). However, there are a few proteins among these groups which impede deleterious effects by orchestrating the pro-apoptotic phenomenon and paving a therapeutic pathway. The present review exposes and discusses such critical mechanisms and some of the key processes involved in carcinogenesis.
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Affiliation(s)
- Rohit Gundamaraju
- ER Stress & Mucosal Immunology Group, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia;
- Correspondence:
| | - Wenying Lu
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia; (W.L.); (S.S.S.)
| | - Iman Azimi
- School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS 7001, Australia;
| | - Rajaraman Eri
- ER Stress & Mucosal Immunology Group, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia;
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia; (W.L.); (S.S.S.)
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Lin KH, Chiang JC, Ho YH, Yao CL, Lee H. Lysophosphatidic Acid and Hematopoiesis: From Microenvironmental Effects to Intracellular Signaling. Int J Mol Sci 2020; 21:ijms21062015. [PMID: 32188052 PMCID: PMC7139687 DOI: 10.3390/ijms21062015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/13/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Vertebrate hematopoiesis is a complex physiological process that is tightly regulated by intracellular signaling and extracellular microenvironment. In recent decades, breakthroughs in lineage-tracing technologies and lipidomics have revealed the existence of numerous lipid molecules in hematopoietic microenvironment. Lysophosphatidic acid (LPA), a bioactive phospholipid molecule, is one of the identified lipids that participates in hematopoiesis. LPA exhibits various physiological functions through activation of G-protein-coupled receptors. The functions of these LPARs have been widely studied in stem cells, while the roles of LPARs in hematopoietic stem cells have rarely been examined. Nonetheless, mounting evidence supports the importance of the LPA-LPAR axis in hematopoiesis. In this article, we have reviewed regulation of hematopoiesis in general and focused on the microenvironmental and intracellular effects of the LPA in hematopoiesis. Discoveries in these areas may be beneficial to our understanding of blood-related disorders, especially in the context of prevention and therapy for anemia.
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Affiliation(s)
- Kuan-Hung Lin
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (K.-H.L.); (J.-C.C.)
| | - Jui-Chung Chiang
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (K.-H.L.); (J.-C.C.)
- Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ya-Hsuan Ho
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK;
| | - Chao-Ling Yao
- Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan 32003, Taiwan;
| | - Hsinyu Lee
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (K.-H.L.); (J.-C.C.)
- Department of Electrical Engineering, National Taiwan University, Taipei 10617, Taiwan
- Angiogenesis Research Center, National Taiwan University, Taipei 10617, Taiwan
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 10617, Taiwan
- Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan
- Correspondence: ; Tel.: +8862-3366-2499; Fax: +8862-2363-6837
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Xu Y. Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside. Cancers (Basel) 2019; 11:E1523. [PMID: 31658655 PMCID: PMC6826372 DOI: 10.3390/cancers11101523] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/02/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022] Open
Abstract
Since the clear demonstration of lysophosphatidic acid (LPA)'s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications.
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Affiliation(s)
- Yan Xu
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, 950 W. Walnut Street R2-E380, Indianapolis, IN 46202, USA.
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LPAR5, GNAT3 and partial amino acid transporters messenger RNA expression patterns in digestive tracts, metabolic organs and muscle tissues of growing goats. Animal 2018; 13:1394-1402. [PMID: 30378518 DOI: 10.1017/s1751731118002823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Sufficient amino acid (AA) transport is essential to ensure the normal physiological function and growth of growing animals. The processes of AA sensing and transport in humans and murine animals, but rarely in goats, have been arousing great interest recently. This study was conducted to investigate the messenger RNA expression patterns of lysophosphatidic acid receptor 5 (LPAR5), guanine nucleotide-binding protein α-transducing 3 (GNAT3) and important partial AA transporters in digestive tracts, metabolic organs and muscles of growing goats. The results showed that these genes were widely expressed in goats, and had different expression patterns. LPAR5, GNAT3, solute carrier (SLC38A2), SLC7A7, SLC7A1 and SLC3A1 were rarely expressed in the rumen, but were highly expressed in the abomasum and intestine which are the main sites of AA absorption. GNAT3, SLC38A1, SLC38A2, SLC6A19, SLC7A7 and SLC7A1 showed comparatively high expression in the pancreas and the vital digestive glands, and the relatively high expression of these nine genes were noted in the tibialis posterior, the active muscle in energy metabolism. The correlation analysis showed that there were certain positive correlation among most genes. The current results indicate that the AA sensing and transport occur extensively in the abomasum and small intestine, metabolic organs and muscle tissues of ruminants, and that related genes have tissue specificity.
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Yang F, Chen GX. Production of extracellular lysophosphatidic acid in the regulation of adipocyte functions and liver fibrosis. World J Gastroenterol 2018; 24:4132-4151. [PMID: 30271079 PMCID: PMC6158478 DOI: 10.3748/wjg.v24.i36.4132] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/24/2018] [Accepted: 05/05/2018] [Indexed: 02/06/2023] Open
Abstract
Lysophosphatidic acid (LPA), a glycerophospholipid, consists of a glycerol backbone connected to a phosphate head group and an acyl chain linked to sn-1 or sn-2 position. In the circulation, LPA is in sub-millimolar range and mainly derived from hydrolysis of lysophosphatidylcholine, a process mediated by lysophospholipase D activity in proteins such as autotaxin (ATX). Intracellular and extracellular LPAs act as bioactive lipid mediators with diverse functions in almost every mammalian cell type. The binding of LPA to its receptors LPA1-6 activates multiple cellular processes such as migration, proliferation and survival. The production of LPA and activation of LPA receptor signaling pathways in the events of physiology and pathophysiology have attracted the interest of researchers. Results from studies using transgenic and gene knockout animals with alterations of ATX and LPA receptors genes, have revealed the roles of LPA signaling pathways in metabolic active tissues and organs. The present review was aimed to summarize recent progresses in the studies of extracellular and intracellular LPA production pathways. This includes the functional, structural and biochemical properties of ATX and LPA receptors. The potential roles of LPA production and LPA receptor signaling pathways in obesity, insulin resistance and liver fibrosis are also discussed.
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Affiliation(s)
- Fang Yang
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan 430065, Hubei Province, China
| | - Guo-Xun Chen
- Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, United States
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Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development. Mediators Inflamm 2017; 2017:9173090. [PMID: 29430083 PMCID: PMC5753009 DOI: 10.1155/2017/9173090] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/22/2017] [Indexed: 12/13/2022] Open
Abstract
Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression.
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Tsutsumi T, Inoue M, Okamoto Y, Ishihara A, Tokumura A. Daily Intake of High-Fat Diet with Lysophosphatidic Acid-Rich Soybean Phospholipids Augments Colon Tumorigenesis in Kyoto Apc Delta Rats. Dig Dis Sci 2017; 62:669-677. [PMID: 28050783 DOI: 10.1007/s10620-016-4434-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 12/21/2016] [Indexed: 12/09/2022]
Abstract
BACKGROUND Oral administration of lysophosphatidic acid (LPA) was shown to attenuate gastric ulceration in rats and mice but aggravate intestinal tumorigenesis in mice. AIMS The present study examined whether dietary LPA induces or prevents development of colorectal tumor in rats. METHODS Kyoto Apc Delta rats fed high-fat diet with or without an LPA-rich soybean phospholipid mixture (LSP, 0.1 or 1%) were treated with azoxymethane and dextran sodium sulfate to induce colorectal tumorigenesis. Rats were killed 15 weeks after azoxymethane treatment, and size, total number, location, and severity of colorectal tumors were assessed. Expression of mRNA of LPA receptors in rat colon tissue was assayed. RESULTS Rats fed the diet supplemented with 1% LSP had a higher number of tumors 2-4 mm long compared than those with or without 0.1% LSP. The mean distance of tumors >4 mm long from the anus was significantly higher than those of tumors <2 and 2-4 mm long in rats fed 1% LSP-supplemented diet. Supplementation of the diet with 0.1% LSP decreased mRNA expression of LPA5 in colon tumors of rats. CONCLUSIONS Dietary supplementation of LPA-rich phospholipids dose-dependently augmented colorectal tumorigenesis. Decreased expression of LPA5 in colon tumors may be relevant to augmented tumorigenesis.
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Affiliation(s)
- Toshihiko Tsutsumi
- Department of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshinomachi, Nobeoka, Japan.
| | - Manami Inoue
- Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, 1-78-1 Shomachi, Tokushima, Japan
| | - Yoko Okamoto
- Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, 1-78-1 Shomachi, Tokushima, Japan
| | - Akira Ishihara
- Department of Anatomic Pathology, Prefectural Nobeoka Hospital, 2-1-10 Shinkoji, Nobeoka, Japan
| | - Akira Tokumura
- Department of Pharmaceutical Health Chemistry, Institute of Health Biosciences, University of Tokushima Graduate School, 1-78-1 Shomachi, Tokushima, Japan
- Department of Life Sciences, Faculty of Pharmacy, Yasuda Women's University, 6-13-1 Yasuhigashi Asaminami-ku, Hiroshima, Japan
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G-Protein-Coupled Lysophosphatidic Acid Receptors and Their Regulation of AKT Signaling. Int J Mol Sci 2016; 17:215. [PMID: 26861299 PMCID: PMC4783947 DOI: 10.3390/ijms17020215] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 01/29/2016] [Accepted: 02/01/2016] [Indexed: 12/13/2022] Open
Abstract
A hallmark of G-protein-coupled receptors (GPCRs) is their ability to recognize and respond to chemically diverse ligands. Lysophospholipids constitute a relatively recent addition to these ligands and carry out their biological functions by activating G-proteins coupled to a large family of cell-surface receptors. This review aims to highlight salient features of cell signaling by one class of these receptors, known as lysophosphatidic acid (LPA) receptors, in the context of phosphatidylinositol 3-kinase (PI3K)-AKT pathway activation. LPA moieties efficiently activate AKT phosphorylation and activation in a multitude of cell types. The interplay between LPA, its receptors, the associated Gαi/o subunits, PI3K and AKT contributes to the regulation of cell survival, migration, proliferation and confers chemotherapy-resistance in certain cancers. However, detailed information on the regulation of PI3K-AKT signals induced by LPA receptors is missing from the literature. Here, some urgent issues for investigation are highlighted.
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