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Centonze M, Di Conza G, Lahn M, Fabregat I, Dituri F, Gigante I, Serino G, Scialpi R, Carrieri L, Negro R, Pizzuto E, Giannelli G. Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models. J Exp Clin Cancer Res 2023; 42:197. [PMID: 37550785 PMCID: PMC10408149 DOI: 10.1186/s13046-023-02780-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/25/2023] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND Autotaxin (ATX) is a secreted enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA stimulates cell proliferation and migration and promotes wound repair following tissue damage. ATX levels are directly correlated with stage and grade in several human cancers. Several small molecule ATX inhibitors have been developed in recent years. IOA-289 is a potent ATX inhibitor, developed to treat cancers containing fibrosis. In this study, we tested IOA-289 treatment on different gastrointestinal tract tumor cell lines, in order to evaluate its effects on viability and motility. METHODS To determine the effects on cell viability and proliferation of treatment with increasing concentrations of IOA-289, we used the crystal violet assay, a clonogenic assay in matrigel, and we evaluated the inhibitor's effect on formation of 3D spheroids in an in vitro model. The effect of IOA-289 on cell cycle phases was analysed with a redox dye reagent. Cell migration capacity was evaluated by wound healing assay and transwell migration assay. To evaluate the pro-apoptotic effect of the inhibitor, cells were stained with Annexin V and immunofluorescence and flow cytometry analysis were performed. An antibody array was also used, to discriminate, in various samples, the differential expression of 43 proteins involved in the apoptosis pathway. RESULTS We found that IOA-289 is able to inhibit both growth and migration of gastrointestinal tract tumor cell lines, both in 2D (crystal violet assay) and 3D in vitro models (spheroid formation and clonogenic assay in matrigel). This effect is dose-dependent, and the drug is most effective when administered in FBS-free culture medium. The inhibitory effect on cell growth is due to a pro-apoptotic effect of IOA-289. Staining with FITC-conjugated Annexin V showed that IOA-289 induced a dose-dependent increase in fluorescence following incubation for 24 h, and apoptotic cells were also distinguished in flow cytometry using Annexin/PI staining. The antibody array shows that treatment with IOA-289 causes the increased expression of several pro-apoptotic proteins in all tested cell lines. CONCLUSIONS These results indicate that IOA-289 may be an effective drug for the treatment of tumors of the gastrointestinal tract, particularly those characterized by a high degree of fibrosis.
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Affiliation(s)
- Matteo Centonze
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Giusy Di Conza
- iOnctura SA, Avenue Secheron 15, 1202, Geneva, Switzerland
| | - Michael Lahn
- iOnctura SA, Avenue Secheron 15, 1202, Geneva, Switzerland
| | - Isabel Fabregat
- TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL) and CIBEREHD - ISCIII, Barcelona, Spain
| | - Francesco Dituri
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Isabella Gigante
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Grazia Serino
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Rosanna Scialpi
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Livianna Carrieri
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Roberto Negro
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Elena Pizzuto
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy
| | - Gianluigi Giannelli
- National Institute of Gastroenterology - IRCCS "Saverio de Bellis", Via Turi 27, 70013, Castellana Grotte, Italy.
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Meng J, Ruan X, Wei F, Xue Q. High expression of ENPP2 is an independent predictor of poor prognosis in liver cancer. Medicine (Baltimore) 2023; 102:e34480. [PMID: 37543832 PMCID: PMC10402965 DOI: 10.1097/md.0000000000034480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/01/2023] [Accepted: 07/03/2023] [Indexed: 08/07/2023] Open
Abstract
Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) has been identified as a potential biomarker in lung and prostate cancers; however, its expression and clinical relevance in hepatocellular carcinoma (HCC) remain incompletely understood. This study comprehensively assessed ENPP2 expression in pan-cancer using bioinformatics. We analyzed the expression of ENPP2 mRNA in primary liver cancer and adjacent tissues of patients with HCC using data from the TCGA database. Cox regression and Kaplan-Meier methods were used to identify clinicopathological factors associated with survival, and the diagnostic value of ENPP2 expression was evaluated using receiver operating characteristic curve analysis. We also validated our findings by performing real-time PCR on clinical liver cancer samples. Furthermore, we conducted gene set enrichment analysis using the Cancer Genome Atlas dataset to gain additional insights into the biological significance of ENPP2 in HCC. High ENPP2 expression in HCC patients is associated with gender and clinical stage, and is a significant prognostic factor for worse outcomes. ENPP2 expression is an independent risk factor for progression-free and disease-specific survival in both cohorts, suggesting its potential as an HCC biomarker. ENPP2's diagnostic value in HCC patients was confirmed by the area under the receiver operating characteristic curve, which was 0.806. real-time PCR analysis validated the higher expression of ENPP2 in clinical liver cancer tissues. Gene set enrichment analysis identified pathways enriched in HCC patients with high ENPP2 expression, including those related to the cell cycle, MTOR and T cell receptor signaling, and phosphatidylinositol signaling systems. We have demonstrated that ENPP2 is highly expressed in HCC and is a potential independent molecular marker for the diagnosis and prognosis of HCC.
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Affiliation(s)
- Jiyu Meng
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China
| | - Xuelian Ruan
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China
| | - Fangyi Wei
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China
| | - Qin Xue
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China
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Chhabra R, Guergues J, Wohlfahrt J, Rockfield S, Espinoza Gonzalez P, Rego S, Park MA, Berglund AE, Stevens SM, Nanjundan M. Deregulated expression of the 14q32 miRNA cluster in clear cell renal cancer cells. Front Oncol 2023; 13:1048419. [PMID: 37139155 PMCID: PMC10150008 DOI: 10.3389/fonc.2023.1048419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/21/2023] [Indexed: 05/05/2023] Open
Abstract
Clear cell renal cell carcinomas (ccRCC) are characterized by arm-wide chromosomal alterations. Loss at 14q is associated with disease aggressiveness in ccRCC, which responds poorly to chemotherapeutics. The 14q locus contains one of the largest miRNA clusters in the human genome; however, little is known about the contribution of these miRNAs to ccRCC pathogenesis. In this regard, we investigated the expression pattern of selected miRNAs at the 14q32 locus in TCGA kidney tumors and in ccRCC cell lines. We demonstrated that the miRNA cluster is downregulated in ccRCC (and cell lines) as well as in papillary kidney tumors relative to normal kidney tissues (and primary renal proximal tubule epithelial (RPTEC) cells). We demonstrated that agents modulating expression of DNMT1 (e.g., 5-Aza-deoxycytidine) could modulate 14q32 miRNA expression in ccRCC cell lines. Lysophosphatidic acid (LPA, a lysophospholipid mediator elevated in ccRCC) not only increased labile iron content but also modulated expression of a 14q32 miRNA. Through an overexpression approach targeting a subset of 14q32 miRNAs (specifically at subcluster A: miR-431-5p, miR-432-5p, miR-127-3p, and miR-433-3p) in 769-P cells, we uncovered changes in cellular viability and claudin-1, a tight junction marker. A global proteomic approach was implemented using these miRNA overexpressing cell lines which uncovered ATXN2 as a highly downregulated target. Collectively, these findings support a contribution of miRNAs at 14q32 in ccRCC pathogenesis.
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Affiliation(s)
- Ravneet Chhabra
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Jennifer Guergues
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Jessica Wohlfahrt
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Stephanie Rockfield
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
- Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Pamela Espinoza Gonzalez
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Shanon Rego
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Margaret A. Park
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Anders E. Berglund
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Stanley M. Stevens
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
| | - Meera Nanjundan
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, FL, United States
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Vít O, Petrák J. Autotaxin and Lysophosphatidic Acid Signalling: the Pleiotropic Regulatory Network in Cancer. Folia Biol (Praha) 2023; 69:149-162. [PMID: 38583176 DOI: 10.14712/fb2023069050149] [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] [Indexed: 04/09/2024]
Abstract
Autotaxin, also known as ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2, is a secreted glycoprotein that plays multiple roles in human physiology and cancer pathology. This protein, by converting lysophosphatidylcholine into lysophosphatidic acid, initiates a complex signalling cascade with significant biological implications. The article outlines the autotaxin gene and protein structure, expression regulation and physiological functions, but focuses mainly on the role of autotaxin in cancer development and progression. Autotaxin and lysophosphatidic acid signalling influence several aspects of cancer, including cell proliferation, migration, metastasis, therapy resistance, and interactions with the immune system. The potential of autotaxin as a diagnostic biomarker and promising drug target is also examined.
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Affiliation(s)
- Ondřej Vít
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
| | - Jiří Petrák
- BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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Pemafibrate improves liver dysfunction and non-invasive surrogates for liver fibrosis in patients with non-alcoholic fatty liver disease with hypertriglyceridemia: a multicenter study. Hepatol Int 2022; 17:606-614. [PMID: 36583842 DOI: 10.1007/s12072-022-10453-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/04/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND This retrospective, multicenter study evaluated the effect of pemafibrate treatment on liver function and fibrosis by liver function tests (LFTs) and various fibrotic biomarkers including FibroScan in non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia. METHODS A total of 138 NAFLD patients treated with pemafibrate at three hospitals between September 2018 and April 2021 were included. To evaluate the effect of pemafibrate treatment, FibroScan-aspartate aminotransferase (FAST) score, a novel index of steatohepatitis that can be calculated based on the aspartate aminotransferase (AST) value, controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) was used. RESULTS Serum TG levels were significantly decreased 4 weeks after pemafibrate treatment (p = 0.003). The levels of AST (p = 0.038), alanine aminotransferase (ALT) (p = 0.003), and gamma-glutamyl transferase (GGT) (p = 0.047) also significantly diminished 12 weeks after pemafibrate administration compared to before administration (p < 0.05). However, serum HDL-cholesterol (p = 0.193), LDL-cholesterol (p = 0.967), and eGFR (p = 0.909) levels were not significantly altered 12 weeks after pemafibrate administration. In addition, the fibrosis biomarkers' Type IV collagen (p = 0.753) and FIB-4 index (p = 0.333) did not significantly differ, while Autotaxin (p = 0.006) and the AST-to-platelet ratio index (APRI) (p = 0.003) significantly decreased 48 weeks after pemafibrate administration. No significant reductions in LSM (p = 0.959) and CAP (p = 0.266) were detected using FibroScan 48 weeks after pemafibrate administration. FAST score was significantly improved (p = 0.0475). CONCLUSION Pemafibrate improved LFTs, including fibrotic biomarkers and FAST score, due to the hepatic anti-inflammatory effect, suggesting that pemafibrate may prevent disease progression in NAFLD patients with hypertriglyceridemia.
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Drosouni A, Panagopoulou M, Aidinis V, Chatzaki E. Autotaxin in Breast Cancer: Role, Epigenetic Regulation and Clinical Implications. Cancers (Basel) 2022; 14:5437. [PMID: 36358855 PMCID: PMC9658281 DOI: 10.3390/cancers14215437] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/31/2022] [Accepted: 10/31/2022] [Indexed: 08/02/2023] Open
Abstract
Autotaxin (ATX), the protein product of Ectonucleotide Pyrophosphatase Phosphodiesterase 2 (ENPP2), is a secreted lysophospholipase D (lysoPLD) responsible for the extracellular production of lysophosphatidic acid (LPA). ATX-LPA pathway signaling participates in several normal biological functions, but it has also been connected to cancer progression, metastasis and inflammatory processes. Significant research has established a role in breast cancer and it has been suggested as a therapeutic target and/or a clinically relevant biomarker. Recently, ENPP2 methylation was described, revealing a potential for clinical exploitation in liquid biopsy. The current review aims to gather the latest findings about aberrant signaling through ATX-LPA in breast cancer and discusses the role of ENPP2 expression and epigenetic modification, giving insights with translational value.
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Affiliation(s)
- Andrianna Drosouni
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
| | - Maria Panagopoulou
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
| | - Vassilis Aidinis
- Institute of BioInnovation, Biomedical Sciences Research Center Alexander Fleming, 16672 Athens, Greece
| | - Ekaterini Chatzaki
- Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece
- Institute of Agri-Food and Life Sciences, Hellenic Mediterranean University Research Centre, 71410 Heraklion, Greece
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Yu Y, Gao L, Wang Y, Xu B, Maswikiti EP, Li H, Zheng P, Tao P, Xiang L, Gu B, Lucas A, Chen H. A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids. Front Oncol 2021; 11:751086. [PMID: 34722305 PMCID: PMC8551635 DOI: 10.3389/fonc.2021.751086] [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: 07/31/2021] [Accepted: 09/22/2021] [Indexed: 01/06/2023] Open
Abstract
In the past decade, cancer immunotherapy has achieved great success owing to the unravelling of unknown molecular forces in cancer immunity. However, it is critical that we address the limitations of current immunotherapy, including immune-related adverse events and drug resistance, and further enhance current immunotherapy. Lipids are reported to play important roles in modulating immune responses in cancer. Cancer cells use lipids to support their aggressive behaviour and allow immune evasion. Metabolic reprogramming of cancer cells destroys the equilibrium between lipid anabolism and catabolism, resulting in lipid accumulation within the tumour microenvironment (TME). Consequently, ubiquitous lipids, mainly fatty acids, within the TME can impact the function and phenotype of infiltrating immune cells. Determining the complex roles of lipids and their interactions with the TME will provide new insight for improving anti-tumour immune responses by targeting lipids. Herein, we present a review of recent literature that has demonstrated how lipid metabolism reprogramming occurs in cancer cells and influences cancer immunity. We also summarise the potential for lipid-based clinical translation to modify immune treatment.
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Affiliation(s)
- Yang Yu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Lei Gao
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Yunpeng Wang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Bo Xu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Ewetse Paul Maswikiti
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Haiyuan Li
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Peng Zheng
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Pengxian Tao
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Lin Xiang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Baohong Gu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
| | - Alexandra Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, The Biodesign Institute, Arizona State University, Tempe, AZ, United States
| | - Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Second Clinical Medical College, Lanzhou University, Lanzhou, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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Yang B, Ji R, Li X, Fang W, Chen Q, Chen Q, Xu W, Mai K, Ai Q. Activation of Autophagy Relieves Linoleic Acid-Induced Inflammation in Large Yellow Croaker ( Larimichthys crocea). Front Immunol 2021; 12:649385. [PMID: 34276647 PMCID: PMC8279755 DOI: 10.3389/fimmu.2021.649385] [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: 01/04/2021] [Accepted: 05/31/2021] [Indexed: 11/13/2022] Open
Abstract
High levels of soybean oil (SO) in fish diets enriched with linoleic acid (LA, 18:2n-6) could induce strong inflammation. However, the molecular mechanism underlying LA-induced inflammation in the liver of large yellow croaker (Larimichthys crocea) has not been elucidated. Based on previous research, autophagy has been considered a new pathway to relieve inflammation. Therefore, the present study was performed to investigate the role of autophagy in regulating LA-induced inflammation in the liver of large yellow croaker in vivo and in vitro. The results of the present study showed that activation of autophagy in liver or hepatocytes could significantly reduce the gene expression of proinflammatory factors, such as tumor necrosis factor α (TNFα) and interleukin 1β (IL1β). The results of the present study also showed that inhibition of autophagy could upregulate the gene expression of proinflammatory factors and downregulate the gene expression of anti-inflammatory factors in vivo and in vitro. Furthermore, autophagy could alleviate LA-induced inflammatory cytokine gene expression in vivo and in vitro, while inhibition of autophagy obtained the opposite results. In conclusion, our study shows that autophagy could regulate inflammation and alleviate LA-induced inflammation in the liver of large yellow croaker in vivo and in vitro for the first time, which may offer considerable benefits to the aquaculture industry and human health.
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Affiliation(s)
- Bo Yang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Renlei Ji
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Xueshan Li
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Wei Fang
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qiuchi Chen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qiang Chen
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Wei Xu
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qinghui Ai
- Key Laboratory of Aquaculture Nutrition and Feed (Ministry of Agriculture and Rural Affairs) & Key Laboratory of Mariculture (Ministry of Education), Ocean University of China, Qingdao, China.,Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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Ahmed NAF, Deiab AG, Hasan ASM, Elbaky AMYA. Serum autotaxin levels in responders to HCV treatment by direct-acting antivirals. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00051-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) infection is considered one of the main causes of chronic liver disease around the world. Liver biopsy has been believed to be the gold standard for the assessment of the degree of liver fibrosis. Thus, there is a need to improve non-invasive evaluation of liver fibrosis. The aim of the present study was to study the changes in serum levels of ATX (Autotaxin) as a marker of hepatic fibrosis in responders to HCV treatment by DAAs. This prospective study was carried out at hepatology outpatient clinics for HCV treatment in Mansoura Specialized Medical Hospital that involved 54 participants: 34 patients with HCV and 20 controls; ATX was measured for the controls and all patients before and after treatment.
Results
We found a significant higher ATX level in control subjects vs HCV patients, 100% of control subjects had ATX > 97.5 and 58.8% of HCV had ATX ≤ 97.5. Also, a significantly higher ATX after treatment with DAAs as a whole was observed.
Conclusion
The authors concluded that ATX should be considered cautiously as a diagnostic marker for liver fibrosis in Egyptian patients with chronic hepatitis C infection. Although this study yielded negative results, this may be important to prevent duplication of the research efforts.
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Tang X, Brindley DN. Lipid Phosphate Phosphatases and Cancer. Biomolecules 2020; 10:biom10091263. [PMID: 32887262 PMCID: PMC7564803 DOI: 10.3390/biom10091263] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 08/28/2020] [Accepted: 08/30/2020] [Indexed: 12/22/2022] Open
Abstract
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.
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Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - David N. Brindley
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2S2, Canada;
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence:
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Lipids in the tumor microenvironment: From cancer progression to treatment. Prog Lipid Res 2020; 80:101055. [PMID: 32791170 DOI: 10.1016/j.plipres.2020.101055] [Citation(s) in RCA: 255] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022]
Abstract
Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.
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12
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Jin M, Gao D, Wang R, Sik A, Liu K. Possible involvement of TGF‑β‑SMAD‑mediated epithelial‑mesenchymal transition in pro‑metastatic property of PAX6. Oncol Rep 2020; 44:555-564. [PMID: 32627030 PMCID: PMC7336511 DOI: 10.3892/or.2020.7644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 05/12/2020] [Indexed: 01/15/2023] Open
Abstract
Paired box 6 (PAX6) is a transcription factor that has oncogenic features. In breast cancer, PAX6 facilitates tumor progression; however, the underlying mechanism is largely unknown. The majority of breast cancer-related mortalities are associated with metastasis of cancer cells. Therefore, the present study aimed to investigate the role of PAX6 in breast tumor metastasis. PAX6 was stably overexpressed in breast cancer cells to perform tumor migration and metastasis assays in vitro and in vivo. In addition, the expression of PAX6 and transforming growth factor β (TGF-β)-SMAD signaling associated proteins on human breast cancer tissue array, as well as key factors involved in epithelial-mesenchymal transition (EMT) were assayed to explore the mechanism underlying metastasis of breast cancer cells. The expression levels of PAX6 were demonstrated to be increased in human breast cancer tissues and associated with poor clinical outcomes. Overexpression of PAX6 markedly promoted metastasis. Further investigation revealed that PAX6 overexpression increased TGF-β-SMAD signaling pathway and induced EMT. These results suggested that highly expressed PAX6 led to EMT through TGF-β-SMAD signaling pathway, thereby promoting cell metastasis and ultimately affecting survival in patients with breast cancer. Taken together, findings indicated that PAX6 may serve as a therapeutic target for the clinical treatment of breast cancer and the underlying mechanism could be used to overcome metastasis of cancer cells.
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Affiliation(s)
- Meng Jin
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Daili Gao
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Rongchun Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Attila Sik
- Institute of Physiology, Medical School, University of Pécs, H‑7624 Pécs, Hungary
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
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13
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Chhabra R, Nanjundan M. Lysophosphatidic acid reverses Temsirolimus-induced changes in lipid droplets and mitochondrial networks in renal cancer cells. PLoS One 2020; 15:e0233887. [PMID: 32492043 PMCID: PMC7269261 DOI: 10.1371/journal.pone.0233887] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 05/14/2020] [Indexed: 01/05/2023] Open
Abstract
Increased cytoplasmic lipid droplets (LDs) and elevated AKT/mTOR signaling are characteristics of clear cell renal cell carcinoma (ccRCC). Lysophosphatidic acid (LPA), a potent lipid mitogen generated via autotaxin (elevated in ccRCC), can modulate tumor progression but its role in altering chemotherapeutic sensitivity to mTOR inhibitors is unclear and thus is the focus of the studies presented herein. Using malignant (A-498, 769-P and 786-O) and normal immortalized kidney (HK-2) cell lines, we investigated their cellular responsiveness to Temsirolimus (TEMS, mTOR inhibitor) in the absence or presence of LPA by monitoring alterations in AKT/mTOR pathway mediators (via western blotting), LDs (using LipidTOX and real-time PCR to assess transcript changes in modulators of LD biogenesis/turnover), mitochondrial networks (via immunofluorescence staining for TOM20 and TOM70), as well as cellular viability. We identified that TEMS reduced cellular viability in all renal cell lines, with increased sensitivity in the presence of an autophagy inhibitor. TEMS also altered activation of AKT/mTOR pathway mediators, abundance of LDs, and fragmentation of mitochondrial networks. We observed that these effects were antagonized by LPA. In HK-2 cells, LPA markedly increased LD size and abundance, coinciding with phospho-MAPK and phospho-S6 activation, increased diacylglycerol O-acetyltransferase 2 (DGAT2) mRNA (which produces triacylglycerides), and survival. Inhibiting MAPK partially antagonized LPA-induced LD changes. Collectively, we have identified that LPA can reverse the effects of TEMS by increasing LDs in a MAPK-dependent manner; these results suggest that LPA may contribute to the pathogenesis and chemotherapeutic resistance of ccRCC.
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Affiliation(s)
- Ravneet Chhabra
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, United States of America
| | - Meera Nanjundan
- Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida, United States of America
- * E-mail:
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14
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Tang X, Benesch MGK, Brindley DN. Role of the autotaxin-lysophosphatidate axis in the development of resistance to cancer therapy. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158716. [PMID: 32305571 DOI: 10.1016/j.bbalip.2020.158716] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/31/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022]
Abstract
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.
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Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada
| | - Matthew G K Benesch
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada; Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada.
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15
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MicroRNA Regulation of the Autotaxin-Lysophosphatidic Acid Signaling Axis. Cancers (Basel) 2019; 11:cancers11091369. [PMID: 31540086 PMCID: PMC6770380 DOI: 10.3390/cancers11091369] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022] Open
Abstract
The revelation that microRNAs (miRNAs) exist within the human genome uncovered an underappreciated mechanism of gene expression. For cells to regulate expression of their genes, miRNA molecules and argonaute proteins bind to mRNAs and interfere with efficient translation of the RNA transcript. Although miRNAs have important roles in normal tissues, miRNAs may adopt aberrant functions in malignant cells depending on their classification as either a tumor suppressor or oncogenic miRNA. Within this review, the current status of miRNA regulation is described in the context of signaling through the lysophosphatidic acid receptors, including the lysophosphatidic acid-producing enzyme, autotaxin. Thus far, research has revealed miRNAs that increase in response to lysophosphatidic acid stimulation, such as miR-21, miR-30c-2-3p, and miR-122. Other miRNAs inhibit the translation of lysophosphatidic acid receptors, such as miR-15b, miR-23a, and miR200c, or proteins that are downstream of lysophosphatidic acid signaling, such as miR-146 and miR-21. With thousands of miRNAs still uncharacterized, it is anticipated that the complex regulation of lysophosphatidic acid signaling by miRNAs will continue to be elucidated. RNA-based therapeutics have entered the clinic with enormous potential in precision medicine. This exciting field is rapidly emerging and it will be fascinating to witness its expansion in scope.
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Autotaxin-Lysophosphatidic Acid Axis Blockade Improves Inflammation by Regulating Th17 Cell Differentiation in DSS-Induced Chronic Colitis Mice. Inflammation 2019; 42:1530-1541. [DOI: 10.1007/s10753-019-01015-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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17
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Semba RD, Moaddel R, Zhang P, Ramsden CE, Ferrucci L. Tetra-linoleoyl cardiolipin depletion plays a major role in the pathogenesis of sarcopenia. Med Hypotheses 2019; 127:142-149. [PMID: 31088638 DOI: 10.1016/j.mehy.2019.04.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 04/16/2019] [Indexed: 12/25/2022]
Abstract
Sarcopenia, the progressive loss of muscle mass, strength, and physical performance that occurs during aging, is highly prevalent among the elderly. Sarcopenia increases the risk of falls, disability, and death. The biological basis for sarcopenia is not well understood. There are no specific preventive or therapeutic strategies for sarcopenia except exercise. The elucidation of biological pathways and identification of therapeutic targets for treating or preventing sarcopenia remain a high priority in aging research. Mitochondria play a critical role in skeletal muscle by providing energy in the form of ATP, regulation of signaling, calcium homeostasis, autophagy, and other functions. Cardiolipin, a unique dimeric phospholipid specific to mitochondria and an essential component of mitochondrial membranes, is involved in mitochondrial protein transport, maintaining structural organization of mitochondrial membranes, cellular signaling, regulating enzymes involved in β-oxidation of fatty acids, and facilitating normal electron transport chain (ETC) function and generation of ATP. The fatty acid species composition of cardiolipin is critical to mitochondrial bioenergetics, as cardiolipin affects membrane biophysical properties, binds and stabilizes ETC protein complexes, and shapes the curvature of the mitochondrial cristae. Tetra-linoleoyl cardiolipin (18:2)4 comprises ∼80% of cardiolipin in mitochondria in normal human skeletal and cardiac muscle and is optimal for effective ETC function and ATP generation. Aging is associated with a decrease in cardiolipin content, decrease in tetra-linoleoyl cardiolipin (18:2)4 and replacement of linoleic acid (18:2) with other fatty acids in cardiolipin composition, decline of ETC function, and increased generation of reactive oxygen species in muscle. Together, these findings from the literature prompt the hypothesis that depletion of the cardiolipin (18:2)4 species may be at the root of mitochondrial dysfunction with aging, in turn leading to sarcopenia. Corroboration of the tetra-linoleoyl cardiolipin depletion hypothesis suggests new leads for the prevention and treatment of sarcopenia by enhancing the biosynthesis, accretion, and integrity of tetra-linoleoyl cardiolipin.
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Affiliation(s)
- Richard D Semba
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Ruin Moaddel
- National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Pingbo Zhang
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christopher E Ramsden
- National Institute on Aging, National Institutes of Health, Baltimore, MD, United States; National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
| | - Luigi Ferrucci
- National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
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18
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Yang L, Yu X, Yang Y. Autotaxin upregulated by STAT3 activation contributes to invasion in pancreatic neuroendocrine neoplasms. Endocr Connect 2018; 7:1299-1307. [PMID: 30352421 PMCID: PMC6240148 DOI: 10.1530/ec-18-0356] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 10/10/2018] [Indexed: 12/14/2022]
Abstract
Although the upregulation of autotaxin (ATX) is associated with many solid tumours, its role in pancreatic neuroendocrine neoplasms (pNEN) has not been well elucidated. The expression of ATX in pNEN tissues and pNEN cell line BON1 was analysed by Western blot, PCR and immunocytochemistry upon exposure to interleukin-6 (IL-6). Additionally, pNEN cell line BON1 was transfected with siRNAs against ATX or signal transducer and activator of transcription 3 (STAT3) and assessed by in vitro invasion assays. The following results were obtained. The expression of ATX in pNEN tissues was significantly increased compared with that in normal pancreatic tissues. High ATX expression was strongly correlated with tumour grade, lymph node metastasis and tumour-node-metastasis stage. Furthermore, ATX downregulation notably inhibited the metastatic capacity of pNEN cells, whereas STAT3 knockdown was found to downregulate the expression of ATX. ATX expression was upregulated in BON1 cells upon stimulation with IL-6, and this was accompanied by activation/phosphorylation of STAT3. Western blot analysis of human pNEN tissue extracts confirmed increased ATX expression and STAT3 phosphorylation with elevated expression levels of IL-6. In conclusion, ATX is upregulated in pNEN and is correlated with the metastatic capacity of pNEN cells, potentially via interaction with STAT3 activation.
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Affiliation(s)
- Linfei Yang
- Center for Medical Experiments, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Yu
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongchao Yang
- Department of Burns and Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China
- European Pancreas Center, Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
- Correspondence should be addressed to Y Yang:
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Kuppa SS, Jia W, Liu S, Nguyen H, Smyth SS, Mills GB, Dobbin KK, Hardman WJ, Murph MM. Autotaxin exacerbates tumor progression by enhancing MEK1 and overriding the function of miR-489-3p. Cancer Lett 2018; 432:84-92. [PMID: 29859298 DOI: 10.1016/j.canlet.2018.05.037] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 05/21/2018] [Accepted: 05/24/2018] [Indexed: 12/11/2022]
Abstract
Upregulated expression of autotaxin, a secreted phospholipase and phosphodiesterase enzyme, appears in malignant disease. The identification of a circulating miRNA signature should distinguish autotaxin-mediated disease and also elucidate unknown molecular mechanisms that rationalize its malignant potential. Using female transgenic 'AT-ATX' mice, whereby human wild-type autotaxin is expressed in liver under the control of the alpha-1 antitrypsin promoter, transgenic animals express augmented autotaxin in circulation and a percentage develop tumors. Serum collected at necropsy had circulating miRNAs analyzed for statistical significance. The ensuing autotaxin-mediated miRNome differentiated between groups: healthy FVB/N mice versus AT-ATX mice with and without tumors. Intriguingly, miR-489-3p was sharply increased in AT-ATX tumor-bearing mice. Tissue analysis showed a correlation between miR-489-3p expression in tumors and surrounding milieu with autotaxin concentration in circulation. Sequence alignment suggested miR-489-3p targets MEK1, which was confirmed through in vitro studies. Exogenously added miR-489-3p, which decreases MEK1 in normal cells, dramatically increased MEK1 expression in cells stably expressing autotaxin. Taken together, this suggests that autotaxin overrides the normal regulatory function of miR-489-3p to inhibit MEK1 via coordinately increased miR-489-3p appearing in serum.
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Affiliation(s)
- Sudeepti S Kuppa
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, 30602, GA, USA
| | - Wei Jia
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, 30602, GA, USA
| | - Shuying Liu
- Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, United States; Department of Systems Biology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, United States
| | - Ha Nguyen
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, 30602, GA, USA
| | - Susan S Smyth
- Division of Cardiovascular Medicine and Department of Pharmacology, The University of Kentucky and the Department of Veterans Affairs Medical Center, Lexington, KY, 40536, United States
| | - Gordon B Mills
- Department of Systems Biology, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, United States
| | - Kevin K Dobbin
- College of Public Health Epidemiology and Biostatistics, The University of Georgia, 101 Buck Road, Athens, 30602, GA, USA
| | - William J Hardman
- Augusta University and the University of Georgia Medical Partnership, 1425 Prince Avenue, Athens, 30606, GA, USA
| | - Mandi M Murph
- Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, College of Pharmacy, 240 W. Green Street, Athens, 30602, GA, USA.
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20
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Fujimori N, Umemura T, Kimura T, Tanaka N, Sugiura A, Yamazaki T, Joshita S, Komatsu M, Usami Y, Sano K, Igarashi K, Matsumoto A, Tanaka E. Serum autotaxin levels are correlated with hepatic fibrosis and ballooning in patients with non-alcoholic fatty liver disease. World J Gastroenterol 2018; 24:1239-1249. [PMID: 29568204 PMCID: PMC5859226 DOI: 10.3748/wjg.v24.i11.1239] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 02/10/2018] [Accepted: 03/03/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the relationship between serum autotaxin (ATX) concentrations and clinicopathological findings in non-alcoholic fatty liver disease (NAFLD) patients. METHODS One hundred eighty-six NAFLD patients who had undergone liver biopsy between 2008 and 2017 were retrospectively enrolled. Serum samples were collected at the time of biopsy and ATX was measured by enzyme immunoassays. Sera obtained from 160 healthy, non-obese individuals were used as controls. Histological findings were graded according to an NAFLD scoring system and correlations with serum ATX were calculated by Spearman's test. Diagnostic accuracy was evaluated using the area under the receiver operating characteristic curve (AUC). Cut-off values were identified by the Youden index, and the nearest clinically applicable value to the cutoff was considered the optimal threshold for clinical convenience. RESULTS Serum ATX levels were significantly higher in NAFLD patients than in controls (0.86 mg/L vs 0.76 mg/L, P < 0.001) and correlated significantly with ballooning score and fibrosis stage (r = 0.36, P < 0.001 and r = 0.45, P < 0.001, respectively). Such tendencies were stronger in female patients. There were no remarkable relationships between ATX and serum alanine aminotransferase, lipid profiles, or steatosis scores. The AUC values of ATX for predicting the presence of fibrosis (≥ F1), significant fibrosis (≥ F2), severe fibrosis (≥ F3), and cirrhosis (F4), were all more than 0.70 in respective analyses. CONCLUSION Serum ATX levels may at least partially reflect histological severity in NAFLD.
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Affiliation(s)
- Naoyuki Fujimori
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Takefumi Kimura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan, and Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, 390-8621, Japan
| | - Ayumi Sugiura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Tomoo Yamazaki
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Satoru Joshita
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Michiharu Komatsu
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Yoko Usami
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Kenji Sano
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto 390-8621, Japan
| | - Koji Igarashi
- Bioscience Division, TOSOH Corporation, Kanagawa 252-1123, Japan
| | - Akihiro Matsumoto
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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