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Li M, Wang X, Guo J, Qu J, Cao Y, Song Q, Lu J. Effects of FABP5 Expression on Clinicopathological and Survival Characteristics in Digestive System Malignancies: A Systematic Review and Meta-Analysis. Cancer Med 2025; 14:e70794. [PMID: 40178066 PMCID: PMC11966564 DOI: 10.1002/cam4.70794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/10/2025] [Accepted: 03/08/2025] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Digestive system malignancies are a major global health burden, and the role of fatty acid binding protein 5 (FABP5) in these tumors remains controversial. AIMS This meta-analysis aimed to evaluate the correlation between FABP5 expression and clinicopathological features, as well as survival outcomes in digestive system malignancies. MATERIALS AND METHODS Data from 11 studies (1207 patients) retrieved from PubMed, Embase, Cochrane Library, CNKI, and WanFang were analyzed. RESULTS FABP5 overexpression was associated with poorer overall survival (OS), larger tumor size, advanced UICC stage, and increased risk of vascular invasion and lymph node metastasis. Notably, FABP5 overexpression is particularly associated with poorer OS in the subgroup of digestive tract malignancies and larger tumor sizes in the subgroup of Chinese patients. DISCUSSION Cellular experiments demonstrated that FABP5 overexpression enhances proliferation, migration, and invasion in hepatocellular carcinoma (Huh7) and gastric cancer (HGC-27) cell lines, while FABP5 knockdown reduces these effects. Mechanistically, FABP5 may drive tumor progression through PPARβ/δ signaling, epithelial-mesenchymal transition induction, angiogenesis regulation, and potential effects on fatty acid metabolism and hypoxia-related pathways. CONCLUSION FABP5 overexpression correlates with adverse clinicopathological features and prognosis in digestive system malignancies, suggesting its potential as a biomarker for these tumors. Further research is warranted.
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Affiliation(s)
- Miaoqing Li
- Department of Medical Oncology, Laboratory for Clinical MedicineBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Xiaoxia Wang
- Department of Medical Oncology, Laboratory for Clinical MedicineBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Jia Guo
- Department of Medical Oncology, Laboratory for Clinical MedicineBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Junchen Qu
- Department of Medical Oncology, Laboratory for Clinical MedicineBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Yu Cao
- Department of Clinical Epidemiology ResearchBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Qingkun Song
- Department of Clinical Epidemiology ResearchBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
| | - Jun Lu
- Department of Medical Oncology, Laboratory for Clinical MedicineBeijing YouAn Hospital, Capital Medical UniversityBeijingChina
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2
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Vecchio E, Gallo R, Mimmi S, Gentile D, Giordano C, Straface E, Marino R, Caiazza C, Pastore A, Ruocco MR, Arcucci A, Schiavone M, Palmieri C, Iaccino E, Stornaiuolo M, Quinto I, Mallardo M, Martini F, Tognon M, Fiume G. FABP5 is a key player in metabolic modulation and NF-κB dependent inflammation driving pleural mesothelioma. Commun Biol 2025; 8:324. [PMID: 40016284 PMCID: PMC11868402 DOI: 10.1038/s42003-025-07754-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 02/17/2025] [Indexed: 03/01/2025] Open
Abstract
Pleural mesothelioma (PM) poses a significant challenge in oncology due to its intricate molecular and metabolic landscape, chronic inflammation, and heightened oxidative stress, which contribute to its notorious resilience and clinical complexities. Despite advancements, the precise mechanisms driving PM carcinogenesis remain elusive, impeding therapeutic progress. Here, we explore the interplay between tumor growth dynamics, lipid metabolism, and NF-κB dysregulation in malignant pleural mesothelioma, shedding light on novel molecular mechanisms underlying its pathogenesis. Our study reveals distinctive growth dynamics in PM cells, characterized by heightened proliferation, altered cell cycle progression, and resistance to apoptosis. Intriguingly, PM cells exhibit increased intracellular accumulation of myristic, palmitic, and stearic acids, suggestive of augmented lipid uptake and altered biosynthesis. Notably, we identify FABP5 as a key player in driving metabolic alterations and inflammation through NF-κB dysregulation in mesothelioma cells, distinguishing them from normal mesothelial cells. Silencing of FABP5 leads to significant alterations in cell dynamics, metabolism, and NF-κB activity, highlighting its potential as a therapeutic target. Our findings unveil a reciprocal relationship between lipid metabolism and inflammation in PM, providing a foundation for targeted therapeutic strategies. Overall, this comprehensive investigation offers insights into the intricate molecular mechanisms driving PM pathogenesis and identifies potential avenues for therapeutic intervention.
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Affiliation(s)
- Eleonora Vecchio
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Raffaella Gallo
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Selena Mimmi
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Debora Gentile
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Caterina Giordano
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Emilio Straface
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Rossana Marino
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Carmen Caiazza
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Arianna Pastore
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Maria Rosaria Ruocco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Alessandro Arcucci
- Department of Public Health, University of Naples "Federico II", Naples, Italy
| | - Marco Schiavone
- Department of Molecular and Translational Medicine, Zebrafish Facility, University of Brescia, Brescia, Italy
| | - Camillo Palmieri
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Enrico Iaccino
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | | | - Ileana Quinto
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy
| | - Massimo Mallardo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy
| | - Fernanda Martini
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Mauro Tognon
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giuseppe Fiume
- Department of Experimental and Clinical Medicine, University of Catanzaro "Magna Graecia", Catanzaro, Italy.
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3
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Zhang J, Ruan K, Chu Z, Wang X, Gu Y, Jin H, Zhang X, Liu Q, Yang J. Reprogramming of fatty acid metabolism: a hidden force regulating the occurrence and progression of cholangiocarcinoma. Cell Death Discov 2025; 11:72. [PMID: 39984452 PMCID: PMC11845788 DOI: 10.1038/s41420-025-02351-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 01/22/2025] [Accepted: 02/11/2025] [Indexed: 02/23/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a malignant tumor that originates from the bile duct epithelium and with a poor outcome due to lack of effective early diagnostic methods. Surgical resection is the preferred method for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Therefore, it is urgent to explore other new treatment methods. As modern living standards rise, the acceptance of high-fat, high-protein, and high-carbohydrate diets is growing among the public, and the resulting metabolic abnormalities are intimately linked to the initiation and spread of tumors. Metabolic reprogramming is a key mechanism in the process of tumor development and progression and is closely related to cancer cell proliferation, metastasis and drug resistance. Fatty acid (FA) metabolism, an integral component of cancer cell metabolism, can provide an energy source for cancer cells and participate in cell signaling, the regulation of the immune response and the maintenance of homeostasis of the internal environment, which are closely linked to the development and progression of CCA. Therefore, a better understanding of FA metabolism may provide promising strategies for early diagnosis, prognostic assessment and targeted therapy for CCA patients. In this paper, we review the effects of FA metabolism on CCA development and progression, summarize related mechanisms and the existing clinical applications of targeted lipid metabolism in CCA, and explore new targets for CCA metabolic therapy.
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Affiliation(s)
- Jinglei Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, 310053, China
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China
| | - Kaiyi Ruan
- Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China
| | - Zhuohuan Chu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, 310053, China
| | - Xiang Wang
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China
| | - Ye Gu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China
| | - Hangbin Jin
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, 310006, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province, 310006, China
| | - Xiaofeng Zhang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, 310053, China
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China
- Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, 310006, China
- Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province, 310006, China
| | - Qiang Liu
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China.
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, 310006, China.
- Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province, 310006, China.
| | - Jianfeng Yang
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, 310053, China.
- Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, Zhejiang Province, 310006, China.
- Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310058, China.
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province, 310006, China.
- Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province, 310006, China.
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Nishikiori N, Ohguro H, Watanabe M, Higashide M, Ogawa T, Furuhashi M, Sato T. High-Glucose-Induced Metabolic and Redox Alterations Are Distinctly Modulated by Various Antidiabetic Agents and Interventions Against FABP5/7, MITF and ANGPTL4 in Melanoma A375 Cells. Int J Mol Sci 2025; 26:1014. [PMID: 39940783 PMCID: PMC11817646 DOI: 10.3390/ijms26031014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/16/2025] Open
Abstract
Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells.
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Affiliation(s)
- Nami Nishikiori
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Hiroshi Ohguro
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Megumi Watanabe
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Megumi Higashide
- Departments of Ophthalmology, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (N.N.); (M.W.); (M.H.)
| | - Toshifumi Ogawa
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
| | - Masato Furuhashi
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
| | - Tatsuya Sato
- Departments of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan; (T.O.); (M.F.)
- Departments of Cellular Physiology and Signal Transduction, Sapporo Medical University, S1W17, Chuo-ku, Sapporo 060-8556, Japan
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5
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Jia F, Liu L, Weng Q, Zhang H, Zhao X. Glycolysis-Metabolism-Related Prognostic Signature for Ewing Sarcoma Patients. Mol Biotechnol 2024; 66:2882-2896. [PMID: 37775679 DOI: 10.1007/s12033-023-00899-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/11/2023] [Indexed: 10/01/2023]
Abstract
Ewing sarcoma (EwS) is a malignant sarcoma which occurs in bone and soft tissues commonly happening in children with poor survival rates. Changes in cell metabolism, such as glycolysis, may provide the environment for the transformation and progression of tumors. We aimed to build a model to predict prognosis of EwS patients based on glycolysis and metabolism genes. Candidate genes were obtained by differential gene expression analysis based on GSE17679, GSE17674 and ICGC datasets. We performed GO and KEGG pathway enrichment analysis on candidate genes. Univariate Cox and LASSO Cox regression analyses were conducted to construct a model to calculate the Risk Score. GSEA was done between high-risk and low-risk groups. CIBERSORT was applied to analyze the immune landscape. We got 295 candidate glycolysis-metabolism-related genes which were enriched in 620 GO terms and 18 KEGG pathways. 12 Genes were selected by univariate Cox model and 5 of them were determined by LASSO Cox regression analysis to be used in the construction of the Risk Score model. The Risk Score could be considered as an independent prognosis factor. The immune landscape and immune checkpoints' expression significantly differed between high- and low-risk groups. Our research constructed a new glycolysis-metabolism-related genes (FABP5, EMILIN1, GLCE, PHF11 and PALM3) based prognostic signature for EwS patients and assisted in gaining insight into prognosis to improve therapies further.
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Affiliation(s)
- Fusen Jia
- Department of Hand & Foot Surgery, Zibo Central Hospital, Zhangdian District, Zibo, 255036, Shandong, People's Republic of China
| | - Lei Liu
- Orthopedic Surgery 2nd, Qilu Hospital Huantai Branch, Huantai County, Zibo, 256400, Shandong, People's Republic of China
| | - Qi Weng
- Department of Psychology, Zibo Maternal and Child Health Hospital, Zhangdian District, Zibo, 255022, Shandong, People's Republic of China
| | - Haiyang Zhang
- Department of Hand & Foot Surgery, Zibo Central Hospital, Zhangdian District, Zibo, 255036, Shandong, People's Republic of China
| | - Xuesheng Zhao
- Orthopedic Surgery 2nd, The Fifth People's Hospital of Jinan, No. 24297 Jingshi Road, Huaiyin District, Jinan, 250000, Shandong, People's Republic of China.
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6
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Wang Q, Liu J, Chen Z, Zheng J, Wang Y, Dong J. Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed Pharmacother 2024; 170:116021. [PMID: 38128187 DOI: 10.1016/j.biopha.2023.116021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/23/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Ziye Chen
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Jingjing Zheng
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China; Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
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George Warren W, Osborn M, Yates A, Wright K, E O'Sullivan S. The emerging role of fatty acid binding protein 5 (FABP5) in cancers. Drug Discov Today 2023:103628. [PMID: 37230284 DOI: 10.1016/j.drudis.2023.103628] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/02/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
Fatty acid binding protein 5 (FABP5, or epidermal FABP) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. In patient-derived tumours, FABP5 expression is increased up to tenfold, often co-expressed with other cancer-related proteins. High tumoral FABP5 expression is associated with poor prognosis. FABP5 activates transcription factors (TFs) leading to increased expression of proteins involved in tumorigenesis. Genetic and pharmacological preclinical studies show that inhibiting FABP5 reduces protumoral markers, whereas elevation of FABP5 promotes tumour growth and spread. Thus, FABP5 might be a valid target for novel therapeutics. The evidence base is currently strongest for liver, prostate, breast, and brain cancers, and squamous cell carcinoma (SCC), which could represent relevant patient populations for any drug discovery programme. Teaser: This review presents the growing evidence that upregulated fatty acid binding protein 5 (FABP5) plays a role in the progression of multiple cancer types, and may represent a novel therapeutic target.
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Affiliation(s)
| | | | - Andy Yates
- Artelo Biosciences, Solana Beach, CA, USA
| | - Karen Wright
- Faculty of Health and Medicine, Lancaster University, Lancaster, UK
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8
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Oncogenic role and potential regulatory mechanism of fatty acid binding protein 5 based on a pan-cancer analysis. Sci Rep 2023; 13:4060. [PMID: 36906605 PMCID: PMC10008585 DOI: 10.1038/s41598-023-30695-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 02/28/2023] [Indexed: 03/13/2023] Open
Abstract
As one member of fatty acid binding proteins (FABPs), FABP5 makes a contribution in the occurrence and development of several tumor types, but existing analysis about FABP5 and FABP5-related molecular mechanism remains limited. Meanwhile, some tumor patients showed limited response rates to current immunotherapy, and more potential targets need to be explored for the improvement of immunotherapy. In this study, we made a pan-cancer analysis of FABP5 based on the clinical data from The Cancer Genome Atlas database for the first time. FABP5 overexpression was observed in many tumor types, and was statistically associated with poor prognosis of several tumor types. Additionally, we further explored FABP5-related miRNAs and corresponding lncRNAs. Then, miR-577-FABP5 regulatory network in kidney renal clear cell carcinoma as well as CD27-AS1/GUSBP11/SNHG16/TTC28-AS1-miR-22-3p-FABP5 competing endogenous RNA regulatory network in liver hepatocellular carcinoma were constructed. Meanwhile, Western Blot and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analysis were used to verify miR-22-3p-FABP5 relationship in LIHC cell lines. Moreover, the potential relationships of FABP5 with immune infiltration and six immune checkpoints (CD274, CTLA4, HAVCR2, LAG3, PDCD1 and TIGIT) were discovered. Our work not only deepens the understanding of FABP5's functions in multiple tumors and supplements existing FABP5-related mechanisms, but also provides more possibilities for immunotherapy.
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9
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Correnti M, Binatti E, Gammella E, Invernizzi P, Recalcati S. The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells. Cancers (Basel) 2022; 15:5. [PMID: 36612000 PMCID: PMC9817521 DOI: 10.3390/cancers15010005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC-TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.
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Affiliation(s)
- Margherita Correnti
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Eleonora Binatti
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
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10
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Topical VX-509 attenuates psoriatic inflammation through the STAT3/FABP5 pathway in keratinocytes. Pharmacol Res 2022; 182:106318. [PMID: 35728766 DOI: 10.1016/j.phrs.2022.106318] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 05/27/2022] [Accepted: 06/15/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Psoriasis is a chronic inflammatory disease, with lesions mainly manifesting as scaly erythematous plaques. The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy. OBJECTIVE To identify potential drugs for psoriasis topical treatment. METHODS We performed drug screening by Imiquimod (IMQ)-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug. The qRT-PCR, WB were performed to test mRNA and protein expression, and Chip assay had been conducted to examine Stat3 bound to promoter of FABP5. RESULTS In this study, we identified VX-509, which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified Epidermal Fatty acid binding protein (E-FABP/FABP5) was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked IL-22 induced signaling pathway, particular in activation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 in KCs. CONCLUSIONS This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.
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11
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Garcia KA, Costa ML, Lacunza E, Martinez ME, Corsico B, Scaglia N. Fatty acid binding protein 5 regulates lipogenesis and tumor growth in lung adenocarcinoma. Life Sci 2022; 301:120621. [PMID: 35545133 DOI: 10.1016/j.lfs.2022.120621] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 12/28/2022]
Abstract
AIMS Lung cancer is the leading cause of cancer-related death. Unfortunately, targeted-therapies have been unsuccessful for most patients with lung adenocarcinoma (LUAD). Thus, new early biomarkers and treatment options are a pressing need. Fatty acid binding protein 5 (FABP5) has been associated with various types of cancers. Its contribution to LUAD onset, progression and metabolic reprogramming is, however, not fully understood. In this study we assessed the importance of FABP5 in LUAD and its role in cancer lipid metabolism. MAIN METHODS By radioactive labeling and metabolite quantification, we studied the function of FABP5 in fatty acid metabolism using genetic/pharmacologic inhibition and overexpression models in LUAD cell lines. Flow cytometry, heterologous transplantation and bioinformatic analysis were used, in combination with other methodologies, to assess the importance of FABP5 for cellular proliferation in vitro and in vivo and in patient survival. KEY FINDINGS We show that high expression of FABP5 is associated with poor prognosis in patients with LUAD. FABP5 regulates lipid metabolism, diverting fatty acids towards complex lipid synthesis, whereas it does not affect their catabolism in vitro. Moreover, FABP5 is required for de novo fatty acid synthesis and regulates the expression of enzymes involved in the pathway (including FASN and SCD1). Consistently with the changes in lipid metabolism, FABP5 is required for cell cycle progression, migration and in vivo tumor growth. SIGNIFICANCE Our results suggest that FABP5 is a regulatory hub of lipid metabolism and tumor progression in LUAD, placing it as a new putative therapeutic target for this disease.
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Affiliation(s)
- Karina Andrea Garcia
- Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina
| | - María Lucía Costa
- Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina
| | - Ezequiel Lacunza
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina
| | - María Elizabeth Martinez
- Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina
| | - Betina Corsico
- Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina
| | - Natalia Scaglia
- Instituto de Investigaciones Bioquímicas de la Plata (INIBIOLP), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP), La Plata, Buenos Aires, Argentina.
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12
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Xu B, Chen L, Zhan Y, Marquez KNS, Zhuo L, Qi S, Zhu J, He Y, Chen X, Zhang H, Shen Y, Chen G, Gu J, Guo Y, Liu S, Xie T. The Biological Functions and Regulatory Mechanisms of Fatty Acid Binding Protein 5 in Various Diseases. Front Cell Dev Biol 2022; 10:857919. [PMID: 35445019 PMCID: PMC9013884 DOI: 10.3389/fcell.2022.857919] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 02/28/2022] [Indexed: 12/11/2022] Open
Abstract
In recent years, fatty acid binding protein 5 (FABP5), also known as fatty acid transporter, has been widely researched with the help of modern genetic technology. Emerging evidence suggests its critical role in regulating lipid transport, homeostasis, and metabolism. Its involvement in the pathogenesis of various diseases such as metabolic syndrome, skin diseases, cancer, and neurological diseases is the key to understanding the true nature of the protein. This makes FABP5 be a promising component for numerous clinical applications. This review has summarized the most recent advances in the research of FABP5 in modulating cellular processes, providing an in-depth analysis of the protein's biological properties, biological functions, and mechanisms involved in various diseases. In addition, we have discussed the possibility of using FABP5 as a new diagnostic biomarker and therapeutic target for human diseases, shedding light on challenges facing future research.
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Affiliation(s)
- Binyue Xu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Lu Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yu Zhan
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Karl Nelson S. Marquez
- Clinical Medicine, Tongji Medical College, Huazhong University of Science and Technology, Hankou, China
| | - Lvjia Zhuo
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Shasha Qi
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jinyu Zhu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Ying He
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xudong Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Hao Zhang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yingying Shen
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Gongxing Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Jianzhong Gu
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yong Guo
- Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuiping Liu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
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Du D, Liu C, Qin M, Zhang X, Xi T, Yuan S, Hao H, Xiong J. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B 2022; 12:558-580. [PMID: 35256934 PMCID: PMC8897153 DOI: 10.1016/j.apsb.2021.09.019] [Citation(s) in RCA: 321] [Impact Index Per Article: 107.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/31/2021] [Accepted: 09/01/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.
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Key Words
- 1,3-BPG, 1,3-bisphosphoglycerate
- 2-DG, 2-deoxy-d-glucose
- 3-BrPA, 3-bromopyruvic acid
- ACC, acetyl-CoA carboxylase
- ACLY, adenosine triphosphate (ATP) citrate lyase
- ACS, acyl-CoA synthease
- AKT, protein kinase B
- AML, acute myeloblastic leukemia
- AMPK, adenosine mono-phosphate-activated protein kinase
- ASS1, argininosuccinate synthase 1
- ATGL, adipose triacylglycerol lipase
- CANA, canagliflozin
- CPT, carnitine palmitoyl-transferase
- CYP4, cytochrome P450s (CYPs) 4 family
- Cancer therapy
- DNL, de novo lipogenesis
- EMT, epithelial-to-mesenchymal transition
- ER, endoplasmic reticulum
- ERK, extracellular-signal regulated kinase
- FABP1, fatty acid binding protein 1
- FASN, fatty acid synthase
- FBP1, fructose-1,6-bisphosphatase 1
- FFA, free fatty acid
- Fatty acid β-oxidation
- G6PD, glucose-6-phosphate dehydrogenase
- GAPDH, glyceraldehyde-3-phosphate dehydrogenase
- GLS1, renal-type glutaminase
- GLS2, liver-type glutaminase
- GLUT1, glucose transporter 1
- GOT1, glutamate oxaloacetate transaminase 1
- Glutamine metabolism
- Glycolysis
- HCC, hepatocellular carcinoma
- HIF-1α, hypoxia-inducible factor-1 alpha
- HK, hexokinase
- HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase
- HSCs, hepatic stellate cells
- Hepatocellular carcinoma
- IDH2, isocitrate dehydrogenase 2
- LCAD, long-chain acyl-CoA dehydrogenase
- LDH, lactate dehydrogenase
- LPL, lipid lipase
- LXR, liver X receptor
- MAFLD, metabolic associated fatty liver disease
- MAGL, monoacyglycerol lipase
- MCAD, medium-chain acyl-CoA dehydrogenase
- MEs, malic enzymes
- MMP9, matrix metallopeptidase 9
- Metabolic dysregulation
- NADPH, nicotinamide adenine nucleotide phosphate
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- OTC, ornithine transcarbamylase
- PCK1, phosphoenolpyruvate carboxykinase 1
- PFK1, phosphofructokinase 1
- PGAM1, phosphoglycerate mutase 1
- PGK1, phosphoglycerate kinase 1
- PI3K, phosphoinositide 3-kinase
- PKM2, pyruvate kinase M2
- PPARα, peroxisome proliferator-activated receptor alpha
- PPP, pentose phosphate pathway
- Pentose phosphate pathway
- ROS, reactive oxygen species
- SCD1, stearoyl-CoA-desaturase 1
- SGLT2, sodium-glucose cotransporter 2
- SLC1A5/ASCT2, solute carrier family 1 member 5/alanine serine cysteine preferring transporter 2
- SLC7A5/LAT1, solute carrier family 7 member 5/L-type amino acid transporter 1
- SREBP1, sterol regulatory element-binding protein 1
- TAGs, triacylglycerols
- TCA cycle, tricarboxylic acid cycle
- TKIs, tyrosine kinase inhibitors
- TKT, transketolase
- Tricarboxylic acid cycle
- VEGFR, vascular endothelial growth factor receptor
- WD-fed MC4R-KO, Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO)
- WNT, wingless-type MMTV integration site family
- mIDH, mutant IDH
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Danyu Du
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chan Liu
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Mengyao Qin
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiao Zhang
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tao Xi
- Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China
| | - Shengtao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
| | - Haiping Hao
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
- Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors.
| | - Jing Xiong
- Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
- Corresponding authors.
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Gyamfi J, Kim J, Choi J. Cancer as a Metabolic Disorder. Int J Mol Sci 2022; 23:ijms23031155. [PMID: 35163079 PMCID: PMC8835572 DOI: 10.3390/ijms23031155] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/08/2023] Open
Abstract
Cancer has long been considered a genetic disease characterized by a myriad of mutations that drive cancer progression. Recent accumulating evidence indicates that the dysregulated metabolism in cancer cells is more than a hallmark of cancer but may be the underlying cause of the tumor. Most of the well-characterized oncogenes or tumor suppressor genes function to sustain the altered metabolic state in cancer. Here, we review evidence supporting the altered metabolic state in cancer including key alterations in glucose, glutamine, and fatty acid metabolism. Unlike genetic alterations that do not occur in all cancer types, metabolic alterations are more common among cancer subtypes and across cancers. Recognizing cancer as a metabolic disorder could unravel key diagnostic and treatments markers that can impact approaches used in cancer management.
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Affiliation(s)
- Jones Gyamfi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Department of Medical Laboratory Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Jinyoung Kim
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
| | - Junjeong Choi
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Veritas Hall D 306, 85 Songdogwahak-ro, Incheon 21983, Korea; (J.G.); (J.K.)
- Correspondence: ; Tel.: +82-32-749-4521; Fax: +82-32-749-4105
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15
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Seo J, Yun J, Fukuda J, Chun YS. Tumor-intrinsic FABP5 is a novel driver for colon cancer cell growth via the HIF-1 signaling pathway. Cancer Genet 2021; 258-259:151-156. [PMID: 34775260 DOI: 10.1016/j.cancergen.2021.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 10/14/2021] [Accepted: 11/02/2021] [Indexed: 12/13/2022]
Abstract
Dysfunctional lipid metabolism is a known cause of cancer development and progression, yet little is known about the underlying molecular mechanisms that contribute to cancer progression. In this study, we demonstrate that fatty acid binding protein 5 (FABP5) is elevated in colon cancer tissue and this increased expression is linked to upregulation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway. Under physiologically in vivo mimicked conditions via a polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture chip, FABP5-knockdown colon cancer cells exhibited attenuated cell growth throughout the culture period. FABP5 was found to regulate HIF-1α protein levels and gene expression levels within the HIF-1α signaling pathway under hypoxic conditions. Our results provide evidence that supports the use of FABP5 as a prognostic factor in colon cancer. The FABP5/HIF-1α axis is a promising target for ameliorating fatty acid-triggered cancer progression.
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Affiliation(s)
- Jieun Seo
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea; Faculty of Engineering, Yokohama National University, Yokohama 240-8501, Japan
| | - JeongEun Yun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea
| | - Junji Fukuda
- Faculty of Engineering, Yokohama National University, Yokohama 240-8501, Japan
| | - Yang-Sook Chun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, South Korea.
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16
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Li M, Li C, Lu P, Wang B, Gao Y, Liu W, Shi Y, Ma Y. Expression and function analysis of CRABP2 and FABP5, and their ratio in esophageal squamous cell carcinoma. Open Med (Wars) 2021; 16:1444-1458. [PMID: 34632074 PMCID: PMC8477672 DOI: 10.1515/med-2021-0350] [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: 04/19/2021] [Revised: 07/26/2021] [Accepted: 08/09/2021] [Indexed: 12/29/2022] Open
Abstract
Objective The purpose of this study was to explore the effect of CRABP2 and FABP5, and their ratio on prognosis in esophageal squamous cell carcinoma. Methods The expression data of CRABP2 in esophageal cancer in TCGA and GEO were collected by the public database GEPIA. The expression levels of CRABP2 and FABP5 were examined using immunohistochemistry. The relationship between the two proteins and related clinicopathological parameters were analyzed by χ2 test. Survival analysis was used to investigate the effect of CRABP2 and FABP5, and their ratio on prognosis. Results Compared with normal esophageal mucosal epithelium, there was lower CRABP2 gene mRNA in the esophageal cancer tissue, and the difference was statistically significant (p < 0.01). For the expression level, no significant difference was observed in patients with stages I–IV in esophageal cancer. Immunohistochemistry showed that CRABP2 and FABP5 were both highly expressed in normal esophageal squamous epithelial cells at 100 and 94.1%, while lower in ESCC (75.6 and 58.7%). There was a significant difference in the expression between cancer and adjacent tissues (p < 0.001). No inherent relationship was manifested between the CRABP2 expression and the clinical parameters of the ESCC. The expression of FABP5 was related to lymph node metastasis (p = 0.032), the depth of invasion (p = 0.041), and the AJCC stage (p = 0.013). The ratio of CRABP2 and FABP5 was related to ethnicity (p = 0.001), nerve invasion (p = 0.031), and postoperative treatment (p = 0.038). CRABP2 is positively associated with FABP5 (r = 0.156, p = 0.041) and the ratio (r = 0.334, p = 0.000), while there was a negative correlation between FABP5 and the ratio (r = −0.269, p = 0.000). Patients with CRABP2-positive expression had a significantly longer overall survival than patients with CRABP2-negative expression (p = 0.025). Conclusion CRABP2 as a suppressor factor is expected to be a potential prognosis marker for esophageal squamous cell carcinoma.
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Affiliation(s)
- Mengyan Li
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Chao Li
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Pengfei Lu
- Departments of Oncology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Bo Wang
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Yongmei Gao
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Wengying Liu
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Yan Shi
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830011, People's Republic of China
| | - Yuqing Ma
- Departments of Pathology, The First Affiliated Hospital, Xinjiang Medical University, 393 Liyushan Road, Urumqi, Xinjiang 830011, People's Republic of China
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Different Immunohistochemical Localization of Fatty Acid Binding Protein 5 in Actinic Keratosis Compared with That in Bowen's Disease: A Retrospective Study. Am J Dermatopathol 2020; 43:356-361. [PMID: 33055535 DOI: 10.1097/dad.0000000000001823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Actinic keratosis (AK) and Bowen's disease (BD) are common premalignant lesions of invasive squamous cell carcinoma that have different pathogenesis and clinical significance. Fatty acid-binding protein 5 (FABP5) is responsible for keratinocyte homeostasis and differentiation; however, no study has revealed its expression in AK and BD. Our study aimed to investigate the differential expression and significance of FABP5 in these lesions. Patients with pathologically confirmed cases of AK (n = 37) and BD (n = 12) were included in this study. FABP5 immunostaining pattern was assessed in the normal skin, AK and BD lesions, with a focus on the staining patterns of basal cells, atypical keratinocytes, and uninvolved epidermal keratinocytes. All patients with AK showed negative FABP5 expression in the atypical cells in the basal layer, whereas the uninvolved upper layers showed diffuse, strong FABP5 expression, regardless of the grade of AK. All patients with BD showed heterogeneous and diffuse FABP5 expression in atypical cells of all layers of the epidermis. This study is the first to investigate the role of FABP5 in premalignant skin lesions. The unique immunohistochemical localization of the FABP5 can be a helpful diagnostic marker, and altered fatty acid metabolism may be the key in understanding the different pathophysiology of AK and BD.
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18
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Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Commun Biol 2020; 3:638. [PMID: 33128030 PMCID: PMC7599230 DOI: 10.1038/s42003-020-01367-5] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 10/08/2020] [Indexed: 12/14/2022] Open
Abstract
Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor essential for cancer cell survival. The reprogramming of lipid metabolism has emerged as a hallmark of cancer, yet the relevance of HIF-1α to this process remains elusive. In this study, we profile HIF-1α-interacting proteins using proteomics analysis and identify fatty acid-binding protein 5 (FABP5) as a critical HIF-1α-binding partner. In hepatocellular carcinoma (HCC) tissues, both FABP5 and HIF-1α are upregulated, and their expression levels are associated with poor prognosis. FABP5 enhances HIF-1α activity by promoting HIF-1α synthesis while disrupting FIH/HIF-1α interaction at the same time. Oleic-acid treatment activates the FABP5/HIF-1α axis, thereby promoting lipid accumulation and cell proliferation in HCC cells. Our results indicate that fatty-acid-induced FABP5 upregulation drives HCC progression through HIF-1-driven lipid metabolism reprogramming. Seo et al. identify fatty acid-binding protein 5 (FABP5) as a booster of HIF-1α activity. They find that oleic-acid treatment activates the FABP5/HIF-1α axis, promoting lipid accumulation and cell proliferation in liver cancer cells. This study provides insights into how fatty acids drive the progression of cancer.
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19
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Celik SD, Ates O. Analysis of CRABP2 and FABP5 genes in primary and recurrent pterygium tissues. Mol Biol Rep 2020; 47:6105-6110. [PMID: 32780252 DOI: 10.1007/s11033-020-05686-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 07/26/2020] [Indexed: 11/29/2022]
Abstract
The etiology of pterygium remains unclear, but ultraviolet (UV) radiation is generally considered to be major risk factor. Pterygium has similarity features with many cancers, including inflammation, invasion, cell proliferation, anti-apoptosis, angiogenesis and recurrence after resection. Retinoic acid via cellular retinoic acid binding protein 2 (CRABP2) is involved in cell cycle arrest, apoptosis and differentiation, while it via fatty acid binding protein 5 (FABP5) is involved in survival, cell proliferation and angiogenesis, which pathway gets activated depends on the CRABP2/FABP5 ratio. Alterations of retinoid signaling were found in many cancer types. The deregulated retinoid signaling may also contribute to the development and/or recurrence of pterygium. The aim of our study was to determine mRNA and protein expressions of CRABP2 and FABP5 and ratio of CRABP2/FABP5 in primer and recurrent pterygium tissues. Pterygia tissues were collected from 30 eyes of 30 patients undergoing pterygium excision. CRABP2 and FABP5 mRNA and protein expression were assessed using Real-time PCR and Western blotting through examination of excised specimens from pterygium and conjunctiva tissues. The ratio of CRABP2/FABP5 gene expression was not altered when primary pterygium tissues compared normal conjunctival tissues (1.00-fold change). Whereas the ratio of CRABP2/ FABP5 gene expression was decreased when recurrent pterygium tissues compared normal conjunctival tissues (0.81-fold change). Understanding etiopathogenesis of pterygium may aid in the find of more promising treatments to prevent pterygium in earlier stages.
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Affiliation(s)
- Sumeyya Deniz Celik
- Medical Faculty, Department of Medical Biology, Gaziosmanpasa University, 60100, Tokat, Turkey.
| | - Omer Ates
- Medical Faculty, Department of Medical Biology, Gaziosmanpasa University, 60100, Tokat, Turkey
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20
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Hughes CS, ChinAleong JA, Kocher HM. CRABP2 and FABP5 expression levels in diseased and normal pancreas. Ann Diagn Pathol 2020; 47:151557. [PMID: 32593808 DOI: 10.1016/j.anndiagpath.2020.151557] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022]
Abstract
Recently, stromal targeting, by agents such as All trans retinoic acid (ATRA), has been regarded as a promising avenue for the treatment of pancreatic ductal adenocarcinoma (PDAC). The intra-cellular transportation of ATRA to the nuclear receptors is performed by either: fatty acid binding protein 5 (FABP5) or cellular retinoic acid binding protein 2 (CRABP2), dictating the transcription of downstream genes and, thus, eventual cell phenotype. Here, we explored the levels of each protein, in pancreatic tissues of patients presenting with a range of pancreatic diseases (pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), cholangiocarcinoma (CC)). We demonstrate that there is a significantly lower CRABP2 and FABP5 expression in activated fibroblasts or pancreatic stellate cells (PSC) in PDAC, as well as other diseased pancreas as in CC and CP, versus quiescent fibroblasts. The quiescent fibroblasts consistently show a pattern of high FABP5:CRABP2 ratio, whereas PSC in all non-PDAC tissues showed a low FABP5:CRABP2 ratio. PSC in PDAC patients had a range of FABP5:CRABP2 ratios (high, even and low). There was a lower CRABP2 expression in cancerous epithelial cells (PDAC) versus normal epithelial cells. This is also present in other disease states (CP, CC). Contrasting to the patterns seen for fibroblasts, the FABP5 expression in PDAC epithelial cells matched that of the normal epithelial cells. However, the normal epithelial cells had a high FABP5:CRABP2 ratio, compared to the PDAC epithelial cells. These ratios may have correlation with tumor progression, and overall survival. These findings could be confirmed in in vitro cell lysates. CRABP2 and FABP5 levels and ratios could serve as valuable biomarkers.
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Affiliation(s)
- Christine S Hughes
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK
| | - Jo-Anne ChinAleong
- Barts and the London HPB Centre, Department of Surgery and Pathology, Barts Health NHS Trust, The Royal London Hospital, London E1 1BB, UK
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute - a CR-UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK; Barts and the London HPB Centre, Department of Surgery and Pathology, Barts Health NHS Trust, The Royal London Hospital, London E1 1BB, UK.
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21
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Xu Y, Xu WH, Yang XL, Zhang HL, Zhang XF. Fatty acid-binding protein 5 predicts poor prognosis in patients with uveal melanoma. Oncol Lett 2020; 19:1771-1780. [PMID: 32194670 PMCID: PMC7038976 DOI: 10.3892/ol.2020.11301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 11/29/2019] [Indexed: 12/18/2022] Open
Abstract
Fatty acid-binding protein 5 (FABP5), which participates in mediating the biological properties of tumor cells, has been recognized in several neoplasms. The present study aims to investigate FABP5 transcriptional expression profiles, reveal its underlying biological interaction networks and define its prognostic value in uveal melanoma (UVM). A total of 80 patients with UVM and their RNA-sequence data, available from The Cancer Genome Atlas (TCGA) database, was analyzed. A differential transcriptional expression profile was obtained from TCGA and the Oncomine databases. The survival benefits were analyzed using the Kaplan-Meier method and log-rank test. The correlation between FABP5 expression and immune infiltration level was analyzed using the Tumor Immune Estimation Resource database. Functional enrichment analyses using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and signaling hallmarks were utilized to describe the biological process, molecular functions, cellular component and significantly involved pathways. The elevated transcriptional expression of FABP5 was significantly associated with shorter overall survival (OS) and worse progression-free survival (PFS) times in patients with UVM (P<0.001). Moreover, FABP5 expression was significantly and positively correlated with tumor purity and CD8+ T cells and was negatively correlated with the infiltrating levels of CD4+ T cells and neutrophils. Gene Set Enrichment Analysis was performed to obtain 100 significantly associated genes of FABP5 and FABP5 was found to be critical in several hallmark pathways, including allograft rejection, complement, interleukin-6/Janus kinase-STAT3 signaling, interferon γ response, inflammatory response and tumor necrosis factor α signaling via NFκB. The present study is the first to demonstrate that FABP5 expression was positively associated with progression-associated clinicopathological factors and poor prognosis in UVM, which suggests its likely function as an oncogene and prognostic marker in patients with UVM.
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Affiliation(s)
- Yue Xu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China.,Department of Ophthalmology, Soochow University Medical College, Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Wen-Hao Xu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 20032, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 20032, P.R. China
| | - Xiao-Long Yang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China.,Department of Ophthalmology, Soochow University Medical College, Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Hai-Liang Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 20032, P.R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 20032, P.R. China
| | - Xiao-Feng Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China.,Department of Ophthalmology, Soochow University Medical College, Soochow University, Suzhou, Jiangsu 215000, P.R. China
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22
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Lu JB, Cai SH, Pan YH, Yun JP. Altered epidermal fatty acid-binding protein expression in hepatocellular carcinoma predicts unfavorable outcomes. Cancer Manag Res 2018; 10:6275-6284. [PMID: 30538573 PMCID: PMC6260128 DOI: 10.2147/cmar.s181555] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Objective Hepatocellular carcinoma (HCC) is a rapidly proliferating malignancy that requires large amounts of fatty acids to synthesize cellular membranes and provide energy. Epidermal fatty acid-binding protein (EFABP) is uniquely expressed in epidermal cells, but its role and expression in HCC are not clear. Subjects and methods A total of 804 HCC specimens were collected to construct a tissue microarray (TMA) and for immunohistochemistry (IHC) analysis. The relationship between EFABP expression and clinical features of patients with HCC was analyzed. Results The EFABP IHC score for HCC tissue was 0.76±0.69, being significantly higher than that for matched nontumorous tissue (0.48±0.55; P<0.001). Using the median IHC score (ie, 0.8) in the tumorous tissue, a high level of EFABP expression was found in 57.3% (461/804) of the cases. Patients with HCC displaying high EFABP expression had poorer tumor differentiation (P=0.029), more vascular invasion (P=0.006), and a higher proportion of late TNM stage disease (P=0.042). Kaplan-Meier analysis revealed that the patients with high EFABP expression had significantly worse outcomes in terms of overall survival (P=0.003), worse disease-free survival (P=0.021), and a higher probability of recurrence (P=0.014). Multivariate analysis indicated that EFABP expression was an independent prognostic variable for overall survival (P=0.021) and disease-free survival (P=0.044). For HCC recurrence, only vascular invasion (P=0.020) and EFABP expression (P=0.026) were independent risk factors. Conclusion Our data revealed that EFABP expression was increased in HCC samples. High EFABP expression was correlated with shorter survival times in patients with HCC and served as an independent factor for worse outcomes. Our study therefore provides a promising bio-marker for the prognostic prediction of HCC and a potential therapeutic target for the disease.
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Affiliation(s)
- Jia-Bin Lu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China,
| | - Shao-Hang Cai
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ying-Hua Pan
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510060, China
| | - Jing-Ping Yun
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China, .,Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China,
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23
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Pan L, Xiao H, Liao R, Chen Q, Peng C, Zhang Y, Mu T, Wu Z. Fatty acid binding protein 5 promotes tumor angiogenesis and activates the IL6/STAT3/VEGFA pathway in hepatocellular carcinoma. Biomed Pharmacother 2018; 106:68-76. [PMID: 29957468 DOI: 10.1016/j.biopha.2018.06.040] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/10/2018] [Accepted: 06/11/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Tumor angiogenesis is an essential process for facilitating tumor growth and metastasis. Fatty acid binding protein 5(FABP5)is highly expressed in hepatocellular carcinoma (HCC). Thus, we investigated the role of FABP5 in tumor angiogenesis during HCC development. METHODS In this study, the protein and mRNA levels of FABP5 in matched HCC and adjacent noncancerous liver tissues from 43 patients were determined using immunohistochemistry and real-time quantitative PCR, respectively. Two HCC cell lines (Huh7 and SMMC-7721) and human umbilical vein endothelial cells (HUVECS) were used to investigate the pro-angiogenic effect of FABP5 by tube formation, CCK8 and Transwell migration assays. The expression levels of interleukin 6 (IL6) and vascular endothelial growth factor A (VEGFA) secreted from HCC cells were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS In 43 HCC patients, the expression of FABP5 mRNA was positively correlated with intratumoral VEGFA mRNA expression. FABP5 mRNA expression was also associated with adverse HCC characteristics. In vitro, cell viability, cell migration and tube formation in HUVECs were enhanced with increasing expression of FABP5 in HCC cells. Downregulation of FABP5 expression inhibited the IL6/STAT3/VEGFA pathway in HCC cells and inhibited tumor angiogenesis. CONCLUSION FABP5 was shown to promote angiogenesis and activate the IL6/STAT3/VEGFA pathway in HCC. FABP5 may be a potential antiangiogenic target in the treatment of HCC.
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Affiliation(s)
- Long Pan
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Heng Xiao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Rui Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Qingsong Chen
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Chong Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Yuchi Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Tong Mu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, PR China.
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24
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Senga S, Kawaguchi K, Kobayashi N, Ando A, Fujii H. A novel fatty acid-binding protein 5-estrogen-related receptor α signaling pathway promotes cell growth and energy metabolism in prostate cancer cells. Oncotarget 2018; 9:31753-31770. [PMID: 30167092 PMCID: PMC6114981 DOI: 10.18632/oncotarget.25878] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/21/2018] [Indexed: 01/16/2023] Open
Abstract
Epidermal or cutaneous fatty acid-binding protein is an intracellular lipid-binding protein, also known as FABP5, and its expression level is closely related to cancer cell proliferation and metastatic activities in various types of carcinoma. However, the molecular mechanisms of FABP5 in cancer cell proliferation and its other functions have remained unclear. In the present study, we have clearly revealed that FABP5 activated expression of metabolic genes (ATP5B, LCHAD, ACO2, FH and MFN2) via a novel signaling pathway in an ERRα (estrogen-related receptor α)-dependent manner in prostate cancer cell lines. To clarify the novel function of FABP5, we examined the activation mechanisms of the ERRα target genes via FABP5. A direct protein-protein interaction between FABP5 and ERRα was demonstrated by immunoprecipitation and GST pull-down assays. We have clearly revealed that FABP5 interacted directly with transcriptional complex containing ERRα and its co-activator PGC-1β to increase expression of the ERRα target genes. In addition, we have shown that FABP5 knockdown induced high energy stress leading to induction of apoptosis and cell cycle arrest via AMPK-FOXO3A signaling pathway in prostate cancer cells, suggesting that FABP5 plays an important role in cellular energy status directing metabolic adaptation to support cellular proliferation and survival.
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Affiliation(s)
- Shogo Senga
- Interdisciplinary Graduate School of Science and Technology, Shinshu University, Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
| | - Koichiro Kawaguchi
- Interdisciplinary Graduate School of Science and Technology, Shinshu University, Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
| | - Narumi Kobayashi
- Department of Biomedical Engineering, Graduate School of Science and Technology, Shinshu University, Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
| | - Akira Ando
- Department of Biomedical Engineering, Graduate School of Science and Technology, Shinshu University, Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
| | - Hiroshi Fujii
- Department of Interdisciplinary Genome Sciences and Cell Metabolism, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting-Edge Research, Shinshu University, Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
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25
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Amiri M, Yousefnia S, Seyed Forootan F, Peymani M, Ghaedi K, Nasr Esfahani MH. Diverse roles of fatty acid binding proteins (FABPs) in development and pathogenesis of cancers. Gene 2018; 676:171-183. [PMID: 30021130 DOI: 10.1016/j.gene.2018.07.035] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 07/04/2018] [Accepted: 07/12/2018] [Indexed: 12/27/2022]
Abstract
One of the most importantly involved pathways in cancer development is fatty-acid signaling pathway. Synthesized lipids as energetic sources are consumed by cancer cells for proliferation, growth, survival, invasion and angiogenesis. Fatty acids as signaling compounds regulate metabolic and transcriptional networks, survival pathways and inflammatory responses. Aggregation of fatty acids with fatty acid binding proteins (FABPs) facilitates their transportation to different cell organelles. FABPs, a group of lipid binding proteins modulate fatty acid metabolism, cell growth and proliferation and cancer development. They may be used as tumor marker in some cancers. FABPs are expressed in most malignancies such as prostate, breast, liver, bladder and lung cancer which are associated with the incidence, proliferation, metastasis, invasion of tumors. This review introduces several isoforms of FABPs (FABP1-12) and summarizes their function and their possible roles in cancer development through some proposed mechanisms.
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Affiliation(s)
- Mina Amiri
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
| | - Saghar Yousefnia
- Division of Cellular and Molecular Biology, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Farzad Seyed Forootan
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran; Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran; Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Kamran Ghaedi
- Division of Cellular and Molecular Biology, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Mohammad Hossein Nasr Esfahani
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
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26
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Guaita-Esteruelas S, Gumà J, Masana L, Borràs J. The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5. Mol Cell Endocrinol 2018; 462:107-118. [PMID: 28163102 DOI: 10.1016/j.mce.2017.02.002] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/11/2017] [Accepted: 02/01/2017] [Indexed: 02/08/2023]
Abstract
The adipose tissue microenvironment plays a key role in tumour initiation and progression because it provides fatty acids and adipokines to tumour cells. The fatty acid-binding protein (FABP) family is a group of small proteins that act as intracellular fatty acid transporters. Adipose-derived FABPs include FABP4 and FABP5. Both have an important role in lipid-related metabolic processes and overexpressed in many cancers, such as breast, prostate, colorectal and ovarian. Moreover, their expression in peritumoural adipose tissue is deregulated, and their circulating levels are upregulated in some tumours. In this review, we discuss the role of the peritumoural adipose tissue and the related adipokines FABP4 and FABP5 in cancer initiation and progression and the possible pathways implicated in these processes.
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Affiliation(s)
- S Guaita-Esteruelas
- Institut d'Investigació Sanitària Pere Virgili (IISPV), Centre d'R+D+I en Nutrició i Salut, Avda. de la Universitat, 43204 Reus, Spain; Research Unit on Lipids and Atherosclerosis, Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Sant Llorenç, 21 43201 Reus, Spain; Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. del Dr, Josep Laporte, 2, 43204 Reus, Spain.
| | - J Gumà
- Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. del Dr, Josep Laporte, 2, 43204 Reus, Spain; Department of Medicine and Surgery, Universitat Rovira i Virgili, Sant Llorenç, 21, 43201 Reus, Spain
| | - L Masana
- Research Unit on Lipids and Atherosclerosis, Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Universitat Rovira i Virgili, Sant Llorenç, 21 43201 Reus, Spain
| | - J Borràs
- Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. del Dr, Josep Laporte, 2, 43204 Reus, Spain; Department of Medicine and Surgery, Universitat Rovira i Virgili, Sant Llorenç, 21, 43201 Reus, Spain
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27
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Schwarz R, Ramer R, Hinz B. Targeting the endocannabinoid system as a potential anticancer approach. Drug Metab Rev 2018; 50:26-53. [PMID: 29390896 DOI: 10.1080/03602532.2018.1428344] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The endocannabinoid system is currently under intense investigation due to the therapeutic potential of cannabinoid-based drugs as treatment options for a broad variety of diseases including cancer. Besides the canonical endocannabinoid system that includes the cannabinoid receptors CB1 and CB2 and the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, recent investigations suggest that other fatty acid derivatives, receptors, enzymes, and lipid transporters likewise orchestrate this system as components of the endocannabinoid system when defined as an extended signaling network. As such, fatty acids acting at cannabinoid receptors (e.g. 2-arachidonoyl glyceryl ether [noladin ether], N-arachidonoyldopamine) as well as endocannabinoid-like substances that do not elicit cannabinoid receptor activation (e.g. N-palmitoylethanolamine, N-oleoylethanolamine) have raised interest as anticancerogenic substances. Furthermore, the endocannabinoid-degrading enzymes fatty acid amide hydrolase and monoacylglycerol lipase, lipid transport proteins of the fatty acid binding protein family, additional cannabinoid-activated G protein-coupled receptors, members of the transient receptor potential family as well as peroxisome proliferator-activated receptors have been considered as targets of antitumoral cannabinoid activity. Therefore, this review focused on the antitumorigenic effects induced upon modulation of this extended endocannabinoid network.
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Affiliation(s)
- Rico Schwarz
- a Institute of Pharmacology and Toxicology , Rostock University Medical Center , Rostock , Germany
| | - Robert Ramer
- a Institute of Pharmacology and Toxicology , Rostock University Medical Center , Rostock , Germany
| | - Burkhard Hinz
- a Institute of Pharmacology and Toxicology , Rostock University Medical Center , Rostock , Germany
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28
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Zhao G, Wu M, Wang X, Du Z, Zhang G. Effect of FABP5 gene silencing on the proliferation, apoptosis and invasion of human gastric SGC-7901 cancer cells. Oncol Lett 2017; 14:4772-4778. [PMID: 29085478 PMCID: PMC5649645 DOI: 10.3892/ol.2017.6748] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 07/10/2017] [Indexed: 01/10/2023] Open
Abstract
The aim of the present study was to examine the effect of fatty acid binding protein-5 (FABP-5) gene on the proliferation, apoptosis and invasion of human gastric cancer SGC-7901 cells. The viability, apoptosis and cell invasion of SGC-7901 cells before and after FABP5 knockdown were taken as the study objects, design and synthesis of siRNA interference sequence were conducted according to FABP-5 mRNA coding sequences, and SGC-7901 cells were transiently transfected. The human gastric cancer SGC-7901 cells were divided into three groups: FABP-5 siRNA group, negative control group and blank control group. FABP-5 gene mRNA and protein expression levels were detected by RT-PCR and western blot analysis. The CCK-8 assay was used to detect in vitro cell proliferation, flow cytometry (FCM) was used to detect changes in cell cycle and apoptosis in each group, TUNEL staining was used to detect apoptosis in each group, and the cell invasion chamber assay was used to detect cell invasiveness in each group. Each test was repeated three times. The results of the RT-PCR and western blot analysis showed that, expression of FABP-5 mRNA and protein in the FABP-5 siRNA group was significantly decreased compared with the negative and blank control groups. The cell growth rate in the FABP-5 siRNA group was significantly retarded, cell cycle was arrested in G0/G1 phase, the number of cells in S phase was reduced, and compared with the negative and blank control groups, the apoptotic rate in the FABP-5 siRNA group was significantly increased (P<0.01), while proliferation and invasiveness were significantly decreased (P<0.05). In conclusion, specific FABP-5 gene silencing may reduce the invasiveness of gastric cancer cells, inhibit cell proliferation, and arrest cell cycle in G0/G1 phase, resulting in a significant increase in apoptosis.
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Affiliation(s)
- Guanjie Zhao
- Research Center of The Second Hospital, Jilin University, Changchun, Jilin 130041, P.R. China.,Department of Nephropathy, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R.China
| | - Minfei Wu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Xiaofeng Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Zhenwu Du
- Research Center of The Second Hospital, Jilin University, Changchun, Jilin 130041, P.R. China.,Orthopedics Institute of The Second Hospital, Jilin University, Changchun, Jilin 130041, P.R.China
| | - Guizhen Zhang
- Research Center of The Second Hospital, Jilin University, Changchun, Jilin 130041, P.R. China.,Orthopedics Institute of The Second Hospital, Jilin University, Changchun, Jilin 130041, P.R.China
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Rong Z, Fan T, Li H, Li J, Wang K, Wang X, Dong J, Chen J, Wang F, Wang J, Wang A. Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice. Mol Cell Proteomics 2017; 16:1475-1490. [PMID: 28512230 DOI: 10.1074/mcp.m116.065474] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2016] [Revised: 04/29/2017] [Indexed: 12/18/2022] Open
Abstract
Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the ras oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peritumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of nontransgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 autodetected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio| > = 1.5, p < = 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared with Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared with that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the upregulated proteins in T compared with Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatocytes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.
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Affiliation(s)
- Zhuona Rong
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Tingting Fan
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Huiling Li
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Juan Li
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Kangwei Wang
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Xinxin Wang
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Jianyi Dong
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Jun Chen
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Fujin Wang
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China
| | - Jingyu Wang
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China.
| | - Aiguo Wang
- From the ‡Laboratory Animal Center, Dalian Medical University, Dalian, Liaoning 116000, China.
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Ohata T, Yokoo H, Kamiyama T, Fukai M, Aiyama T, Hatanaka Y, Hatanaka K, Wakayama K, Orimo T, Kakisaka T, Kobayashi N, Matsuno Y, Taketomi A. Fatty acid-binding protein 5 function in hepatocellular carcinoma through induction of epithelial-mesenchymal transition. Cancer Med 2017; 6:1049-1061. [PMID: 28374947 PMCID: PMC5430096 DOI: 10.1002/cam4.1020] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 12/27/2016] [Accepted: 01/03/2017] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly prevalent cancer with poor prognosis. The correlation between overexpression of fatty acid-binding protein 5 (FABP5) and malignant potential of tumor growth and metastasis in several cancers has been previously reported. However, the correlation between FABP5 expression and HCC malignant behavior remains unknown. We compared FABP5 expression and patient characteristics in paired HCC and adjacent noncancerous liver tissues from 243 patients who underwent surgical resection of primary HCC. Cell proliferation, invasion, and migration assays were performed in HCC cell lines overexpressing FABP5 or downregulated for FABP5. Tumor growths were monitored in xenograft model, and liver and lung metastasis models were established. In the 243 HCC patients, FABP5-positive staining (n = 139/243, 57.2%) was associated with poor prognosis and recurrence (P < 0.0001) and showed positive correlation with distant metastasis, tumor size and vascular invasion (P < 0.05). Cell proliferation, invasion, and migration in vitro were enhanced by upregulation of FABP5 and decreased by downregulation of FABP5 in HCC cell lines. Similar results in tumor formation and metastasis were obtained through in vivo analyses. PCR array results revealed upregulation of SNAI1 in FABP5-overexpressing HepG2 cells. Western blot analysis showed significantly increased expression of E-cadherin and ZO-1 and decreased SNAI1 expression and nuclear translocation of β-catenin by knockdown of FABP5. We revealed a significant role for FABP5 in HCC progression and metastasis through the induction of epithelial-to-mesenchymal transition. FABP5 may be a potential novel prognostic biomarker and new therapeutic target for HCC.
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Affiliation(s)
- Takanori Ohata
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Hideki Yokoo
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Moto Fukai
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Takeshi Aiyama
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Yutaka Hatanaka
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Kanako Hatanaka
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Kenji Wakayama
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Tatsuya Orimo
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Tatsuhiko Kakisaka
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Nozomi Kobayashi
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
| | - Yoshihiro Matsuno
- Department of Surgical PathologyHokkaido University HospitalSapporoJapan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery IHokkaido University Graduate School of MedicineSapporoJapan
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Fujita K, Kume H, Matsuzaki K, Kawashima A, Ujike T, Nagahara A, Uemura M, Miyagawa Y, Tomonaga T, Nonomura N. Proteomic analysis of urinary extracellular vesicles from high Gleason score prostate cancer. Sci Rep 2017; 7:42961. [PMID: 28211531 PMCID: PMC5314323 DOI: 10.1038/srep42961] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 01/17/2017] [Indexed: 12/20/2022] Open
Abstract
Extracellular vesicles (EVs) are microvesicles secreted from various cell types. We aimed to discover a new biomarker for high Gleason score (GS) prostate cancer (PCa) in urinary EVs via quantitative proteomics. EVs were isolated from urine after massage from 18 men (negative biopsy [n = 6], GS 6 PCa [n = 6], or GS 8–9 PCa [n = 6]). EV proteins were labeled with iTRAQ and analyzed by LC-MS/MS. We identified 4710 proteins and quantified 3528 proteins in the urinary EVs. Eleven proteins increased in patients with PCa compared to those with negative biopsy (ratio >1.5, p-value < 0.05). Eleven proteins were chosen for further analysis and verified in 29 independent urine samples (negative [n = 11], PCa [n = 18]) using selected reaction monitoring/multiple reaction monitoring. Among these candidate markers, fatty acid binding protein 5 (FABP5) was higher in the cancer group than in the negative group (p-value = 0.009) and was significantly associated with GS (p-value for trend = 0.011). Granulin, AMBP, CHMP4A, and CHMP4C were also higher in men with high GS prostate cancer (p-value < 0.05). FABP5 in urinary EVs could be a potential biomarker of high GS PCa.
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Affiliation(s)
- Kazutoshi Fujita
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hideaki Kume
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Kyosuke Matsuzaki
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsunari Kawashima
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takeshi Ujike
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Akira Nagahara
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Motohide Uemura
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yasushi Miyagawa
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan
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Wang W, Chu HJ, Liang YC, Huang JM, Shang CL, Tan H, Liu D, Zhao YH, Liu TY, Yao SZ. FABP5 correlates with poor prognosis and promotes tumor cell growth and metastasis in cervical cancer. Tumour Biol 2016; 37:14873-14883. [DOI: 10.1007/s13277-016-5350-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 09/06/2016] [Indexed: 12/18/2022] Open
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Kawaguchi K, Senga S, Kubota C, Kawamura Y, Ke Y, Fujii H. High expression of Fatty Acid-Binding Protein 5 promotes cell growth and metastatic potential of colorectal cancer cells. FEBS Open Bio 2016; 6:190-9. [PMID: 27047747 PMCID: PMC4794781 DOI: 10.1002/2211-5463.12031] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 01/06/2016] [Accepted: 01/08/2016] [Indexed: 01/25/2023] Open
Abstract
Fatty acid‐binding proteins (FABPs) are responsible for binding and storing hydrophobic ligands such as long‐chain fatty acids, and for transporting these ligands to the appropriate compartments within the cell. The present study demonstrates that the FABP5 gene is upregulated in colorectal cancer cells compared to normal colon cells in a manner that correlates with disease stage and that FABP5 significantly promotes colorectal cancer cell growth and metastatic potential. Thus, FABP5 might be a promising prognostic or therapeutic biomarker candidate in human colorectal cancer.
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Affiliation(s)
- Koichiro Kawaguchi
- Interdisciplinary Graduate School of Science and Technology Shinshu University Minami-minowa Kami-ina Nagano Japan
| | - Shogo Senga
- Department of Bioscience and Biotechnology Faculty of Agriculture Shinshu University Minami-minowa Kami-ina Nagano Japan
| | - Chiaki Kubota
- Department of Bioscience and Biotechnology Faculty of Agriculture Shinshu University Minami-minowa Kami-ina Nagano Japan
| | - Yuki Kawamura
- Department of Bioscience and Biotechnology Faculty of Agriculture Shinshu University Minami-minowa Kami-ina Nagano Japan
| | - Youqiang Ke
- Molecular Pathology Laboratory Department of Molecular and Clinical Cancer Medicine The University of Liverpool UK
| | - Hiroshi Fujii
- Interdisciplinary Graduate School of Science and Technology Shinshu University Minami-minowa Kami-ina Nagano Japan; Department of Bioscience and Biotechnology Faculty of Agriculture Shinshu University Minami-minowa Kami-ina Nagano Japan; Department of Interdisciplinary Genome Sciences and Cell Metabolism Institute for Biomedical Sciences Interdisciplinary Cluster for Cutting-Edge Research Shinshu University Minami-minowa Kami-ina Nagano Japan
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The cancer-promoting gene fatty acid-binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis. Biochem J 2016; 473:449-61. [DOI: 10.1042/bj20150926] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 11/27/2015] [Indexed: 12/12/2022]
Abstract
The DNA methylation status of CpG islands in the FABP5 promoter is critical for its expression. Epigenetic regulation of FABP5 gene expression plays an important role during human prostate carcinogenesis, along with up-regulation of c-Myc and Sp1.
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35
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Harjes U, Kalucka J, Carmeliet P. Targeting fatty acid metabolism in cancer and endothelial cells. Crit Rev Oncol Hematol 2016; 97:15-21. [DOI: 10.1016/j.critrevonc.2015.10.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 09/03/2015] [Accepted: 10/27/2015] [Indexed: 12/15/2022] Open
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Ju YT, Kwag SJ, Park HJ, Jung EJ, Jeong CY, Jeong SH, Lee YJ, Choi SK, Kang KR, Hah YS, Hong SC. Decreased expression of heat shock protein 20 in colorectal cancer and its implication in tumorigenesis. J Cell Biochem 2015; 116:277-86. [PMID: 25187324 DOI: 10.1002/jcb.24966] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 08/29/2014] [Indexed: 12/11/2022]
Abstract
Heat shock protein 20 (HSP20), which is a member of the small heat shock protein family, is known to participate in many pathological processes, such as asthma, intimal hyperplasia, and insulin resistance. However, the function of HSP20 in cancer development is not yet fully understood. In this study, we identified HSP20 as a down-regulated protein in 20 resected colorectal cancer (CRC) specimens compared with their paired normal tissues. Because HSP20 proteins were barely detectable in HCT-116 cells (a human colorectal cancer cell line), recombinant adenovirus encoding HSP20 (Ad-HSP20) was used to induce HSP20 overexpression in HCT-116 cells. Infection of Ad-HSP20, but not control adenovirus (Ad-GFP), reduced viability, and induced massive apoptosis in a time-dependent manner. The forced expression of HSP20 enhanced caspase-3/7 activity and down-regulated the anti-apoptotic Bcl-xL and Bcl-2 mRNA and protein levels. In addition, immunohistochemical analysis of 94 CRC specimens for HSP20 protein showed that reduced HSP20 expression was related to advanced TNM stage, lymph node metastasis, and tumor recurrence. Our study shows, for the first time, that expression of the HSP20 protein has a pro-death role in colorectal cancer cells. Therefore, HSP20 may have value as a prognostic tumor marker and its overexpression might be a novel strategy for CRC therapy.
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Affiliation(s)
- Young-Tae Ju
- Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea
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Dolcino M, Ottria A, Barbieri A, Patuzzo G, Tinazzi E, Argentino G, Beri R, Lunardi C, Puccetti A. Gene Expression Profiling in Peripheral Blood Cells and Synovial Membranes of Patients with Psoriatic Arthritis. PLoS One 2015; 10:e0128262. [PMID: 26086874 PMCID: PMC4473102 DOI: 10.1371/journal.pone.0128262] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 04/24/2015] [Indexed: 12/22/2022] Open
Abstract
Background Psoriatic arthritis (PsA) is an inflammatory arthritis whose pathogenesis is poorly understood; it is characterized by bone erosions and new bone formation. The diagnosis of PsA is mainly clinical and diagnostic biomarkers are not yet available. The aim of this work was to clarify some aspects of the disease pathogenesis and to identify specific gene signatures in paired peripheral blood cells (PBC) and synovial biopsies of patients with PsA. Moreover, we tried to identify biomarkers that can be used in clinical practice. Methods PBC and synovial biopsies of 10 patients with PsA were used to study gene expression using Affymetrix arrays. The expression values were validated by Q-PCR, FACS analysis and by the detection of soluble mediators. Results Synovial biopsies of patients showed a modulation of approximately 200 genes when compared to the biopsies of healthy donors. Among the differentially expressed genes we observed the upregulation of Th17 related genes and of type I interferon (IFN) inducible genes. FACS analysis confirmed the Th17 polarization. Moreover, the synovial trascriptome shows gene clusters (bone remodeling, angiogenesis and inflammation) involved in the pathogenesis of PsA. Interestingly 90 genes are modulated in both compartments (PBC and synovium) suggesting that signature pathways in PBC mirror those of the inflamed synovium. Finally the osteoactivin gene was upregulared in both PBC and synovial biopsies and this finding was confirmed by the detection of high levels of osteoactivin in PsA sera but not in other inflammatory arthritides. Conclusions We describe the first analysis of the trancriptome in paired synovial tissue and PBC of patients with PsA. This study strengthens the hypothesis that PsA is of autoimmune origin since the coactivity of IFN and Th17 pathways is typical of autoimmunity. Finally these findings have allowed the identification of a possible disease biomarker, osteoactivin, easily detectable in PsA serum.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Antonio Puccetti
- Institute G. Gaslini, Genova, Italy
- University of Genova, Genova, Italy
- * E-mail:
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Zhou LL, Cao J, Li W, Luo W, Yang XD, Yang C, Luo CP, Tang YP, Li Y. Effect of RNA interference targeting FABP-5 on cell proliferation, apoptosis and invasion in human hepatocellular carcinoma cell line HepG2. Shijie Huaren Xiaohua Zazhi 2015; 23:179-188. [DOI: 10.11569/wcjd.v23.i2.179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of recombinant lentiviral mediated RNA interference (RNAi) targeting the fatty acid binding protein-5 (FABP-5) gene on cell proliferation, apoptosis and invasiveness in human hepatocellular carcinoma cell line HepG2, and to explore the possible underlying mechanisms.
METHODS: Three vectors carrying short hairpin RNAs (shRNAs) targeting the FABP-5 gene (FABP-5-shRNA expression vectors) were constructed and selected for the most effective one. HepG2 cells were divided into three groups: an experimental group, a normal control group and a negative control group. For the experimental group, HepG2 cells were transfected with the recombinant lentiviral vector (LV-shRNA-FABP-5), the negative control group was transfected with a control lentiviral vector (LV-shRNA-NC), and the normal control group did not undergo any treatment. The mRNA level of FABP-5 was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time polymerase chain reaction (qPCR). The relative expression of FABP-5 protein was analyzed by Western blot. Cell proliferation was detected by MTT assay, cell colony formation was detected by Giemsa staining, cell invasion ability was assessed using the cell invasion chamber method, and cell cycle and apoptosis were observed by flow cytometry (FCM).
RESULTS: FABP-5-shRNA expression vectors were transfected into HepG2 cells, and fluorescence analysis indicated that > 90% of cells showed fluorescence signal. Compared with the normal control group and negative control group, FABP-5 mRNA and protein expression was significantly down-regulated in cells transfected with the three shRNA carrying vectors, with the LV-shRNA-FABP-5 having the highest efficiency ( P < 0.05). HepG2 cell transfected with the FABP-5-shRNA had significantly reduced proliferation and invasion compared with the other two groups ( P < 0.05). Flow cytometry analysis showed that the experimental group showed obvious apoptosis ( P < 0.05). The percentage of cells in G2/M phase significantly increased in cells transfected with the FABP-5-shRNA ( P < 0.05).
CONCLUSION: The high expression of the FABP-5 gene could be silenced by RNAi, and RNAi-induced FABP-5 knockdown could effectively inhibit the proliferation and invasion of HepG2 cells, block the cell cycle in G2/M phase, and significantly increase cell apoptosis.
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Rabilloud T, Lescuyer P. Proteomics in mechanistic toxicology: History, concepts, achievements, caveats, and potential. Proteomics 2014; 15:1051-74. [DOI: 10.1002/pmic.201400288] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 07/25/2014] [Accepted: 08/25/2014] [Indexed: 12/19/2022]
Affiliation(s)
- Thierry Rabilloud
- Laboratory of Chemistry and Biology of Metals; CNRS UMR; 5249 Grenoble France
- Laboratory of Chemistry and Biology of Metals; Université Grenoble Alpes; Grenoble France
- Laboratory of Chemistry and Biology of Metals; CEA Grenoble; iRTSV/CBM; Grenoble France
| | - Pierre Lescuyer
- Department of Human Protein Sciences; Clinical Proteomics and Chemistry Group; Geneva University; Geneva Switzerland
- Toxicology and Therapeutic Drug Monitoring Laboratory; Department of Genetic and Laboratory Medicine; Geneva University Hospitals; Geneva Switzerland
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Sanada Y, Kawashita Y, Okada S, Azuma T, Matsuo S. Review to better understand the macroscopic subtypes and histogenesis of intrahepatic cholangiocarcinoma. World J Gastrointest Pathophysiol 2014; 5:188-199. [PMID: 25133021 PMCID: PMC4133518 DOI: 10.4291/wjgp.v5.i3.188] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/18/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Intrahepatic cholangiocarcinoma is macroscopically classified into three subtypes, mass-forming-type, periductal infiltrating-type, and intraductal growth-type. Each subtype should be preoperatively differentiated to perform the valid surgical resection. Recent researches have revealed the clinical, radiologic, pathobiological characteristics of each subtype. We reviewed recently published studies covering various aspects of intrahepatic cholangiocarcinoma (ICC), focusing especially on the macroscopic subtypes and stem cell features to better understand the pathophysiology of ICC and to establish the valid therapeutic strategy.
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Armstrong EH, Goswami D, Griffin PR, Noy N, Ortlund EA. Structural basis for ligand regulation of the fatty acid-binding protein 5, peroxisome proliferator-activated receptor β/δ (FABP5-PPARβ/δ) signaling pathway. J Biol Chem 2014; 289:14941-54. [PMID: 24692551 DOI: 10.1074/jbc.m113.514646] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Fatty acid-binding proteins (FABPs) are a widely expressed group of calycins that play a well established role in solubilizing cellular fatty acids. Recent studies, however, have recast FABPs as active participants in vital lipid-signaling pathways. FABP5, like its family members, displays a promiscuous ligand binding profile, capable of interacting with numerous long chain fatty acids of varying degrees of saturation. Certain "activating" fatty acids induce the protein's cytoplasmic to nuclear translocation, stimulating PPARβ/δ transactivation; however, the rules that govern this process remain unknown. Using a range of structural and biochemical techniques, we show that both linoleic and arachidonic acid elicit FABP5's translocation by permitting allosteric communication between the ligand-sensing β2 loop and a tertiary nuclear localization signal within the α-helical cap of the protein. Furthermore, we show that more saturated, nonactivating fatty acids inhibit nuclear localization signal formation by destabilizing this activation loop, thus implicating FABP5 specifically in cis-bonded, polyunsaturated fatty acid signaling.
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Affiliation(s)
- Eric H Armstrong
- From the Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Devrishi Goswami
- the Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, and
| | - Patrick R Griffin
- the Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, and
| | - Noa Noy
- the Departments of Pharmacology and Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Eric A Ortlund
- From the Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322,
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Identification of biomarkers for lymph node metastasis in early-stage cervical cancer by tissue-based proteomics. Br J Cancer 2014; 110:1748-58. [PMID: 24569473 PMCID: PMC3974096 DOI: 10.1038/bjc.2014.92] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 12/09/2013] [Accepted: 01/22/2014] [Indexed: 12/14/2022] Open
Abstract
Background: Pelvic lymph node metastasis (PLNM) is the key to determining the treatment and prognosis of early-stage cervical cancer (CC, I–IIst). The aim of this study was to identify biomarkers for PLNM of CC, I–IIst. Methods: Two-dimensional fluorescence difference gel electrophoresis and matrix-assisted laser desorption/ionisation-time-of-flight mass spectrometry (MALDI-TOF/TOF MS) were used to identify differentially expressed proteins in primary CC, I–IIst tissue with (n=8) and without (n=10) PLNM. The expression levels of three differential proteins (FABP5, HspB1, and MnSOD) were validated using western blotting and immunohistochemistry. An independent cohort of 105 CC, I–IIst patients was analysed to assess the correlation of FABP5, HspB1, and MnSOD with clinicopathologic factors and clinical outcomes. Results: Forty-one differential proteins were identified. Upregulation of FABP5, HspB1, and MnSOD in CC, I–IIst with PLNM was confirmed and was significantly correlated with PLNM. FABP5, HspB1, and MnSOD were significant predictors of PLNM in univariate analysis. FABP5, HspB1, and lymphovascular space invasion (LVSI) were independent predictors of PLNM in multivariate analysis. Survival curves indicated that CC, I–IIst patients with FABP5, HspB1, and MnSOD upregulation had poor prognosis. Conclusions: FABP5, HspB1, and MnSOD may be potential biomarkers for PLNM of CC, I–IIst and may have important roles in the pathogenesis of PLNM.
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Yazici C, Niemeyer DJ, Iannitti DA, Russo MW. Hepatocellular carcinoma and cholangiocarcinoma: an update. Expert Rev Gastroenterol Hepatol 2014; 8:63-82. [PMID: 24245910 DOI: 10.1586/17474124.2014.852468] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide and is rising in incidence. Ultrasound is the preferred modality for screening high-risk patients for HCC because it detects clinically significant nodules, widespread availability and lower cost. HCC does not require a biopsy for diagnosis if specific imaging criteria are fulfilled. Transarterial chemoembolization (TACE) is the most common modality used to treat HCC followed by ablation. Cholangiocarcinoma (CCA) is increasing in incidence and the second most common primary malignancy of the liver. There is no effective screening strategy for CCA although magnetic resonance imaging and carbohydrate antigen 19-9 (CA 19-9) are commonly used without proven benefit. Therapy for CCA is challenging and resection, when possible, is the mainstay of therapy. Gemcitabine in combination with cisplatin or biologics may offer a modest survival benefit. Liver transplantation for CCA is associated with reasonable survival in select cases. Molecular diagnostics offer the potential to develop personalized approaches in the management of HCC and CCA.
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Affiliation(s)
- Cemal Yazici
- Division of Hepatology and HPB Surgery, Carolinas Medical Center, Charlotte, NC, USA
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Wang YX, Liu W, Tan XY, Tang HH. In vitro neuraotropic growth of cholangiocarcinoma: an experimental study. JRSM SHORT REPORTS 2013; 4:2042533313476690. [PMID: 24319575 PMCID: PMC3831859 DOI: 10.1177/2042533313476690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective Perineural invasion of cholangiocarcinoma happens in the early stage of the disease but is often not recognized until its later stages. Research about the behaviour and mechanism of perineural invasion by cholangiocarcinoma is urgently needed for a useful new model. The aim of this work is to establish a novel model to address the problem. Design Neural cells and cholangiocarcinoma cells were co-cultured to mimic the neurotropic invasion of cholangiocarcinoma. Setting Human embryonic stem cells were induced to form neural cells by glial cell-derived neurotropic factor and retinoic acid; neural cells and cholangiocarcinoma cells were co-cultured in Transwell chamber. Participants Human embryonic stem cells and cholangiocarcinoma cells were applied. Main outcome measures Paired t-test was used to compare the counts of penetrating cholangiocarcinoma cells in co-culture and control group. Results Formation of neurospheres and neural-like cells were observed following induction at 24 and 48 h, respectively; synapses were viewed to protrude from neural-like cell bodies after incubation for 96 h. Forty-eight hours after incubation, immunocytochemical staining of the cells showed that synaptophysin and glial fibrillary acidic protein were expressed in the neuron-like cells and gliocytes-like cells, respectively. The cholangiocarcinoma cells that had penetrated through the Matrigel/polyethylene terephthalate membrane from the upper chamber to the lower chamber of the Transwell in the co-culture group were significantly more numerous than those in the control group (68 ± 8.3/field versus 46 ± 5.7/field, P < 0.05). Conclusion The novel model is a valuable tool to study the perineural invasion of cholangiocarcinoma.
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Affiliation(s)
- Yu-Xue Wang
- Department of Emergency Medicine, Xiang Ya Hospital, Central South University, Changsha 410008, China
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Jo HJ, Shim HE, Han ME, Kim HJ, Kim KS, Baek S, Choi KU, Hur GY, Oh SO. WTAP regulates migration and invasion of cholangiocarcinoma cells. J Gastroenterol 2013; 48:1271-82. [PMID: 23354623 DOI: 10.1007/s00535-013-0748-7] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Accepted: 12/25/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Wilms' tumor 1-associating protein (WTAP) is a nuclear protein that has been associated with the regulation of proliferation and apoptosis. Although its dynamic expression and physiological functions in vascular cells have been reported, its expression and roles in cholangiocarcinoma cells are poorly characterized. METHODS To examine the expression of WTAP in patient tissues, we performed immunohistochemistry. To examine motility of cholangiocarcinoma cells, we employed Boyden chamber, wound healing and Matrigel invasion assays, and a liver xenograft model. RESULTS Immunohistochemistry in patient tissues showed WTAP overexpression in cholangiocarcinoma tissues and correlation of WTAP expression with metastasis of cholangiocarcinoma cells. Overexpression or knockdown of WTAP significantly increased or decreased the motility of cholangiocarcinoma cells. Moreover, WTAP overexpression or knockdown significantly increased or decreased tumorigenicity of cholangiocarcinoma cells in an orthotopic xenograft model. Furthermore, microarray study showed that WTAP induce the expressions of MMP7, MMP28, cathepsin H and Muc1. CONCLUSION WTAP is overexpressed in cholangiocarcinoma and regulates motility of cholangiocarcinoma cells.
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Affiliation(s)
- Hong-Jae Jo
- Departments of Surgery, School of Medicine, Pusan National University, Busan, Republic of Korea
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