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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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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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Shand H, Patra S, Ghorai S. Fatty acid binding protein as a new age biomarker. Clin Chim Acta 2025; 565:120029. [PMID: 39515633 DOI: 10.1016/j.cca.2024.120029] [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: 07/09/2024] [Revised: 10/28/2024] [Accepted: 11/04/2024] [Indexed: 11/16/2024]
Abstract
Small lipid-binding proteins known as fatty acid-binding proteins (FABPs) are extensively expressed in cells having elevated levels of fatty acid (FA) metabolism. There are ten known FABPs in mammals that exhibit expression patterns specific to tissues and tertiary structures that are substantially preserved. FABPs were first investigated as FA transport proteins inside cells. Subsequent research has shown that they are involved in signalling within their expression cells and in metabolism of lipid, directly and through the control of expression of gene. Additionally, there is evidence that they might be released and influence circulatory function. It has been observed that some tissues and organs linked to inflammatory, metabolic illnesses and also infectious disease have markedly elevated expression levels of FABPs. Thus, in addition to previously identified markers, FABPs represent a promising new biomarker that require additional investigation to optimise illness detection and prognosis techniques.
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Affiliation(s)
- Harshita Shand
- Infection and Disease Biology Laboratory, Department of Microbiology, Raiganj University, Raiganj, West Bengal- 733134, India
| | - Soumendu Patra
- Infection and Disease Biology Laboratory, Department of Microbiology, Raiganj University, Raiganj, West Bengal- 733134, India
| | - Suvankar Ghorai
- Infection and Disease Biology Laboratory, Department of Microbiology, Raiganj University, Raiganj, West Bengal- 733134, India; Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA.
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Wang Q, Zhou J, Cheng A, Liu Y, Guo J, Li X, Chen M, Hu D, Wu J. Artesunate-binding FABP5 promotes apoptosis in lung cancer cells via the PPARγ-SCD pathway. Int Immunopharmacol 2024; 143:113381. [PMID: 39405934 DOI: 10.1016/j.intimp.2024.113381] [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: 06/15/2024] [Revised: 09/25/2024] [Accepted: 10/07/2024] [Indexed: 10/30/2024]
Abstract
Artesunate holds excellent promise for lung cancer treatment, but its target is still unclear. We used molecular docking techniques to predict artesunate and Fatty acid binding protein 5 (FABP5) binding sites. Cellular thermal shift assay (CETSA) verified that artesunate treatment could promote the stability of the FABP5 protein. There was no significant change in the strength of the FABP5 protein after the mutation of binding sites by adding artesunate treatment. Mechanistically, artesunate promotes apoptosis in lung cancer cells by binding to FABP5, inhibiting the expression of the lipid metabolism gene SCD, and suppressing the expression of the SCD transcription factor regulated by the transcription factor PPARγ. In summary, our study shows that the protein targeted by artesunate is FABP5 and that artesunate promotes apoptosis through the FABP5-PPARγ-SCD pathway, which offers excellent potential for treating lung cancer.
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Affiliation(s)
- Qingsen Wang
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232000, Anhui, China
| | - Jiawei Zhou
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan 232000, Anhui, China
| | - Anqi Cheng
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232000, Anhui, China
| | - Yafeng Liu
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Huainan 232000, Anhui, China
| | - Jianqiang Guo
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232000, Anhui, China
| | - Xuan Li
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232000, Anhui, China
| | - Maoqian Chen
- School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China; Anhui Occupational Health and Safety Engineering Laboratory, Huainan 232000, Anhui, China
| | - Dong Hu
- The First Affiliated Hospital of Anhui University of Science and Technology Huainan First People's Hospital, School of Medicine, Huainan 232000, Anhui, China; Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 232001, Anhui, China.
| | - Jing Wu
- Joint Research Center for Occupational Medicine and Health of IHM, School of Medicine, Anhui University of Science and Technology, Huainan 232000, Anhui, China.
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Shodry S, Hasan YTN, Ahdi IR, Ulhaq ZS. Gene targets with therapeutic potential in hepatocellular carcinoma. World J Gastrointest Oncol 2024; 16:4543-4547. [PMID: 39678796 PMCID: PMC11577361 DOI: 10.4251/wjgo.v16.i12.4543] [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] [Received: 06/27/2024] [Revised: 08/03/2024] [Accepted: 08/13/2024] [Indexed: 11/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Syifaus Shodry
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Yuliono Trika Nur Hasan
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Iwal Reza Ahdi
- Faculty of Medicine and Health Sciences, Maulana Ibrahim Islamic State University of Malang, Malang 65144, Jawa Timur, Indonesia
| | - Zulvikar Syambani Ulhaq
- Research Center for Preclinical and Clinical Medicine, National Research and Innovation Agency Republic of Indonesia, Cibinong 16911, Indonesia
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Wu X, Tang N, Zhao Q, Xiong J. Spatiotemporal evolutionary process of osteosarcoma immune microenvironment remodeling and C1QBP-driven drug resistance deciphered through single-cell multi-dimensional analysis. Bioeng Transl Med 2024; 9:e10654. [PMID: 39553438 PMCID: PMC11561849 DOI: 10.1002/btm2.10654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 11/19/2024] Open
Abstract
The tumor immune microenvironment has manifested a crucial correlation with tumor occurrence, development, recurrence, and metastasis. To explore the mechanisms intrinsic to osteosarcoma (OS) initiation and progression, this study synthesizes multiple single-cell RNA sequencing data sets, constructing a comprehensive landscape of the OS microenvironment. Integrating single-cell RNA sequencing with bulk RNA sequencing data has enabled the identification of a significant correlation between heightened expression of the fatty acid metabolism-associated gene (C1QBP) and patient survival in OS. C1QBP not only amplifies the proliferation, migration, invasion, and anti-apoptotic properties of OS but also instigates cisplatin resistance. Subsequent investigations suggest that C1QBP potentially promotes macrophage polarization from monocytes/macrophages toward M2 and M3 phenotypes. Consequently, C1QBP may emerge as a novel target for modulating OS progression and resistance therapy.
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Affiliation(s)
- Xin Wu
- Department of Spine Surgery, Third Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Ning Tang
- Department of Orthopaedics, Third Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Qiangqiang Zhao
- Department of HematologyLiuzhou People's Hospital affiliated to Guangxi Medical UniversityLiuzhouGuangxiChina
- Department of HematologyThe Qinghai Provincial People's HospitalXiningQinghaiChina
| | - Jianbin Xiong
- Department of OrthopaedicsLiuzhou Municipal Liutie Central HospitalLiuzhouGuangxiChina
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7
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Saizonou I, Lascombe I, Monnien F, Bedgedjian I, Kleinclauss F, Algros MP, Fauconnet S. Concomitant decrease of E- and A-FABP expression predicts worse survival in urothelial bladder cancer patients. Sci Rep 2024; 14:15390. [PMID: 38965292 PMCID: PMC11224272 DOI: 10.1038/s41598-024-65972-8] [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: 03/13/2023] [Accepted: 06/25/2024] [Indexed: 07/06/2024] Open
Abstract
Non-muscle invasive bladder cancers (NMIBC) pTa-pT1 are depicted by a high risk of recurrence and/or progression with an unpredictable clinical evolution. Our aim was to identify, from the original resection specimen, tumors that will progress to better manage patients. We previously showed that A-FABP (Adipocyte- Fatty Acid Binding Protein) loss predicted NMIBC progression. Here we determined by immunohistochemistry the prognostic value of E-FABP (Epidermal-Fatty Acid Binding Protein) expression in 210 tumors (80 pTa, 75 pT1, 55 pT2-T4). Thus, E-FABP low expression was correlated with a high grade/stage, the presence of metastatic lymph nodes, and visceral metastases (p < 0.001). Unlike A-FABP in NMIBC, E-FABP low expression was not associated with RFS or PFS in Kaplan-Meier analysis. But patients of the overall cohort with a high E-FABP expression had a longer mOS (53.8 months vs. 29.3 months, p = 0.029). The immunohistochemical analysis on the same NMIBC tissue sections revealed that when A-FABP is absent, a high E-FABP expression is detected. E-FABP could compensate A-FABP loss. Interestingly, patients, whose original tumor presents both low E-FABP and negative A-FABP, had the worse survival, those maintaining the expression of both markers had better survival. To conclude, the combined evaluation of A- and E-FABP expression allowed to stratify patients with urothelial carcinoma for optimizing treatment and follow-up.
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Affiliation(s)
- Inès Saizonou
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Isabelle Lascombe
- Université Franche-Comté, SINERGIES - LabEx LipSTIC ANR-11-LABX-0021, 25030, Besançon, France
| | - Franck Monnien
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Isabelle Bedgedjian
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - François Kleinclauss
- CHU Besançon, Service Urologie, Andrologie et Transplantation Rénale, 25000, Besançon, France
| | - Marie-Paule Algros
- CHU Besançon, Service Anatomie et Cytologie Pathologiques, 25000, Besançon, France
| | - Sylvie Fauconnet
- Université Franche-Comté, SINERGIES - LabEx LipSTIC ANR-11-LABX-0021, 25030, Besançon, France.
- CHU Besançon, Service Urologie, Andrologie et Transplantation Rénale, 25000, Besançon, France.
- CHU Besançon, Centre Investigation Clinique, Inserm CIC 1431, 25000, Besançon, France.
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8
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Szilveszter RM, Muntean M, Florea A. Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments-An Overview. Biomolecules 2024; 14:656. [PMID: 38927059 PMCID: PMC11201617 DOI: 10.3390/biom14060656] [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: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial-mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages-predominantly with a pro-tumoral role-hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines.
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Affiliation(s)
- Raluca-Margit Szilveszter
- Department of Pathology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400340 Cluj-Napoca, Romania
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
- Cluj County Emergency Clinical Hospital, 400340 Cluj-Napoca, Romania
| | - Mara Muntean
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
| | - Adrian Florea
- Department of Cell and Molecular Biology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (M.M.); (A.F.)
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Chakraborty S, Anand S, Bhandari RK. Sex-specific expression of the human NAFLD-NASH transcriptional signatures in the liver of medaka with a history of ancestral bisphenol A exposure. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.19.594843. [PMID: 38826193 PMCID: PMC11142124 DOI: 10.1101/2024.05.19.594843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
The progression of fatty liver disease to non-alcoholic steatohepatitis (NASH) is a leading cause of death in humans. Lifestyles and environmental chemical exposures can increase the susceptibility of humans to NASH. In humans, the presence of bisphenol A (BPA) in urine is associated with fatty liver disease, but whether ancestral BPA exposure leads to the activation of human NAFLD-NASH-associated genes in the unexposed descendants is unclear. In this study, using medaka fish as an animal model for human NAFLD, we investigated the transcriptional signatures of human NAFLD-NASH and their associated roles in the pathogenesis of the liver of fish who were not directly exposed but their ancestors were exposed to BPA during embryonic and perinatal development three generations prior. Comparison of bulk RNA-Seq data of the liver in BPA lineage male and female medaka with publicly available human NAFLD-NASH patient data revealed transgenerational alterations in the transcriptional signature of human NAFLD-NASH in medaka liver. Twenty percent of differentially expressed genes (DEGs) were upregulated in both human NAFLD patients and medaka. Specifically in females, among the total shared DEGs in the liver of BPA lineage fish and NAFLD patient groups, 27.69% DEGs were downregulated and 20% DEGs were upregulated. Off all DEGs, 52.31% DEGs were found in ancestral BPA-lineage females, suggesting that NAFLD in females shared majority of human NAFLD gene networks. Pathway analysis revealed beta-oxidation, lipoprotein metabolism, and HDL/LDL-mediated transport processes linked to downregulated DEGs in BPA lineage males and females. In contrast, the expression of genes encoding lipogenesis-related proteins was significantly elevated in the liver of BPA lineage females only. BPA lineage females exhibiting activation of myc, atf4, xbp1, stat4, and cancerous pathways, as well as inactivation of igf1, suggest their possible association with an advanced NAFLD phenotype. The present results suggest that gene networks involved in the progression of human NAFLD and the transgenerational NAFLD in medaka are conserved and that medaka can be an excellent animal model to understand the development and progression of liver disease and environmental influences in the liver.
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Affiliation(s)
- Sourav Chakraborty
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
| | - Santosh Anand
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
| | - Ramji Kumar Bhandari
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211, U.S.A
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Gabriel V, Lincoln A, Zdyrski C, Ralston A, Wickham H, Honold S, Ahmed BH, Paukner K, Feauto R, Merodio MM, Piñeyro P, Meyerholz D, Allenspach K, Mochel JP. Evaluation of different media compositions promoting hepatocyte differentiation in the canine liver organoid model. Heliyon 2024; 10:e28420. [PMID: 38590903 PMCID: PMC10999936 DOI: 10.1016/j.heliyon.2024.e28420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 04/10/2024] Open
Abstract
Organoids are 3-dimensional (3D) self-assembled structures capable of replicating the microanatomy and physiology of the epithelial components of their organ of origin. Adult stem cell (ASC) derived organoids from the liver have previously been shown to differentiate into primarily mature cholangiocytes, and their partial differentiation into functional hepatocytes can be promoted using specific media compositions. While full morphological differentiation of mature hepatocytes from ASCs has not yet been reported for any species, the functional differentiation can be approximated using various media compositions. Six differentiation media formulations from published studies on hepatic organoids were used for the differentiation protocol. Target species for these protocols were humans, mice, cats, and dogs, and encompassed various combinations and concentrations of four major hepatocyte media components: Bone morphogenetic protein 7 (BMP7), Fibroblast Growth Factor 19 (FGF19), Dexamethasone (Dex), and Gamma-Secretase Inhibitor IX (DAPT). Additionally, removing R-spondin from basic organoid media has previously been shown to drive the differentiation of ASC into mature hepatocytes. Differentiation media (N = 20) were designed to encompass combinations of the four major hepatocyte media components. The preferred differentiation of ASC-derived organoids from liver tissue into mature hepatocytes over cholangiocytes was confirmed by albumin production in the culture supernatant. Out of the twenty media compositions tested, six media resulted in the production of the highest amounts of albumin in the supernatant of the organoids. The cell lines cultured using these six media were further characterized via histological staining, transmission electron microscopy, RNA in situ hybridization, analysis of gene expression patterns, immunofluorescence, and label-free proteomics. The results indicate that preferential hepatocyte maturation from canine ADC-derived organoids from liver tissue is mainly driven by Dexamethasone and DAPT components. FGF19 did not enhance organoid differentiation but improved cell culture survival. Furthermore, we confirm that removing R-spondin from the media is crucial for establishing mature hepatic organoid cultures.
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Affiliation(s)
- Vojtech Gabriel
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Addison Lincoln
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Christopher Zdyrski
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
- 3D Health Solutions Inc., Ames, IA, USA
- Precision One Health Initiative, Department of Pathology, University of Georgia College of Veterinary Medicine, 30602, Athens, GA, USA
| | | | - Hannah Wickham
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Sydney Honold
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Basant H. Ahmed
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Karel Paukner
- Laboratory for Atherosclerosis Research, Institute for Clinical and Experimental Medicine, Prague, CZ, Czech Republic
| | - Ryan Feauto
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Maria M. Merodio
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
| | - Pablo Piñeyro
- Veterinary Diagnostic Laboratory, Iowa State University, Ames, IA, USA
| | - David Meyerholz
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Karin Allenspach
- SMART Lab, Department of Biomedical Sciences, Iowa State University, Ames, IA, USA
- 3D Health Solutions Inc., Ames, IA, USA
- Precision One Health Initiative, Department of Pathology, University of Georgia College of Veterinary Medicine, 30602, Athens, GA, USA
| | - Jonathan P. Mochel
- 3D Health Solutions Inc., Ames, IA, USA
- Precision One Health Initiative, Department of Pathology, University of Georgia College of Veterinary Medicine, 30602, Athens, GA, USA
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11
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Zhang Q, Liu Y, Ren L, Li J, Lin W, Lou L, Wang M, Li C, Jiang Y. Proteomic analysis of DEN and CCl 4-induced hepatocellular carcinoma mouse model. Sci Rep 2024; 14:8013. [PMID: 38580754 PMCID: PMC10997670 DOI: 10.1038/s41598-024-58587-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/01/2024] [Indexed: 04/07/2024] Open
Abstract
Hepatocellular carcinoma (HCC) seriously threatens human health, mostly developed from liver fibrosis or cirrhosis. Since diethylnitrosamine (DEN) and carbon tetrachloride (CCl4)-induced HCC mouse model almost recapitulates the characteristic of HCC with fibrosis and inflammation, it is taken as an essential tool to investigate the pathogenesis of HCC. However, a comprehensive understanding of the protein expression profile of this model is little. In this study, we performed proteomic analysis of this model to elucidate its proteomic characteristics. Compared with normal liver tissues, 432 differentially expressed proteins (DEPs) were identified in tumor tissues, among which 365 were up-regulated and 67 were down-regulated. Through Gene Ontology (GO) analysis, Ingenuity Pathway Analysis (IPA), protein-protein interaction networks (PPI) analysis and Gene-set enrichment analysis (GSEA) analysis of DEPs, we identified two distinguishing features of DEN and CCl4-induced HCC mouse model in protein expression, the upregulation of actin cytoskeleton and branched-chain amino acids metabolic reprogramming. In addition, matching DEPs from the mouse model to homologous proteins in the human HCC cohort revealed that the DEN and CCl4-induced HCC mouse model was relatively similar to the subtype of HCC with poor prognosis. Finally, combining clinical information from the HCC cohort, we screened seven proteins with prognostic significance, SMAD2, PTPN1, PCNA, MTHFD1L, MBOAT7, FABP5, and AGRN. Overall, we provided proteomic data of the DEN and CCl4-induced HCC mouse model and highlighted the important proteins and pathways in it, contributing to the rational application of this model in HCC research.
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Affiliation(s)
- Qian Zhang
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Yuhui Liu
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Liangliang Ren
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Junqing Li
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
- School of Basic Medical Science, Anhui Medical University, Hefei, 230032, China
| | - Weiran Lin
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Lijuan Lou
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Minghan Wang
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Chaoying Li
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China
| | - Ying Jiang
- State Key Laboratory of Medicle Proteomics, Beijing Institute of Lifeomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, China.
- School of Basic Medical Science, Anhui Medical University, Hefei, 230032, China.
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12
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Sun J, Esplugues E, Bort A, Cardelo MP, Ruz-Maldonado I, Fernández-Tussy P, Wong C, Wang H, Ojima I, Kaczocha M, Perry R, Suárez Y, Fernández-Hernando C. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nat Metab 2024; 6:741-763. [PMID: 38664583 DOI: 10.1038/s42255-024-01019-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 02/26/2024] [Indexed: 04/28/2024]
Abstract
Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.
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Affiliation(s)
- Jonathan Sun
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Enric Esplugues
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Alicia Bort
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Magdalena P Cardelo
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Inmaculada Ruz-Maldonado
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Pablo Fernández-Tussy
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Clara Wong
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Hehe Wang
- Department of Chemistry, Stony Brook University, New York, NY, USA
| | - Iwao Ojima
- Department of Chemistry, Stony Brook University, New York, NY, USA
- Institute of Chemical Biology and Drug Discovery, Stony Brook University, New York, NY, USA
| | - Martin Kaczocha
- Institute of Chemical Biology and Drug Discovery, Stony Brook University, New York, NY, USA
- Department of Anesthesiology, Renaissance School of Medicine. Stony Brook University, New York, NY, USA
| | - Rachel Perry
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine (Endocrinology), Yale University School of Medicine, New Haven, CT, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA.
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Molecular and System Metabolism, Yale University School of Medicine, New Haven, CT, USA.
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA.
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
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13
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Jiang M, Karsenberg R, Bianchi F, van den Bogaart G. CD36 as a double-edged sword in cancer. Immunol Lett 2024; 265:7-15. [PMID: 38122906 DOI: 10.1016/j.imlet.2023.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/13/2023] [Accepted: 12/18/2023] [Indexed: 12/23/2023]
Abstract
The membrane protein CD36 is a lipid transporter, scavenger receptor, and receptor for the antiangiogenic protein thrombospondin 1 (TSP1). CD36 is expressed by cancer cells and by many associated cells including various cancer-infiltrating immune cell types. Thereby, CD36 plays critical roles in cancer, and it has been reported to affect cancer growth, metastasis, angiogenesis, and drug resistance. However, these roles are partly contradictory, as CD36 has been both reported to promote and inhibit cancer progression. Moreover, the mechanisms are also partly contradictory, because CD36 has been shown to exert opposite cellular effects such as cell division, senescence and cell death. This review provides an overview of the diverse effects of CD36 on tumor progression, aiming to shed light on its diverse pro- and anti-cancer roles, and the implications for therapeutic targeting.
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Affiliation(s)
- Muwei Jiang
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Nijenborgh 7, Groningen, the Netherlands
| | - Renske Karsenberg
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Nijenborgh 7, Groningen, the Netherlands
| | - Frans Bianchi
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Nijenborgh 7, Groningen, the Netherlands
| | - Geert van den Bogaart
- Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747AG, Nijenborgh 7, Groningen, the Netherlands.
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14
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Li Y, Lee W, Zhao ZG, Liu Y, Cui H, Wang HY. Fatty acid binding protein 5 is a novel therapeutic target for hepatocellular carcinoma. World J Clin Oncol 2024; 15:130-144. [PMID: 38292656 PMCID: PMC10823939 DOI: 10.5306/wjco.v15.i1.130] [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] [Received: 08/30/2023] [Revised: 12/02/2023] [Accepted: 12/25/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer and is one of the most common cancers with high mortality worldwide. Reprogrammed lipid metabolism plays crucial roles in HCC cancer cell survival, growth, and evolution. Emerging evidence suggests the importance of fatty acid binding proteins (FABPs) in contribution to cancer progression and metastasis; however, how these FABPs are dysregulated in cancer cells, especially in HCC, and the roles of FABPs in cancer progression have not been well defined. AIM To understand the genetic alterations and expression of FABPs and their associated cancer hallmarks and oncogenes in contributing to cancer malignancies. METHODS We used The Cancer Genome Atlas datasets of pan cancer and liver hepatocellular carcinoma (LIHC) as well as patient cohorts with other cancer types in this study. We investigated genetic alterations of FABPs in various cancer types. mRNA expression was used to determine if FABPs are abnormally expressed in tumor tissues compared to non-tumor controls and to investigate whether their expression correlates with patient clinical outcome, enriched cancer hallmarks and oncogenes previously reported for patients with HCC. We determined the protein levels of FABP5 and its correlated genes in two HCC cell lines and assessed the potential of FABP5 inhibition in treating HCC cells. RESULTS We discovered that a gene cluster including five FABP family members (FABP4, FABP5, FABP8, FABP9 and FABP12) is frequently co-amplified in cancer. Amplification, in fact, is the most common genetic alteration for FABPs, leading to overexpression of FABPs. FABP5 showed the greatest differential mRNA expression comparing tumor with non-tumor tissues. High FABP5 expression correlates well with worse patient outcomes (P < 0.05). FABP5 expression highly correlates with enrichment of G2M checkpoint (r = 0.33, P = 1.1e-10), TP53 signaling pathway (r = 0.22, P = 1.7e-5) and many genes in the gene sets such as CDK1 (r = 0.56, P = 0), CDK4 (r = 0.49, P = 0), and TP53 (r = 0.22, P = 1.6e-5). Furthermore, FABP5 also correlates well with two co-expressed oncogenes PLK1 and BIRC5 in pan cancer especially in LIHC patients (r = 0.58, P = 0; r = 0.58, P = 0; respectively). FABP5high Huh7 cells also expressed higher protein levels of p53, BIRC5, CDK1, CDK2, and CDK4 than FABP5low HepG2 cells. FABP5 inhibition more potently inhibited the tumor cell growth in Huh7 cells than in HepG2 cells. CONCLUSION We discovered that FABP5 gene is frequently amplified in cancer, especially in HCC, leading to its significant elevated expression in HCC. Its high expression correlates well with worse patient outcome, enriched cancer hallmarks and oncogenes in HCC. FABP5 inhibition impaired the cell viability of FABP5high Huh7 cells. All these support that FABP5 is a novel therapeutic target for treating FABP5high HCC.
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Affiliation(s)
- Yan Li
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - William Lee
- Biomedical Engineering, Texas A&M University, College Station, TX 77843, United States
| | - Zhen-Gang Zhao
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Yi Liu
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao Cui
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
| | - Hao-Yu Wang
- Department of Gastroenterology, Tianjin Third Central Hospital, Tianjin 300170, China
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15
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Wu X, Yang SY, Zhang YH, Fang JZ, Wang S, Xu ZW, Zhang XJ. Prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma. World J Clin Oncol 2024; 15:45-61. [PMID: 38292659 PMCID: PMC10823936 DOI: 10.5306/wjco.v15.i1.45] [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] [Received: 09/11/2023] [Revised: 12/03/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Heat shock protein A4 (HSPA4) belongs to molecular chaperone protein family which plays important roles within variable cellular activities, including cancer initiation and progression. However, the prognostic and immunological significance of HSPA4 in lung adenocarcinoma (LUAD) has not been revealed yet. AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD. METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database. The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test. Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors, including HSPA4, in LUAD. Gene set enrichment analysis (GSEA) was conducted to identify the key signaling pathways associated with HSPA4. The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA). RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage, advanced pathologic stage, progression disease status of primary therapy outcome and female subgroups with LUAD. In addition, increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival. GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response, particularly through diminishing the function of cytotoxicity cells and CD8 T cells. The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells, while a negative correlation was observed with cytotoxic cell infiltration levels. CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.
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Affiliation(s)
- Xuan Wu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shen-Ying Yang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Yi-Hua Zhang
- Graduate School, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Jin-Zhou Fang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Shuai Wang
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Zhi-Wei Xu
- Department of Respiratory and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
| | - Xiao-Ju Zhang
- Department of Pulmonary and Critical Care Medicine, Zhengzhou University People’s Hospital, Zhengzhou 450008, Henan Province, China
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16
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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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17
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Gaffar S, Aathirah AS. Fatty-Acid-Binding Proteins: From Lipid Transporters to Disease Biomarkers. Biomolecules 2023; 13:1753. [PMID: 38136624 PMCID: PMC10741572 DOI: 10.3390/biom13121753] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 10/20/2023] [Accepted: 10/26/2023] [Indexed: 12/24/2023] Open
Abstract
Fatty-acid-binding proteins (FABPs) serve a crucial role in the metabolism and transport of fatty acids and other hydrophobic ligands as an intracellular protein family. They are also recognized as a critical mediator in the inflammatory and ischemic pathways. FABPs are found in a wide range of tissues and organs, allowing them to contribute to various disease/injury developments that have not been widely discussed. We have collected and analyzed research journals that have investigated the role of FABPs in various diseases. Through this review, we discuss the findings on the potential of FABPs as biomarkers for various diseases in different tissues and organs, looking at their expression levels and their roles in related diseases according to available literature data. FABPs have been reported to show significantly increased expression levels in various tissues and organs associated with metabolic and inflammatory diseases. Therefore, FABPs are a promising novel biomarker that needs further development to optimize disease diagnosis and prognosis methods along with previously discovered markers.
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Affiliation(s)
- Shabarni Gaffar
- Graduate School, Padjadjaran University, Bandung 40132, Indonesia;
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Padjadjaran University, Sumedang 45363, Indonesia
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18
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Zhang Y, Song Y, Zhang J, Li L, He L, Bo J, Gong Z, Xiao W. L-theanine regulates the immune function of SD rats fed high-protein diets through the FABP5/IL-6/STAT3/PPARα pathway. Food Chem Toxicol 2023; 181:114095. [PMID: 37827328 DOI: 10.1016/j.fct.2023.114095] [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: 08/17/2023] [Revised: 10/07/2023] [Accepted: 10/08/2023] [Indexed: 10/14/2023]
Abstract
The protein levels in a diet are correlated with immunity but the long-term intake of excessive protein can compromise various aspects of health. L-theanine regulates immunity and protein metabolism; however, how its regulatory immunity effects under a high-protein diet are unclear. We used proteomics, metabonomics, and western blotting to analyze the effects of diets with different protein levels on immune function in rats to determine the role of L-theanine in immunity under a high-protein diet. The long-term intake of high-protein diets (≥40% protein) promoted oxidative imbalance and inflammation. These were alleviated by L-theanine. High-protein diets inhibited peroxisome proliferator-activated receptor (PPAR)α expression through the interleukin (IL)-6/signal transducer and activator of transcription (STAT)3 pathway and mediated inflammation. L-theanine downregulated anti-fatty acid-binding protein 5 (FABP5), inhibited the IL-6/STAT3 axis, and reduced high-protein diet-induced PPARα inhibition. Therefore, L-theanine alleviates the adverse effects of high-protein diets via the FABP5/IL-6/STAT3/PPARα pathway and regulates the immunity of normally fed rats through the epoxide hydrolase (EPHX)2/nuclear factor-kappa B inhibitor (IκB)α/triggering receptor expressed on myeloid cells (TREM)1 axis.
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Affiliation(s)
- Yangling Zhang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China; Lushan Tea Science Research Institute, Jiujiang, Jiangxi, 332000, China
| | - Yuxin Song
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Jiao Zhang
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Lanlan Li
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Lin He
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Jiahui Bo
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China
| | - Zhihua Gong
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China.
| | - Wenjun Xiao
- Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan, 410128, China.
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19
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Kang Z, Jiang L, Chen D, Yan G, Zhang G, Lai Y, Zeng Q, Wang X. Whole genome methylation sequencing reveals epigenetic landscape and abnormal expression of FABP5 in extramammary Paget's disease. Skin Res Technol 2023; 29:e13497. [PMID: 37881057 PMCID: PMC10579628 DOI: 10.1111/srt.13497] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 09/27/2023] [Indexed: 10/27/2023]
Abstract
BACKGROUND Extramammary Paget's disease (EMPD) is a rare cutaneous malignant tumor with a high recurrence rate after surgery. However, the genetic and epigenetic alterations underlying its pathogenesis remain unknown. DNA methylation is an important epigenetic modification involved in many biological processes. METHODS In this study, enzymatic methyl-sequencing (EM-seq) technique was used to investigate the landscape of genome-wide DNA methylation from three pairs of tumor tissues and adjacent tissues of patients with EMPD. Additionally, we conducted histopathological examinations to assess the expression of fatty acid-binding protein 5 (FABP5) in another three paired samples from EMPD patients. RESULTS The cluster analysis showed the good quality of the samples. A differential methylation region (DMR) heat map was used to quantitatively characterize genome-wide methylation differences between tumors and controls. Global DNA methylation level is lower in EMPD tissue compared to matched controls, indicating that DNA methylation discriminates between tumor and normal skin. And the top hypomethylation gene on the promoter region in tumor tissues was FABP5 on chromosome 8 with 38.44% decreased median methylation. We next identified the expression of FABP5 in paired tumors and adjacent tissues in three additional patients with EMPD. Immunofluorescence results showed FABP5 highly expressed in tumor tissues and co-located with CK7, CK20 and EMA. GO and KEGG enrichment analysis showed DMR genes on promoter are mainly enriched in the calcium ion transport, GTPase mediated signal transduction, Rap1 signaling pathway and GnRH signaling pathway. CONCLUSION Taken together, our findings provide the first description of the whole genome methylation map of EMPD and identify FABP5 as a pathogenic target of EMPD.
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Affiliation(s)
- Ziwei Kang
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Long Jiang
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Diyan Chen
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Guorong Yan
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Guolong Zhang
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Yongxian Lai
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Qingyu Zeng
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
| | - Xiuli Wang
- Institute of PhotomedicineShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
- Skin Cancer CenterShanghai Skin Disease HospitalSchool of MedicineTongji UniversityShanghaiChina
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20
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Duan J, Huang Z, Nice EC, Xie N, Chen M, Huang C. Current advancements and future perspectives of long noncoding RNAs in lipid metabolism and signaling. J Adv Res 2023; 48:105-123. [PMID: 35973552 PMCID: PMC10248733 DOI: 10.1016/j.jare.2022.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 08/04/2022] [Accepted: 08/10/2022] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The investigation of lncRNAs has provided a novel perspective for elucidating mechanisms underlying diverse physiological and pathological processes. Compelling evidence has revealed an intrinsic link between lncRNAs and lipid metabolism, demonstrating that lncRNAs-induced disruption of lipid metabolism and signaling contribute to the development of multiple cancers and some other diseases, including obesity, fatty liver disease, and cardiovascular disease. AIMOF REVIEW The current review summarizes the recent advances in basic research about lipid metabolism and lipid signaling-related lncRNAs. Meanwhile, the potential and challenges of targeting lncRNA for the therapy of cancers and other lipid metabolism-related diseases are also discussed. KEY SCIENTIFIC CONCEPT OF REVIEW Compared with the substantial number of lncRNA loci, we still know little about the role of lncRNAs in metabolism. A more comprehensive understanding of the function and mechanism of lncRNAs may provide a new standpoint for the study of lipid metabolism and signaling. Developing lncRNA-based therapeutic approaches is an effective strategy for lipid metabolism-related diseases.
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Affiliation(s)
- Jiufei Duan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China.
| | - Mingqing Chen
- Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, 430079 Wuhan, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041 Chengdu, China.
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21
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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: 28] [Impact Index Per Article: 14.0] [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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22
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Qiu MQ, Wang HJ, Ju YF, Sun L, Liu Z, Wang T, Kan SF, Yang Z, Cui YY, Ke YQ, He HM, Zhang S. Fatty Acid Binding Protein 5 (FABP5) Promotes Aggressiveness of Gastric Cancer Through Modulation of Tumor Immunity. J Gastric Cancer 2023; 23:340-354. [PMID: 37129157 PMCID: PMC10154133 DOI: 10.5230/jgc.2023.23.e19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 04/02/2023] [Accepted: 06/28/2022] [Indexed: 05/03/2023] Open
Abstract
PURPOSE Gastric cancer (GC) is the second most lethal cancer globally and is associated with poor prognosis. Fatty acid-binding proteins (FABPs) can regulate biological properties of carcinoma cells. FABP5 is overexpressed in many types of cancers; however, the role and mechanisms of action of FABP5 in GC remain unclear. In this study, we aimed to evaluate the clinical and biological functions of FABP5 in GC. MATERIALS AND METHODS We assessed FABP5 expression using immunohistochemical analysis in 79 patients with GC and evaluated its biological functions following in vitro and in vivo ectopic expression. FABP5 targets relevant to GC progression were determined using RNA sequencing (RNA-seq). RESULTS Elevated FABP5 expression was closely associated with poor outcomes, and ectopic expression of FABP5 promoted proliferation, invasion, migration, and carcinogenicity of GC cells, thus suggesting its potential tumor-promoting role in GC. Additionally, RNA-seq analysis indicated that FABP5 activates immune-related pathways, including cytokine-cytokine receptor interaction pathways, interleukin-17 signaling, and tumor necrosis factor signaling, suggesting an important rationale for the possible development of therapies that combine FABP5-targeted drugs with immunotherapeutics. CONCLUSIONS These findings highlight the biological mechanisms and clinical implications of FABP5 in GC and suggest its potential as an adverse prognostic factor and/or therapeutic target.
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Affiliation(s)
- Mei-Qing Qiu
- Shandong University Cancer Center, Jinan, China
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Oncology, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Hui-Jun Wang
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Ya-Fei Ju
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Li Sun
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Zhen Liu
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Tao Wang
- Department of Oncology, Zaozhuang Cancer Hospital, Zaozhuang, China
| | - Shi-Feng Kan
- Department of Oncology, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Zhen Yang
- Department of Oncology, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Ya-Yun Cui
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - You-Qiang Ke
- Molecular Pathology Laboratory, Department of Molecular and Clinical Cancer Medicine, Liverpool University, Liverpool, United Kingdom
| | - Hong-Min He
- Department of Oncology, Zaozhuang Municipal Hospital, Zaozhuang, China
| | - Shu Zhang
- Shandong University Cancer Center, Jinan, China
- Department of Gastroenterology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
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23
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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: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [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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24
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Tang Y, Li K, Hu B, Cai Z, Li J, Tao H, Cao J. Fatty acid binding protein 5 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by degradation of Krüppel-like factor 9 mediated by miR-889-5p via cAMP-response element binding protein. Cancer Biol Ther 2022; 23:424-438. [PMID: 35816613 PMCID: PMC9275499 DOI: 10.1080/15384047.2022.2094670] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Mounting evidence has demonstrated that fatty acid binding protein 5 (FABP5) is commonly upregulated in many human malignancies. However, the mechanisms explaining the involvement of FABP5 in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated the involvement of FABP5 and its downstream signaling molecules in HCC progression. We first confirmed that FABP5 expression was upregulated in HCC. Additionally, FABP5 promoted HCC cells proliferation, migration, and invasion. Mechanistic investigation showed that FABP5 could improve cAMP-response element binding protein (CREB) phosphorylation. Meanwhile, CREB, as a transcription factor, upregulated the miR-889-5p expression by binding to the miR-889-5p promoter region. Consequently, miR-889-5p led to downregulation of Krüppel-like factor 9 (KLF9) by binding to the 3ʹ-UTR of the KLF9 mRNA, potentiating the PI3K/AKT signaling pathway and promoting the proliferation, migration, and invasion of HCC cells. Our findings have identified a FABP5/CREB/miR-889-5p/KLF9 axis for HCC progression, and we postulate that blocking this key signaling pathway may represent a promising strategy for HCC treatment.
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Affiliation(s)
- Yanping Tang
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Kezhi Li
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Bangli Hu
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Zhengmin Cai
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Jilin Li
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Hao Tao
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Ji Cao
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China.,Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, China
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25
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Huang X, Zhou Y, Sun Y, Wang Q. Intestinal fatty acid binding protein: A rising therapeutic target in lipid metabolism. Prog Lipid Res 2022; 87:101178. [PMID: 35780915 DOI: 10.1016/j.plipres.2022.101178] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 06/27/2022] [Indexed: 10/17/2022]
Abstract
Fatty acid binding proteins (FABPs) are key proteins in lipid transport, and the isoforms are segregated according to their tissue origins. Several isoforms, such as adipose-FABP and epidermal-FABP, have been shown to participate in multiple pathologic processes due to their ubiquitous expression. Intestinal fatty acid binding protein, also termed FABP2 or I-FABP, is specifically expressed in the small intestine. FABP2 can traffic lipids from the intestinal lumen to enterocytes and bind superfluous fatty acids to maintain a steady pool of fatty acids in the epithelium. As a lipid chaperone, FABP2 can also carry lipophilic drugs to facilitate targeted transport. When the integrity of the intestinal epithelium is disrupted, FABP2 is released into the circulation. Thus, it can potentially serve as a clinical biomarker. In this review, we discuss the pivotal role of FABP2 in intestinal lipid metabolism. We also summarize the molecular interactions that have been reported to date, highlighting the clinical prospects of FABP2 research.
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Affiliation(s)
- Xi Huang
- Shanghai Institute of Immunology, Department of Gastroenterology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Youci Zhou
- Shanghai Institute of Immunology, Department of Gastroenterology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yunwei Sun
- Shanghai Institute of Immunology, Department of Gastroenterology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qijun Wang
- Shanghai Institute of Immunology, Department of Gastroenterology of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
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26
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Basak S, Mallick R, Banerjee A, Pathak S, Duttaroy AK. Cytoplasmic fatty acid-binding proteins in metabolic diseases and cancers. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 132:143-174. [PMID: 36088074 DOI: 10.1016/bs.apcsb.2022.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cytoplasmic fatty acid-binding proteins (FABPs) are multipurpose proteins that can modulate lipid fluxes, trafficking, signaling, and metabolism. FABPs regulate metabolic and inflammatory pathways, its inhibition can improve type 2 diabetes mellitus and atherosclerosis. In addition, FABPs are involved in obesity, metabolic disease, cardiac dysfunction, and cancers. FABPs are promising tissue biomarkers in solid tumors for diagnostic and/or prognostic targets for novel therapeutic strategies. The signaling responsive elements of FABPs and determinants of FABP-mediated functions may be exploited in preventing or treating these diseases.
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Affiliation(s)
- Sanjay Basak
- Molecular Biology Division, ICMR-National Institute of Nutrition, Indian Council of Medical Research, Hyderabad, India
| | - Rahul Mallick
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, India
| | - Asim K Duttaroy
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
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27
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Hiraoka M, Takashima S, Wakihara Y, Kamatari YO, Shimizu K, Okada A, Inoshima Y. Identification of Potential mRNA Biomarkers in Milk Small Extracellular Vesicles of Enzootic Bovine Leukosis Cattle. Viruses 2022; 14:1022. [PMID: 35632763 PMCID: PMC9146096 DOI: 10.3390/v14051022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 01/27/2023] Open
Abstract
Enzootic bovine leukosis (EBL) is a disease caused by bovine leukemia virus (BLV); only a small percentage of BLV-infected cattle develop EBL and present with B-cell lymphosarcoma. There is no vaccine against BLV, treatment for EBL, or method for predicting the possibility of EBL onset, thus making EBL control difficult. Herein, to explore biomarkers for EBL in milk, we examined the mRNA profiles of small extracellular vesicles (sEVs) in milk from four BLV-uninfected and four EBL cattle by microarray analysis. It was revealed that 14 mRNAs were encapsulated in significantly higher quantities, and these mRNAs were therefore selected as biomarker candidates. Primers for these mRNAs were designed, and nine primer sets were available for quantitative real-time PCR. Nine mRNAs were evaluated for their availability as biomarkers for EBL using sEVs from newly-collected milk of 7 uninfected and 10 EBL cattle. The quantities of eight mRNAs (TMEM156, SRGN, CXCL8, DEFB4A, FABP5, LAPTM5, LGALS1, and VIM) were significantly higher in milk sEVs of EBL cattle than in those of uninfected cattle. Therefore, our findings indicate that these eight mRNAs in milk sEVs can be used as potential EBL biomarkers with combination use, although single mRNA use is not enough. Consequently, cattle at risk of EBL onset can be identified by monitoring the fluctuation in quantities of these mRNAs in milk before they develop EBL.
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Affiliation(s)
- Mami Hiraoka
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (M.H.); (K.S.); (A.O.)
| | - Shigeo Takashima
- Division of Genomics Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (S.T.); (Y.W.)
| | - Yoshiko Wakihara
- Division of Genomics Research, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (S.T.); (Y.W.)
| | - Yuji O. Kamatari
- Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan;
| | - Kaori Shimizu
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (M.H.); (K.S.); (A.O.)
| | - Ayaka Okada
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (M.H.); (K.S.); (A.O.)
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), 1-1 Yanagido, Gifu 501-1193, Japan
| | - Yasuo Inoshima
- Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; (M.H.); (K.S.); (A.O.)
- Education and Research Center for Food Animal Health, Gifu University (GeFAH), 1-1 Yanagido, Gifu 501-1193, Japan
- The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
- Joint Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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28
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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: 333] [Impact Index Per Article: 111.0] [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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Gomez-Quiroz LE, Roman S. Influence of genetic and environmental risk factors in the development of hepatocellular carcinoma in Mexico. Ann Hepatol 2022; 27 Suppl 1:100649. [PMID: 34902602 DOI: 10.1016/j.aohep.2021.100649] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023]
Abstract
The latest studies on the epidemiology of diverse types of cancers have located in the scene the relevance of liver tumors, particularly hepatocellular carcinoma (HCC). HCC is a life-threatening malignancy triggered by chronic exposure to hepatitis B and C viruses, excessive alcohol intake, hepatic lipid droplet accumulation, and aflatoxins that lead to persistent liver damage. The occurrence of such etiological risk factors deeply marks the variability in the incidence of HCC worldwide reflected by geography, ethnicity, age, and lifestyle factors influenced by cultural aspects. New perspectives on the primary risk factors and their potential gene-environment interactions (GxE) have been well-addressed in some cancers; however, it continues to be a partially characterized issue in liver malignancies. In this review, the epidemiology of the risk factors for HCC are described enhancing the GxE interactions identified in Mexico, which could mark the risk of this liver malignancy among the population and the measures needed to revert them. Updated healthcare policies focusing on preventive care should be tailored based on the genetic and environmental risk factors, which may influence the effect of the etiological agents of HCC. Robust regional investigations related to epidemiological, clinical, and basic studies are warranted to understand this health problem complying with the rules of ethnic, genetic, environmental, and social diversity.
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Affiliation(s)
- Luis E Gomez-Quiroz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde," Guadalajara, Jalisco, Mexico; Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico.
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31
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Huang J, Wang J, He H, Huang Z, Wu S, Chen C, Liu W, Xie L, Tao Y, Cong L, Jiang Y. Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer. Int J Biol Sci 2021; 17:4493-4513. [PMID: 34803512 PMCID: PMC8579446 DOI: 10.7150/ijbs.66181] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/01/2021] [Indexed: 12/19/2022] Open
Abstract
Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.
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Affiliation(s)
- Jingjing Huang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Jin Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Hua He
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Zichen Huang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Sufang Wu
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Chao Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Wenbing Liu
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Li Xie
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078 Hunan, China
| | - Li Cong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Yiqun Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
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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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33
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Fatty acid-binding protein 5 activates cyclooxygenase-2 and promotes hypoxic injury in LO2 cells. Mol Cell Toxicol 2021. [DOI: 10.1007/s13273-021-00158-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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34
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Chen J, Alduais Y, Zhang K, Zhu X, Chen B. CCAT1/FABP5 promotes tumour progression through mediating fatty acid metabolism and stabilizing PI3K/AKT/mTOR signalling in lung adenocarcinoma. J Cell Mol Med 2021; 25:9199-9213. [PMID: 34431227 PMCID: PMC8500980 DOI: 10.1111/jcmm.16815] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 01/17/2023] Open
Abstract
Long non‐coding RNA (lncRNA) colon cancer associated transcript 1 (CCAT1) has been identified as an oncogene in many cancers, but its role in lung adenocarcinoma (LUAD) remains to be further investigated. We identified the upregulation of CCAT1 in LUAD tissues and LUAD cells. Through RNA pull‐down and mass spectrometry analysis, we obtained the interacting proteins with CCAT1 and discovered their functional relation with ‘signal transduction’, ‘energy pathways’ and ‘metabolism’ and revealed the potential of CCAT1 on fatty acid (FA) metabolism. For mechanism exploration, we uncovered the mediation of CCAT1 on the translocation of fatty acid binding protein 5 (FABP5) into nucleus by confirming their interaction and localization. Also, CCAT1 was discovered to promote the formation of the transcription complex by RXR and PPARγ so as to activate the transcription of CD36, PDK1 and VEGFA. Moreover, we found that CCAT1 regulated the activity of AKT by promoting the ubiquitination of FKBP51 through binding with USP49. Subsequently, cell function assays revealed the enhancement of CCAT1 on LUAD cell proliferation and angiogenesis in vitro and in vivo. Collectively, CCAT1 regulated cell proliferation and angiogenesis through regulating FA metabolism in LUAD, providing a novel target for LUAD treatment.
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Affiliation(s)
- Jing Chen
- Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yaser Alduais
- Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Kai Zhang
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing, China
| | - Xiaoli Zhu
- Department of Respiratory Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Baoan Chen
- Department of Hematology and Oncology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
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Fatty acids and evolving roles of their proteins in neurological, cardiovascular disorders and cancers. Prog Lipid Res 2021; 83:101116. [PMID: 34293403 DOI: 10.1016/j.plipres.2021.101116] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 01/03/2023]
Abstract
The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
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36
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Wang W, Liu Z, Chen X, Lu Y, Wang B, Li F, Lu S, Zhou X. Downregulation of FABP5 Suppresses the Proliferation and Induces the Apoptosis of Gastric Cancer Cells Through the Hippo Signaling Pathway. DNA Cell Biol 2021; 40:1076-1086. [PMID: 34160301 DOI: 10.1089/dna.2021.0370] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Fatty acid binding protein 5 (FABP5) has been reported to play an important role in various cancers. We found that high FABP5 expression was associated with poor histological differentiation and vascular invasion. High FABP5 expression indicated a poor prognosis. Downregulation of FABP5 suppressed cell proliferation, cell migration and invasion, and induced cell apoptosis. Bioinformatic analysis revealed that the Hippo signaling pathway was related to FABP5. We found that overexpression of yes-associated protein 1 (YAP1) could partially reverse the effect of FABP5 knockdown on growth and apoptosis. The FABP5 inhibitor SBFI-26 suppressed the proliferation and promoted the apoptosis of gastric cancer (GC) cells and interfered with the Hippo signaling pathway by inhibiting YAP1. Our data suggested that FABP5 might act as a potential target associated with the Hippo signaling pathway for GC treatment.
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Affiliation(s)
- Wendong Wang
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Zhenzhen Liu
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Xin Chen
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Yongqu Lu
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Bingyan Wang
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Fei Li
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Siyi Lu
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
| | - Xin Zhou
- Department of General Surgery, Peking University Third Hospital, Peking University, Beijing, China
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Ohira M, Yokoo H, Ogawa K, Fukai M, Kamiyama T, Sakamoto N, Taketomi A. Serum fatty acid-binding protein 5 is a significant factor in hepatocellular carcinoma progression independent of tissue expression level. Carcinogenesis 2021; 42:794-803. [PMID: 33754641 DOI: 10.1093/carcin/bgab025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 02/05/2023] Open
Abstract
Fatty acid-binding protein 5 (FABP5) is highly expressed in hepatocellular carcinoma (HCC) tissues and is related to HCC progression. In this study, we analyzed the potential of serum FABP5 (sFABP5) as a tumor marker in HCC and its clinical significance in HCC progression. We compared the sFABP5 concentration in patients with HCC (HCC group) with that of patients with hepatitis without HCC (hepatitis group). Moreover, we measured the FABP5 expression levels in resected HCC tissues (tFABP5) and analyzed their relationship with sFABP5. We also performed cell-based assays using FABP5 knockout and overexpressing HCC cell lines to analyze the effect of extrinsic FABP5 (exFABP5) on HCC cells. We showed that sFABP5 was not a useful tumor marker for HCC, as HCC and sFABP5 were not correlated. However, sFABP5 and tFABP5 significantly correlated with survival after surgery for HCC, while sFABP5 and tFABP5 were independent of each other. In cell-based assays, exFABP5 was taken up by HCC cell lines and positively affected cell survival under glucose-depleted conditions by complementing the endogenous FABP5 function. In conclusion, sFABP5 had a significant impact on HCC progression irrespective of tFABP5 by augmenting cell viability under glucose-depleted conditions. As tFABP5 and sFABP5 are important factors that are independent of each other in HCC progression, both of them should be considered independently in improving the prognosis of patients with HCC.
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Affiliation(s)
- Masafumi Ohira
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideki Yokoo
- Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Toshiya Kamiyama
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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De Mattos-Arruda L, Cortes J, Blanco-Heredia J, Tiezzi DG, Villacampa G, Gonçalves-Ribeiro S, Paré L, Souza CA, Ortega V, Sammut SJ, Cusco P, Fasani R, Chin SF, Perez-Garcia J, Dienstmann R, Nuciforo P, Villagrasa P, Rubio IT, Prat A, Caldas C. The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers. NPJ Breast Cancer 2021; 7:73. [PMID: 34099718 PMCID: PMC8185105 DOI: 10.1038/s41523-021-00282-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 05/03/2021] [Indexed: 12/30/2022] Open
Abstract
The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
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Affiliation(s)
- Leticia De Mattos-Arruda
- IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain.
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.
- Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK.
| | - Javier Cortes
- Oncology Department International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain
- Medica Scientia Innovation Research (MedSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA
- Breast Cancer Research program, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain
| | - Juan Blanco-Heredia
- IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Daniel G Tiezzi
- Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
- Breast Disease Division, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Guillermo Villacampa
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Laia Paré
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
| | - Carla Anjos Souza
- IrsiCaixa, Germans Trias i Pujol University Hospital, Badalona, Spain
- Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
| | - Vanesa Ortega
- Breast Cancer Research program, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Stephen-John Sammut
- Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Pol Cusco
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Roberta Fasani
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Suet-Feung Chin
- Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
| | - Jose Perez-Garcia
- Oncology Department International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain
- Medica Scientia Innovation Research (MedSIR), Barcelona, Spain
- Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA
| | - Rodrigo Dienstmann
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Isabel T Rubio
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Barcelona, Spain
| | - Aleix Prat
- Department of Medical Oncology, Hospital Clinic of Barcelona, Barcelona, Spain
- SOLTI Breast Cancer Research Group, Barcelona, Spain
- Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Simoni-Nieves A, Salas-Silva S, Chávez-Rodríguez L, Escobedo-Calvario A, Desoteux M, Bucio L, Souza V, Miranda-Labra RU, Muñoz-Espinosa LE, Coulouarn C, Gutiérrez-Ruiz MC, Marquardt JU, Gomez-Quiroz LE. The Consumption of Cholesterol-Enriched Diets Conditions the Development of a Subtype of HCC with High Aggressiveness and Poor Prognosis. Cancers (Basel) 2021; 13:1721. [PMID: 33917315 PMCID: PMC8038696 DOI: 10.3390/cancers13071721] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 02/19/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH) result as a consequence of diverse conditions, mainly unbalanced diets. Particularly, high-fat and cholesterol content, as well as carbohydrates, such as those commonly ingested in Western countries, frequently drive adverse metabolic alterations in the liver and promote NAFLD development. Lipid liver overload is also one of the main risk factors for initiation and progression of hepatocellular carcinoma (HCC), but detailed knowledge on the relevance of high nutritional cholesterol remains elusive. We were aimed to characterize HCC development in mice fed with a Western diet (high in lipids and cholesterol) and to identify molecular alterations that define a subtype of liver cancer induced by lipid overload. Mice under western or high cholesterol diets more frequently developed tumors with a more aggressive phenotype than animals fed with a chow diet. Associated changes involved macrophage infiltration, angiogenesis, and stemness features. RNA-seq revealed a specific gene expression signature (Slc41a; Fabp5; Igdcc4 and Mthfd1l) resembling the adverse phenotypic features and poor clinical outcomes seen in patients with HCC. In conclusion; consumption of lipid enriched diets; particularly cholesterol; could accelerate HCC development with an aggressive phenotype and poor prognosis.
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Affiliation(s)
- Arturo Simoni-Nieves
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City 09340, Mexico; (A.S.-N.); (S.S.-S.); (L.C.-R.); (A.E.-C.)
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
| | - Soraya Salas-Silva
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City 09340, Mexico; (A.S.-N.); (S.S.-S.); (L.C.-R.); (A.E.-C.)
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
| | - Lisette Chávez-Rodríguez
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City 09340, Mexico; (A.S.-N.); (S.S.-S.); (L.C.-R.); (A.E.-C.)
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
| | - Alejandro Escobedo-Calvario
- Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City 09340, Mexico; (A.S.-N.); (S.S.-S.); (L.C.-R.); (A.E.-C.)
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
| | - Matthis Desoteux
- Centre de Lutte contre le Cancer Eugène Marquis, Inserm, Univ Rennes, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, 35042 Rennes, France; (M.D.); (C.C.)
| | - Leticia Bucio
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional, IIB, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Verónica Souza
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional, IIB, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Roxana U. Miranda-Labra
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional, IIB, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Linda E. Muñoz-Espinosa
- Liver Unit, Department of Internal Medicine, “Dr. José E. González” University Hospital, Universidad Autónoma de Nuevo León, Monterrey 64460, NL, Mexico;
| | - Cédric Coulouarn
- Centre de Lutte contre le Cancer Eugène Marquis, Inserm, Univ Rennes, COSS (Chemistry, Oncogenesis Stress Signaling), UMR_S 1242, 35042 Rennes, France; (M.D.); (C.C.)
| | - María Concepción Gutiérrez-Ruiz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional, IIB, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
| | - Jens U. Marquardt
- Department of Medicine I, University Hospital Schleswig-Holstein, 23562 Lübeck, Germany;
| | - Luis E. Gomez-Quiroz
- Área de Medicina Experimental y Traslacional, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City 09340, Mexico; (L.B.); (V.S.); (R.U.M.-L.); (M.C.G.-R.)
- Laboratorio de Medicina Experimental, Unidad de Medicina Traslacional, IIB, UNAM/Instituto Nacional de Cardiología Ignacio Chavez, Mexico City 14080, Mexico
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Abstract
Metastasis formation is the major cause of death in most patients with cancer. Despite extensive research, targeting metastatic seeding and colonization is still an unresolved challenge. Only recently, attention has been drawn to the fact that metastasizing cancer cells selectively and dynamically adapt their metabolism at every step during the metastatic cascade. Moreover, many metastases display different metabolic traits compared with the tumours from which they originate, enabling survival and growth in the new environment. Consequently, the stage-dependent metabolic traits may provide therapeutic windows for preventing or reducing metastasis, and targeting the new metabolic traits arising in established metastases may allow their eradication.
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Affiliation(s)
- Gabriele Bergers
- Laboratory of Tumor Microenvironment and Therapeutic Resistance, VIB-KU Leuven Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.
- UCSF Comprehensive Cancer Center, Department of Neurological Surgery, UCSF, San Francisco, CA, USA.
| | - Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
- Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
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41
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Tsai CF, Zhang P, Scholten D, Martin K, Wang YT, Zhao R, Chrisler WB, Patel DB, Dou M, Jia Y, Reduzzi C, Liu X, Moore RJ, Burnum-Johnson KE, Lin MH, Hsu CC, Jacobs JM, Kagan J, Srivastava S, Rodland KD, Steven Wiley H, Qian WJ, Smith RD, Zhu Y, Cristofanilli M, Liu T, Liu H, Shi T. Surfactant-assisted one-pot sample preparation for label-free single-cell proteomics. Commun Biol 2021; 4:265. [PMID: 33649493 PMCID: PMC7921383 DOI: 10.1038/s42003-021-01797-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 12/24/2020] [Indexed: 12/12/2022] Open
Abstract
Large numbers of cells are generally required for quantitative global proteome profiling due to surface adsorption losses associated with sample processing. Such bulk measurement obscures important cell-to-cell variability (cell heterogeneity) and makes proteomic profiling impossible for rare cell populations (e.g., circulating tumor cells (CTCs)). Here we report a surfactant-assisted one-pot sample preparation coupled with mass spectrometry (MS) method termed SOP-MS for label-free global single-cell proteomics. SOP-MS capitalizes on the combination of a MS-compatible nonionic surfactant, n-Dodecyl-β-D-maltoside, and hydrophobic surface-based low-bind tubes or multi-well plates for ‘all-in-one’ one-pot sample preparation. This ‘all-in-one’ method including elimination of all sample transfer steps maximally reduces surface adsorption losses for effective processing of single cells, thus improving detection sensitivity for single-cell proteomics. This method allows convenient label-free quantification of hundreds of proteins from single human cells and ~1200 proteins from small tissue sections (close to ~20 cells). When applied to a patient CTC-derived xenograft (PCDX) model at the single-cell resolution, SOP-MS can reveal distinct protein signatures between primary tumor cells and early metastatic lung cells, which are related to the selection pressure of anti-tumor immunity during breast cancer metastasis. The approach paves the way for routine, precise, quantitative single-cell proteomics. Tsai, Zhang, Scholten et al. develop a surfactant- assisted one-pot sample preparation coupled with mass spectrometry method (SOP-MS) for label-free global single-cell proteomics. This method allows researchers to measure hundreds of proteins from single human cells, suggesting its utility for quantitative single-cell proteomics.
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Affiliation(s)
- Chia-Feng Tsai
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Pengfei Zhang
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.,NHC Key Laboratory of Cancer Proteomics, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China
| | - David Scholten
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Kendall Martin
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Yi-Ting Wang
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Rui Zhao
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - William B Chrisler
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Dhwani B Patel
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Maowei Dou
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Yuzhi Jia
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Carolina Reduzzi
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Xia Liu
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ronald J Moore
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | | | - Miao-Hsia Lin
- Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chuan-Chih Hsu
- Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan
| | - Jon M Jacobs
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Jacob Kagan
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Sudhir Srivastava
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Karin D Rodland
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - H Steven Wiley
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Wei-Jun Qian
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Richard D Smith
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ying Zhu
- Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Massimo Cristofanilli
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Tao Liu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
| | - Huiping Liu
- Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. .,Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. .,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
| | - Tujin Shi
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
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42
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In Silico Identification of Novel Interactions for FABP5 (Fatty Acid-Binding Protein 5) with Nutraceuticals: Possible Repurposing Approach. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1308:589-599. [PMID: 33861460 DOI: 10.1007/978-3-030-64872-5_29] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Fatty Acid Binding-Protein 5 (FABP5) is a cytoplasmic protein, which binds long-chain fatty acids and other hydrophobic ligands. This protein is implicated in several physiological processes including mitochondrial β-oxidation and transport of fatty acids, membrane phospholipid synthesis, lipid metabolism, inflammation and pain. In the present study, we used molecular docking tools to determine the possible interaction of FABP5 with six selected compounds retrieved form Drugbank. Our results showed that FABP5 binding pocket included 31 polar and non-polar amino acids, and these residues may be related to phosphorylation, acetylation, ubiquitylation, and mono-methylation. Docking results showed that the most energetically favorable compounds are NADH (-9.12 kcal/mol), 5'-O-({[(Phosphonatooxy)phosphinato]oxy}phosphinato)adenosine (-8.62 kcal/mol), lutein (-8.25 kcal/mol), (2S)-2-[(4-{[(2-Amino-4-oxo-1,4,5,6,7,8-hexahydro-6-pteridinyl)methyl]amino}benzoyl)amino]pentanedioate (-7.17 kcal/mol), Pteroyl-L-glutamate (-6.86 kcal/mol) and (1S,3R,5E,7Z)-9,10-Secocholesta-5,7,10-triene-1,3,25-triol (-6.79 kcal/mol). Common interacting residues of FABP5 with nutraceuticals included SER16, LYS24, LYS34, LYS40 and LYS17. Further, we used the SwissADME server to determine the physicochemical and pharmacokinetic characteristics and to predict the ADME parameters of the selected nutraceuticals after molecular analysis by docking with the FABP5 protein. Amongst all compounds, pteroyl-L-glutamate is the only one meeting the Lipinski's rule of five criteria, demonstrating its potential pharmacological use. Finally, our results also suggest the importance of FABP5 in mediating the anti-inflammatory activity of the nutraceutical compounds.
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43
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Liu RZ, Godbout R. An Amplified Fatty Acid-Binding Protein Gene Cluster in Prostate Cancer: Emerging Roles in Lipid Metabolism and Metastasis. Cancers (Basel) 2020; 12:E3823. [PMID: 33352874 PMCID: PMC7766576 DOI: 10.3390/cancers12123823] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/12/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
Treatment for early stage and localized prostate cancer (PCa) is highly effective. Patient survival, however, drops dramatically upon metastasis due to drug resistance and cancer recurrence. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. It is therefore crucial to decipher the key genetic alterations and relevant molecular pathways driving PCa metastatic progression so that predictive biomarkers and precise therapeutic targets can be developed. Through PCa cohort analysis, we found that a fatty acid-binding protein (FABP) gene cluster (containing five FABP family members) is preferentially amplified and overexpressed in metastatic PCa. All five FABP genes reside on chromosome 8 at 8q21.13, a chromosomal region frequently amplified in PCa. There is emerging evidence that these FABPs promote metastasis through distinct biological actions and molecular pathways. In this review, we discuss how these FABPs may serve as drivers/promoters for PCa metastatic transformation using patient cohort analysis combined with a review of the literature.
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Affiliation(s)
| | - Roseline Godbout
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
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44
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Quantitative proteomics and phosphoproteomic analyses of mouse livers after tick-borne Babesia microti infection. Int J Parasitol 2020; 51:167-182. [PMID: 33242464 DOI: 10.1016/j.ijpara.2020.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022]
Abstract
Babesia microti is a tick-borne protozoan parasite that infects the red blood cells of mice, humans, and other mammals. The liver tissues of BALB/c mice infected with B. microti exhibit severe injury. To further investigate the molecular mechanisms underlying liver injury and liver self-repair after B. microti infection, data-independent acquisition (DIA) quantitative proteomics was used to analyse changes in the expression and phosphorylation of proteins in liver tissues of BALB/c mice during a B. microti infection period and a recovery period. The expression of FABP1 and ACBP, which are related to fatty acid transport in the liver, was downregulated after infection with B. microti, as was the expression of Acox1, Ehhadh and Acaa1a, which are crucial rate-limiting enzymes in the process of fatty acid β oxidation. The phosphorylation levels of AMP-activated protein kinase (AMPK) and Hormone-sensitive lipase (HSL) were also downregulated. In addition, the expression of PSMB9, CTSC, and other immune-related proteins was increased, reflecting an active immune regulation mechanism in the mice. The weights of mice infected with B. microti were significantly reduced, and the phosphorylation levels of IRS-1, c-Raf, mTOR, and other proteins related to growth and development were downregulated.
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45
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Tierney C, Bazou D, Lê G, Dowling P, O'Gorman P. Saliva-omics in plasma cell disorders- Proof of concept and potential as a non-invasive tool for monitoring disease burden. J Proteomics 2020; 231:104015. [PMID: 33068749 DOI: 10.1016/j.jprot.2020.104015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 09/09/2020] [Accepted: 10/10/2020] [Indexed: 12/12/2022]
Abstract
Multiple Myeloma (MM), the second most common lymphoid cancer worldwide, is characterised by the uninhibited proliferation of terminally differentiated B-lymphocytes. Leading to The diagnosis typically requires the presence of a monoclonal protein (M protein) and the demonstration of CRAB features (hypercalcemia, renal impairment, anaemia and bone lesions). MM is considered incurable as, due to serial clonal evolution, the vast majority of patients succumb to treatment-refractory disease. MGUS (Monoclonal Gammopathy of Unknown Uncertain Significance) is the pre-malignant form of MM and, although 93% of MM patients exhibit M protein production associated with MGUS before diagnosis, little is known about the switch from pre-malignant to malignant disease. To explore this disease transition further, LC-MS/MS analysis was carried out to identify potential salivary biomarkers to monitor disease burden. FABP5 was detected in saliva as having a significant increase in abundance when MGUS was compared to symptomatic MM. The levels of FABP5 decreased after treatment indicating correlation with tumour burden. This finding was validated using western blot analysis and ELISA analysis. SIGNIFICANCE: The field of biomarker discovery has focused largely on serum as a biofluid. Saliva is a readily available biofluid that, as a biomarker resource, has been relatively un-explored. The identification of changes in saliva indicating disease progression underlines the utility of saliva as a non-invasive source of informative biomarkers reflecting disease burden and progression.
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Affiliation(s)
- Ciara Tierney
- Department of Biology, National University of Ireland, Maynooth, Ireland
| | - Despina Bazou
- Department of Hematology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Giao Lê
- National Institute for Cellular Biotechnology, DCU, Dublin, Ireland
| | - Paul Dowling
- Department of Biology, National University of Ireland, Maynooth, Ireland
| | - Peter O'Gorman
- Department of Hematology, Mater Misericordiae University Hospital, Dublin, Ireland.
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O'Sullivan SE, Kaczocha M. FABP5 as a novel molecular target in prostate cancer. Drug Discov Today 2020; 25:S1359-6446(20)30375-5. [PMID: 32966866 PMCID: PMC8059105 DOI: 10.1016/j.drudis.2020.09.018] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/07/2020] [Accepted: 09/15/2020] [Indexed: 12/22/2022]
Abstract
Emerging evidence suggests that dysregulated lipid signaling is a key factor in prostate cancer (PC), through fatty acid activation of the nuclear receptors peroxisome proliferator-activated receptors (PPARs), leading to the upregulation of protumoral genes. Fatty acid-binding proteins (FABPs) are intracellular lipid-binding proteins that transport fatty acid to PPARs, facilitating their activation. FABP5 is overexpressed in PC, and correlates with poor patient prognosis and survival. Genetic knockdown or silencing of FABP5 decreases the proliferation and invasiveness of PC cells in vitro, and reduces tumor growth and metastasis in vivo. Pharmacological FABP5-specific inhibitors also reduce tumor growth and metastases, and produce synergistic effects with taxanes. In this review, we present current data supporting FABP5 as a novel molecular target for PC.
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Affiliation(s)
| | - Martin Kaczocha
- Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NYH, USA
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47
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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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48
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Butler LM, Perone Y, Dehairs J, Lupien LE, de Laat V, Talebi A, Loda M, Kinlaw WB, Swinnen JV. Lipids and cancer: Emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev 2020; 159:245-293. [PMID: 32711004 PMCID: PMC7736102 DOI: 10.1016/j.addr.2020.07.013] [Citation(s) in RCA: 379] [Impact Index Per Article: 75.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/02/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple preclinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of preclinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.
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Affiliation(s)
- Lisa M Butler
- Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Ylenia Perone
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine, London, UK
| | - Jonas Dehairs
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Leslie E Lupien
- Program in Experimental and Molecular Medicine, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 037560, USA
| | - Vincent de Laat
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Ali Talebi
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium
| | - Massimo Loda
- Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
| | - William B Kinlaw
- The Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Johannes V Swinnen
- Laboratory of Lipid Metabolism and Cancer, KU Leuven Cancer Institute, 3000 Leuven, Belgium.
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Zhang C, Liao Y, Liu P, Du Q, Liang Y, Ooi S, Qin S, He S, Yao S, Wang W. FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism. Theranostics 2020; 10:6561-6580. [PMID: 32550890 PMCID: PMC7295046 DOI: 10.7150/thno.44868] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 04/24/2020] [Indexed: 12/21/2022] Open
Abstract
Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.
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Affiliation(s)
| | | | | | | | | | | | | | - Shanyang He
- Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Shuzhong Yao
- Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
| | - Wei Wang
- Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, China
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Nakagawa R, Hiep NC, Ouchi H, Sato Y, Harada K. Expression of fatty-acid-binding protein 5 in intrahepatic and extrahepatic cholangiocarcinoma: the possibility of different energy metabolisms in anatomical location. Med Mol Morphol 2020; 53:42-49. [PMID: 31432248 DOI: 10.1007/s00795-019-00230-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/13/2019] [Indexed: 02/07/2023]
Abstract
The biliary tract cancer (BTC) covers a range of carcinomas, including intrahepatic cholangiocarcinoma (ICC), cholangiolocellular carcinoma (CoCC), perihilar cholangiocarcinoma (perihilar CC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), defined according to the anatomical location. These adenocarcinomas mostly comprise biliary epithelial cell-derived malignant cells. In addition to anatomical differences, there are morphological and biological differences in BTC starting from embryonic development of the tissues extending to physiological differences. Fatty acid-binding proteins (FABPs) are closely associated with the energy metabolism. Using surgical specimens from 74 BTCs, we performed immunohistochemistry for FABP5 and its associated molecules, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1 (PGC-1), and estrogen-related receptor α (ERRα). We found that the expression patterns of small BTCs (ICC and CoCC) considerably differed from those of large BTCs (perihilar CC, ECC, and GBC). Expression of FABP5 and PGC-1 in large BTCs was high compared with those of small BTCs, but no difference in the expression of PPARγ and ERRα was observed. FABP5 appears to play a role in malignant progression in large BTCs. Small and large BTCs possess different energy metabolism systems owing to their different anatomical locations and course of carcinogenesis, although all BTCs originate from biliary epithelial cells.
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Affiliation(s)
- Risa Nakagawa
- Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan
| | - Nguyen Canh Hiep
- Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan
| | - Hirofumi Ouchi
- Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan.
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