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Asgharzadeh F, Memarzia A, Alikhani V, Beigoli S, Boskabady MH. Peroxisome proliferator-activated receptors: Key regulators of tumor progression and growth. Transl Oncol 2024; 47:102039. [PMID: 38917593 PMCID: PMC11254173 DOI: 10.1016/j.tranon.2024.102039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 04/30/2024] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
One of the main causes of death on the globe is cancer. Peroxisome-proliferator-activated receptors (PPARs) are nuclear hormone receptors, including PPARα, PPARδ and PPARγ, which are important in regulating cancer cell proliferation, survival, apoptosis, and tumor growth. Activation of PPARs by endogenous or synthetic compounds regulates tumor progression in various tissues. Although each PPAR isotype suppresses or promotes tumor development depending on the specific tissues or ligands, the mechanism is still unclear. PPARs are receiving interest as possible therapeutic targets for a number of disorders. Numerous clinical studies are being conducted on PPARs as possible therapeutic targets for cancer. Therefore, this review will focus on the existing and future uses of PPARs agonists and antagonists in treating malignancies. PubMed, Science Direct, and Scopus databases were searched regarding the effect of PPARs on various types of cancers until the end of May 2023. The results of the review articles showed the therapeutic influence of PPARs on a wide range of cancer on in vitro, in vivo and clinical studies. However, further experimental and clinical studies are needed to be conducted on the influence of PPARs on various cancers.
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Affiliation(s)
- Fereshteh Asgharzadeh
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arghavan Memarzia
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vida Alikhani
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Sima Beigoli
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Boskabady
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Baghcheghi Y, Beheshti F, Seyedi F, Hedayati-Moghadam M, Askarpour H, Kheirkhah A, Golkar A, Dalfardi M, Hosseini M. The effects of pioglitazone and rosiglitazone on liver function in hypothyroid rats. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2024; 21:123-130. [PMID: 38253264 DOI: 10.1515/jcim-2023-0147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024]
Abstract
OBJECTIVES This study aimed to investigate the antioxidant effect of rosiglitazone (ROG) and pioglitazone (POG) on oxidative damage and dysfunction of hepatic tissue in hypothyroid rats. METHODS The male rats were classified into six groups: (1) Control; (2) Hypothyroid, (3) Hypothyroid-POG 10, (4) Hypothyroid-POG 20, (5) Hypothyroid-ROG 2, and (6) Hypothyroid-ROG 4. To induction hypothyroidism in rats, propylthiouracil (PTU) (0.05 %w/v) was added to drinking water. In groups 2-6, besides PTU, the rats were also intraperitoneal administrated with 10 or 20 mg/kg POG or 2 or 4 mg/kg ROG for six weeks. Finally, after deep anesthesia, the blood was collected to measure the serum biochemical markers and hepatic tissue was separated for biochemical oxidative stress markers. RESULTS Administration of PTU significantly reduced serum thyroxin concentration, total thiol levels, activity of superoxide dismutase (SOD) and catalase (CAT) enzymes, and increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (Alk-P) and malondialdehyde (MDA) in the liver. Additionally, our results showed that prescription of POG or ROG for six weeks to hypothyroid rats resulted in an improvement in liver dysfunction (decrease in serum levels of AST, ALT, and ALK-P) through reducing oxidative damage in hepatic tissue (increase in CAT, SOD, or total thiols and decrease in MDA levels). CONCLUSIONS The findings of the present study presented that the IP administration of POG and ROG for six weeks improves liver dysfunction induced by hypothyroidism in juvenile rats by reducing oxidative damage.
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Affiliation(s)
- Yousef Baghcheghi
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Farimah Beheshti
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Department of Physiology, School of Medicine, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Fatemeh Seyedi
- Department of Anatomical Sciences, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Mahdiyeh Hedayati-Moghadam
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
- Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Hedyeh Askarpour
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Aliasghar Kheirkhah
- Clinical Research Development Center of Imam Khomeini Hospital, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Ahmad Golkar
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Mohammad Dalfardi
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Mahmoud Hosseini
- Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Cernea S, Onișor D. Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:286-309. [PMID: 36687124 PMCID: PMC9846941 DOI: 10.3748/wjg.v29.i2.286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/06/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer worldwide, with hepatocellular carcinoma (HCC) comprising most cases. Besides hepatitis B and C viral infections, heavy alcohol use, and nonalcoholic steatohepatitis (NASH)-associated advanced fibrosis/cirrhosis, several other risk factors for HCC have been identified (i.e. old age, obesity, insulin resistance, type 2 diabetes). These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection. HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease (NAFLD) patients, and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment. Patients with NASH-cirrhosis should undergo systematic HCC surveillance, while this might be considered in patients with advanced fibrosis based on individual risk assessment. In this context, interventions that potentially prevent NAFLD/ NASH-associated HCC are needed. This paper provided an overview of evidence related to lifestyle changes (i.e. weight loss, physical exercise, adherence to healthy dietary patterns, intake of certain dietary components, etc.) and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms. However, well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureş 540139, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
| | - Danusia Onișor
- Department ME2/Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540139, Romania
- Gastroenterology Department, Mureș County Clinical Hospital, Târgu Mureș 540072, Romania
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Metre TV, Kodasi B, Bayannavar PK, Bheemayya L, Nadoni VB, Hoolageri SR, Shettar AK, Joshi SD, Kumbar VM, Kamble RR. Coumarin-4-yl‐1,2,3‐triazol‐4-yl-methyl-thiazolidine-2,4-diones: Synthesis, Glucose uptake activity and Cytotoxic Evaluation. Bioorg Chem 2022; 130:106235. [DOI: 10.1016/j.bioorg.2022.106235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/20/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022]
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Katoch S, Sharma V, Patial V. Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios. World J Gastroenterol 2022; 28:3535-3554. [PMID: 36161051 PMCID: PMC9372809 DOI: 10.3748/wjg.v28.i28.3535] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/25/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.
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Affiliation(s)
- Swati Katoch
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vinesh Sharma
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vikram Patial
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
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Wei CY, Zhu MX, Zhang PF, Huang XY, Wan JK, Yao XZ, Hu ZT, Chai XQ, Peng R, Yang X, Gao C, Gao J, Wang SW, Zheng YM, Tang Z, Gao Q, Zhou J, Fan JB, Ke AW, Fan J. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma. J Hepatol 2022; 77:163-176. [PMID: 35219791 DOI: 10.1016/j.jhep.2022.02.019] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 01/28/2022] [Accepted: 02/09/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed. METHODS We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64. RESULTS We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis. CONCLUSIONS We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC. LAY SUMMARY Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma.
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Affiliation(s)
- Chuan-Yuan Wei
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China; Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Meng-Xuan Zhu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Peng-Fei Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Xiao-Yong Huang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Jin-Kai Wan
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China
| | - Xiu-Zhong Yao
- Department of Radiology, Zhongshan Hospital of Fudan University, Fudan University, Shanghai Institute of Medical Imaging, Shanghai, 200032, P. R. China
| | - Ze-Tao Hu
- Department of Biochemistry, School of Life Sciences, Fudan University, Shanghai, 200433, P. R. China
| | - Xiao-Qiang Chai
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Rui Peng
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Xuan Yang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Chao Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Jian Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Si-Wei Wang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Yi-Min Zheng
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Zheng Tang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China
| | - Jia-Bin Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China.
| | - Ai-Wu Ke
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China.
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, P. R. China.
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Polvani S, Pepe S, Tempesti S, Tarocchi M, Marroncini G, Bencini L, Ceni E, Mello T, Picariello L, Simeone I, Grappone C, Dragoni G, Antonuzzo L, Giommoni E, Milani S, Galli A. Isoforms of the orphan nuclear receptor COUP‑TFII differentially modulate pancreatic cancer progression. Int J Oncol 2022; 60:55. [PMID: 35348189 PMCID: PMC8997336 DOI: 10.3892/ijo.2022.5345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 02/07/2022] [Indexed: 12/24/2022] Open
Abstract
The expression of the nuclear receptor transcription factor (TF) COUP‑TFII is broadly associated with cell differentiation and cancer development, including of pancreatic ductal adenocarcinoma (PDAC), a devastating disease with one of the poorest prognoses among cancers worldwide. Recent studies have started to investigate the pathological and physiological roles of a novel COUP‑TFII isoform (COUP‑TFII_V2) that lacks the DNA‑binding domain. As the role of the canonical COUP‑TFII in PDAC was previously demonstrated, the present study evaluated whether COUP‑TFII_V2 may have a functional role in PDAC. It was demonstrated that COUP‑TFII_V2 naturally occurs in PDAC cells and in primary samples, where its expression is consistent with shorter overall survival and peripheral invasion. Of note, COUP‑TFII_V2, exhibiting nuclear and cytosolic expression, is linked to epithelial to mesenchymal transition (EMT) and cancer progression, as confirmed by nude mouse experiments. The present results demonstrated that COUP‑TFII_V2 distinctively regulates the EMT of PDAC and, similarly to its sibling, it is associated with tumor aggressiveness. The two isoforms have both overlapping and exclusive functions that cooperate with cancer growth and dissemination. By studying how PDAC cells switch from one isoform to the other, novel insight into cancer biology was gained, indicating that this receptor may serve as a novel possible target for PDAC management.
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Affiliation(s)
- Simone Polvani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Sara Pepe
- Core Research Laboratory, Institute for Cancer Research and Prevention, I-50139 Florence, Italy
- Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy
| | - Sara Tempesti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Mirko Tarocchi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Giada Marroncini
- Endocrinology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50139 Florence, Italy
| | - Lapo Bencini
- Oncology General Surgery, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Elisabetta Ceni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Tommaso Mello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Lucia Picariello
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Irene Simeone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
- Department of Medical Biotechnologies, University of Siena, I-53100 Siena, Italy
| | - Cecilia Grappone
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Lorenzo Antonuzzo
- Department of Experimental and Clinical Medicine, University of Florence, I-50139 Florence, Italy
| | - Elisa Giommoni
- Medical Oncology, Azienda Ospedaliero Universitaria Careggi, I-50139 Florence, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, I-50134 Florence, Italy
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High S100A7 expression is associated with early muscle invasion and poor survival in bladder carcinoma. Ann Diagn Pathol 2021; 56:151847. [PMID: 34742033 DOI: 10.1016/j.anndiagpath.2021.151847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/09/2021] [Accepted: 10/23/2021] [Indexed: 11/22/2022]
Abstract
Muscle-invasive bladder carcinoma (MIBC) accounts for 25% of newly diagnosed bladder carcinomas (BCs) and presents a high risk of progression and metastasis. This study aimed to identify reliable biomarkers associated with muscle invasion and prognosis to identify potential therapeutic targets for MIBC. Four gene datasets were downloaded from the Gene Expression Omnibus, and the integrated differentially expressed genes (DEGs) were then subjected to gene ontology (GO) terms and pathway enrichment analyses. Correlation analysis between the expression of the top-ranking DEGs and pathological T stages was performed to identify the genes associated with early muscle invasion. The corresponding prognostic values were evaluated, and co-expressed genes mined in the cBioPortal database were loaded into ClueGo in Cytoscape for pathway enrichment analysis. Using data mining from the STRING and TCGA databases, protein-protein interaction and competitive endogenous RNA networks were constructed. In total, 645 integrated DEGs were identified and these were mainly enriched in 26 pathways, including cell cycle, bladder cancer, DNA replication, and PPAR signaling pathway. S100A7 expression was significantly increased from the T2 stage and showed significantly worse overall survival and disease-specific survival in patients with BC. In total, 144 genes co-expressed with S100A7 in BC were significantly enriched in the IL-17 pathway. S100A7 was predicted to directly interact with LYZ, which potentially shows competitive binding with hsa-mir-140 to affect the expression of six lncRNAs in MIBC. In conclusion, high S100A7 expression was predicted to be associated with early muscle invasion and poor survival in patients with BC.
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Arvind A, Memel ZN, Philpotts LL, Zheng H, Corey KE, Simon TG. Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis. Metabolism 2021; 120:154780. [PMID: 33891949 PMCID: PMC8217281 DOI: 10.1016/j.metabol.2021.154780] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/15/2021] [Accepted: 04/17/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. METHODS We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). RESULTS Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I2 = 72%). CONCLUSIONS Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.
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Affiliation(s)
- Ashwini Arvind
- Harvard Medical School, Boston, MA, United States of America; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, United States of America
| | - Zoe N Memel
- Harvard Medical School, Boston, MA, United States of America; Department of Medicine, Massachusetts General Hospital, Boston, MA, United States of America
| | - Lisa L Philpotts
- Treadwell Library, Massachusetts General Hospital, Boston, MA, United States of America
| | - Hui Zheng
- Harvard Medical School, Boston, MA, United States of America; Biostatistics Center, Massachusetts General Hospital, Boston, MA, United States of America
| | - Kathleen E Corey
- Harvard Medical School, Boston, MA, United States of America; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, United States of America; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States of America
| | - Tracey G Simon
- Harvard Medical School, Boston, MA, United States of America; Liver Center and Gastrointestinal Division, Massachusetts General Hospital, Boston, MA, United States of America; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States of America.
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10
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Nath M, Nath S, Choudhury Y. The impact of thiazolidinediones on the risk for prostate cancer in patients with type 2 diabetes mellitus: A review and meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2020.100840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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11
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Prashantha Kumar BR, Kumar AP, Jose JA, Prabitha P, Yuvaraj S, Chipurupalli S, Jeyarani V, Manisha C, Banerjee S, Jeyabalan JB, Mohankumar SK, Dhanabal SP, Justin A. Minutes of PPAR-γ agonism and neuroprotection. Neurochem Int 2020; 140:104814. [PMID: 32758586 DOI: 10.1016/j.neuint.2020.104814] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/08/2020] [Accepted: 07/13/2020] [Indexed: 12/25/2022]
Abstract
Peroxisome proliferator-activated receptor gamma (PPAR-γ) is one of the ligand-activated transcription factors which regulates a number of central events and considered as a promising target for various neurodegenerative disease conditions. Numerous reports implicate that PPAR-γ agonists have shown neuroprotective effects by regulating genes transcription associated with the pathogenesis of neurodegeneration. In regards, this review critically appraises the recent knowledge of PPAR-γ receptors in neuroprotection in order to hypothesize potential neuroprotective mechanism of PPAR-γ agonism in chronic neurological conditions. Of note, the PPAR-γ's interaction dynamics with PPAR-γ coactivator-1α (PGC-1α) has gained significant attention for neuroprotection. Likewise, a plethora of studies suggest that the PPAR-γ pathway can be actuated by the endogenous ligands present in the CNS and thus identification and development of novel agonist for the PPAR-γ receptor holds a vow to prevent neurodegeneration. Together, the critical insights of this review enlighten the translational possibilities of developing novel neuroprotective therapeutics targeting PPAR-γ for various neurodegenerative disease conditions.
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Affiliation(s)
- B R Prashantha Kumar
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - Ashwini Prem Kumar
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Jincy A Jose
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - P Prabitha
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - S Yuvaraj
- Department of Pharmaceutical Chemistry, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Mysuru, Karnataka, India
| | - Sandhya Chipurupalli
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Victoria Jeyarani
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Chennu Manisha
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Sayani Banerjee
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Jeyaram Bharathi Jeyabalan
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Suresh Kumar Mohankumar
- TIFAC CORE in HD, Department of Pharmacognosy, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - S P Dhanabal
- TIFAC CORE in HD, Department of Pharmacognosy, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India
| | - Antony Justin
- Department of Pharmacology, JSS Academy of Higher Education & Research, JSS College of Pharmacy, Ooty, Nilgiris, Tamilnadu, India.
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12
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Song C, Liu B, Xu P, Ge X, Zhang H. Emodin ameliorates metabolic and antioxidant capacity inhibited by dietary oxidized fish oil through PPARs and Nrf2-Keap1 signaling in Wuchang bream (Megalobrama amblycephala). FISH & SHELLFISH IMMUNOLOGY 2019; 94:842-851. [PMID: 31585245 DOI: 10.1016/j.fsi.2019.10.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/25/2019] [Accepted: 10/01/2019] [Indexed: 06/10/2023]
Abstract
Dietary lipids and fatty acids are involved in cell metabolism and animal physiological regulation. However, oxidized lipids could induce oxidative stress and disorder normal growth and physiological health in fish. A 12-week rearing experiment with 6% fish oil (6F), 6% oxidized fish oil (6OF) and emodin supplemented diets (6F + E, 6OF + E) was conducted to evaluate the protective mechanism of emodin on oxidized fish oil stress in Megalobrama amblycephala. Results indicate that, under oxidized fish oil stress, emodin rescued the growth performance inhibition, improved special growth ratio (SGR), and reduced feed conversion ratio (FCR) and hepatosomatic index (HSI); rescued intestine histological impairment, ameliorated the structural expansion and membrane damage of mitochondria in intestine cells, and increased the length and intensity of intestinal villus. Moreover, emodin enhanced serum immune and antioxidant enzyme activity, increased metabolic activity through PPARs signaling, increased antioxidant capacity through PPARs and Nrf2-Keap1 signaling based on the transcriptional expression of specific genes. These results indicate emodin could be used as an effective immunostimulant to protect organism form oxidative stress induced by dietary oxidized lipid. This may provide insights for oxidized lipid prevention in aquaculture production.
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Affiliation(s)
- Changyou Song
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| | - Bo Liu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China.
| | - Xianping Ge
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
| | - Huimin Zhang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, 214081, China
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13
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Mello T, Simeone I, Galli A. Mito-Nuclear Communication in Hepatocellular Carcinoma Metabolic Rewiring. Cells 2019; 8:cells8050417. [PMID: 31060333 PMCID: PMC6562577 DOI: 10.3390/cells8050417] [Citation(s) in RCA: 20] [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: 03/22/2019] [Revised: 04/29/2019] [Accepted: 05/01/2019] [Indexed: 12/24/2022] Open
Abstract
As the main metabolic and detoxification organ, the liver constantly adapts its activity to fulfill the energy requirements of the whole body. Despite the remarkable adaptive capacity of the liver, prolonged exposure to noxious stimuli such as alcohol, viruses and metabolic disorders results in the development of chronic liver disease that can progress to hepatocellular carcinoma (HCC), which is currently the second leading cause of cancer-related death worldwide. Metabolic rewiring is a common feature of cancers, including HCC. Altered mito-nuclear communication is emerging as a driving force in the metabolic reprogramming of cancer cells, affecting all aspects of cancer biology from neoplastic transformation to acquired drug resistance. Here, we explore relevant aspects (and discuss recent findings) of mito-nuclear crosstalk in the metabolic reprogramming of hepatocellular carcinoma.
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Affiliation(s)
- Tommaso Mello
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
| | - Irene Simeone
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
- University of Siena, 53100 Siena, Italy.
| | - Andrea Galli
- Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, V.le Pieraccini 6, Florence 50129, Italy.
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14
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Wang Z, Li F, Quan Y, Shen J. Avicularin ameliorates human hepatocellular carcinoma via the regulation of NF‑κB/COX‑2/PPAR‑γ activities. Mol Med Rep 2019; 19:5417-5423. [PMID: 31059053 PMCID: PMC6522888 DOI: 10.3892/mmr.2019.10198] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 03/20/2019] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has become a global public health problem. Therefore, the development of novel and effective therapeutic agents for the treatment of HCC is considered an emergency. Avicularin, a bio-active flavonoid from plants, has been reported to exhibit diverse pharmacological properties. The aim of the present study was to investigate the role of avicularin in HCC and the underlying mechanism of action. Huh7 cells were treated with avicularin in a concentration-dependent manner, and the cell proliferation was examined using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay kit. The cell migration and invasion abilities were detected using wounding-healing assays and Transwell assays. Flow cytometric analysis was performed to investigate the cell cycle distribution and cell apoptosis. The activity of nuclear factor (NF)-κB (p65), cyclooxygenase-2 (COX-2) and peroxisome proliferator-activated receptor γ (PPAR-γ) were measured by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. The results indicated that avicularin treatment markedly decreased cell proliferation concentration-dependently in HCC, and inhibited cell migration and invasion in Huh7 cells. It was also found that the treatment of avicularin markedly inhibited the G0/G1-phase cells and decreased the accumulation of S-phase cells in the cell cycle and induced cell apoptosis. In addition, it was confirmed that the anticancer efficacy of avicularin in HCC was dependent on the regulation of NF-κB (p65), COX-2 and PPAR-γ activities. In conclusion, the findings suggested that avicularin serves an antineoplastic role in HCC and may provide a potential therapeutic strategy for the treatment of HCC.
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Affiliation(s)
- Zhimin Wang
- Department of Basic Medicine, Qujing Medical College, Qujing, Yunnan 655000, P.R. China
| | - Fang Li
- Department of Basic Medicine, Qujing Medical College, Qujing, Yunnan 655000, P.R. China
| | - Yuan Quan
- School of Nursing, Qujing Medical College, Qujing, Yunnan 655000, P.R. China
| | - Junye Shen
- Department of Traditional Chinese Medicine, Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315000, P.R. China
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15
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Chen LY, Fan XP, Fan YC, Zhao J, Gao S, Li F, Qi ZX, Wang K. BATF Interference Blocks Th17 Cell Differentiation and Inflammatory Response in Hepatitis B Virus Transgenic Mice. Dig Dis Sci 2019; 64:773-780. [PMID: 30498928 DOI: 10.1007/s10620-018-5392-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 11/22/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND B cell-activating transcription factor (BATF) contributes to Th17 cell differentiation and pathological inflammatory responses. AIMS This study explored BATF as a regulator of Th17 differentiation in normal and hepatitis B virus (HBV) transgenic mice. METHODS Normal mice were divided into control, short hairpin RNA (shRNA) scramble, and shRNA BATF groups. HBV transgenic mice were divided into control, entecavir, shRNA scramble, entecavir + vector control, entecavir + shRNA scramble, shRNA BATF, and entecavir + shRNA BATF groups. Serum concentrations of AST, ALT, HBV-DNA, BATF, IL-17, and IL-22 and Th17 cell frequencies in the liver were compared among the groups. Correlations of serum HBV surface antigen (HBsAg), e-antigen (HBeAg), and core antigen (HBcAg) concentrations with BATF mRNA expression and the proportion of Th17 cells in the livers of HBV transgenic mice were also analyzed. RESULTS Serum AST, ALT, BATF, IL-17, and IL-22 concentrations and Th17 cell proportions were higher in HBV transgenic mice relative to normal controls. Positive correlations of the HBcAg concentration with BATF mRNA and the proportion of Th17 cells were observed in HBV transgenic mice. BATF interference reduced the proportion of Th17 cells and serum IL-17 and IL-22 concentrations and led to obvious downregulation of AST, ALT, BATF, IL-17, and IL-22 expression and a reduced proportion of Th17 cells when combined with entecavir. CONCLUSION HBV markedly upregulated BATF expression and promoted Th17 cell activation. By contrast, BATF interference significantly impeded the proliferation of Th17 cells and secretion of IL-17 and IL-22 while alleviating hepatic lesions.
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Affiliation(s)
- Long-Yan Chen
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiao-Peng Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Jing Zhao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Feng Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Zhao-Xia Qi
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, 250012, China.
- Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, 250012, China.
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Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor- γ and Digestive Cancers. PPAR Res 2018; 2018:5289859. [PMID: 29483923 PMCID: PMC5816837 DOI: 10.1155/2018/5289859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 10/14/2017] [Accepted: 10/25/2017] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPARγ is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.
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Abraham R, Singh S, Nair SR, Hulyalkar NV, Surendran A, Jaleel A, Sreekumar E. Nucleophosmin (NPM1)/B23 in the Proteome of Human Astrocytic Cells Restricts Chikungunya Virus Replication. J Proteome Res 2017; 16:4144-4155. [PMID: 28959884 DOI: 10.1021/acs.jproteome.7b00513] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chikungunya virus (CHIKV), a positive-stranded RNA virus, can cause neurological complications by infecting the major parenchymal cells of the brain such as neurons and astrocytes. A proteomic analysis of CHIKV-infected human astrocytic cell line U-87 MG revealed tight functional associations among the modulated proteins. The predominant cellular pathways involved were of transcription-translation machinery, cytoskeletol reorganization, apoptosis, ubiquitination, and metabolism. In the proteome, we could also identify a few proteins that are reported to be involved in host-virus interactions. One such protein, Nucleophosmin (NPM1)/B23, a nucleolar protein, showed enhanced cytoplasmic aggregation in CHIKV-infected cells. NPM1 aggregation was predominantly localized in areas wherein CHIKV antigen could be detected. Furthermore, we observed that inhibition of this aggregation using a specific NPM1 oligomerization inhibitor, NSC348884, caused a significant dose-dependent enhancement in virus replication. There was a marked increase in the amount of intracellular viral RNA, and ∼105-fold increase in progeny virions in infected cells. Our proteomic analysis provides a comprehensive spectrum of host proteins modulated in response to CHIKV infection in astrocytic cells. Our results also show that NPM1/B23, a multifunctional chaperone, plays a critical role in restricting CHIKV replication and is a possible target for antiviral strategies.
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Affiliation(s)
- Rachy Abraham
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Sneha Singh
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Sreeja R Nair
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Neha Vijay Hulyalkar
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Arun Surendran
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Abdul Jaleel
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
| | - Easwaran Sreekumar
- Molecular Virology Laboratory and ‡Proteomics Core Facility, Rajiv Gandhi Centre for Biotechnology (RGCB) , Thiruvananthapram 695014, Kerala, India
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Kamala L, Veena BS, Anantha Lakshmi PV, Vasantha P, Sujatha E. Synthesis and antimicrobial activity of novel 5-[(1H-indol-3-yl)methylene]thiazolidine-2,4-dione–[1,2,3]triazole hybrids. RUSS J GEN CHEM+ 2017. [DOI: 10.1134/s107036321702027x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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PPARs and Mitochondrial Metabolism: From NAFLD to HCC. PPAR Res 2016; 2016:7403230. [PMID: 28115925 PMCID: PMC5223052 DOI: 10.1155/2016/7403230] [Citation(s) in RCA: 297] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 11/08/2016] [Accepted: 11/10/2016] [Indexed: 11/17/2022] Open
Abstract
Metabolic related diseases, such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD), are widespread threats which bring about a significant burden of deaths worldwide, mainly due to cardiovascular events and cancer. The pathogenesis of these diseases is extremely complex, multifactorial, and only partially understood. As the main metabolic organ, the liver is central to maintain whole body energetic homeostasis. At the cellular level, mitochondria are the metabolic hub connecting and integrating all the main biochemical, hormonal, and inflammatory signaling pathways to fulfill the energetic and biosynthetic demand of the cell. In the liver, mitochondria metabolism needs to cope with the energetic regulation of the whole body. The nuclear receptors PPARs orchestrate lipid and glucose metabolism and are involved in a variety of diseases, from metabolic disorders to cancer. In this review, focus is placed on the roles of PPARs in the regulation of liver mitochondrial metabolism in physiology and pathology, from NAFLD to HCC.
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20
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Gamma-Glutamylcysteine Ethyl Ester Protects against Cyclophosphamide-Induced Liver Injury and Hematologic Alterations via Upregulation of PPAR γ and Attenuation of Oxidative Stress, Inflammation, and Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:4016209. [PMID: 28074115 PMCID: PMC5198194 DOI: 10.1155/2016/4016209] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 11/24/2016] [Indexed: 12/23/2022]
Abstract
Gamma-glutamylcysteine ethyl ester (GCEE) is a precursor of glutathione (GSH) with promising hepatoprotective effects. This investigation aimed to evaluate the hepatoprotective effects of GCEE against cyclophosphamide- (CP-) induced toxicity, pointing to the possible role of peroxisome proliferator activated receptor gamma (PPARγ). Wistar rats were given GCEE two weeks prior to CP. Five days after CP administration, animals were sacrificed and samples were collected. Pretreatment with GCEE significantly alleviated CP-induced liver injury by reducing serum aminotransferases, increasing albumin, and preventing histopathological and hematological alterations. GCEE suppressed lipid peroxidation and nitric oxide production and restored GSH and enzymatic antioxidants in the liver, which were associated with downregulation of COX-2, iNOS, and NF-κB. In addition, CP administration significantly increased serum proinflammatory cytokines and the expression of liver caspase-3 and BAX, an effect that was reversed by GCEE. CP-induced rats showed significant downregulation of PPARγ which was markedly upregulated by GCEE treatment. These data demonstrated that pretreatment with GCEE protected against CP-induced hepatotoxicity, possibly by activating PPARγ, preventing GSH depletion, and attenuating oxidative stress, inflammation, and apoptosis. Our findings point to the role of PPARγ and suggest that GCEE might be a promising agent for the prevention of CP-induced liver injury.
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Nojima H, Kuboki S, Shinoda K, Shimizu H, Ohtsuka M, Kato A, Yoshitomi H, Furukawa K, Takayashiki T, Miyazaki M. Activation of peroxisome proliferator-activated receptor-gamma inhibits tumor growth by negatively regulating nuclear factor-κB activation in patients with hepatocellular carcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 23:574-584. [PMID: 27451128 DOI: 10.1002/jhbp.378] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 07/15/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The prognosis of advanced hepatocellular carcinoma (HCC) is poor because of its rapid progression. Peroxisome proliferator-activated receptor-gamma (PPARγ) is known to inhibit tumor growth in vitro; however, the behavior of PPARγ in clinical cases of HCC remains uncertain. METHODS Surgical specimens were collected from 104 HCC patients. The anti-neoplastic effects of PPARγ were evaluated. RESULTS PPARγ and its ligand expression were increased in some cases of HCC. When HCC patients were divided into two groups, tumor size was larger in patients with low PPARγ expression. Moreover, low PPARγ expression in HCC was an independent predictor of poorer prognosis. PPARγ expression was positively correlated with PPARγ activation and negatively correlated with NF-κB activation in HCC. PPARγ activation inhibited cell proliferation by inducing cell cycle arrest, through increased expression of p27(kip1) and decreased expression of cyclin D1 and interleukin-8. When HCC cells were treated with PPARγ ligands, PPARγ activation was increased and cell proliferation was inhibited in a dose-dependent manner. In contrast, PPARγ ligands negatively regulated NF-κB activation. CONCLUSIONS Activation of PPARγ induces cell cycle arrest and inhibits tumor progression by negatively regulating NF-κB activation in HCC. Therefore, PPARγ is an important endogenous regulator of HCC progression, and is a potential therapeutic target for HCC.
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Affiliation(s)
- Hiroyuki Nojima
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan.
| | - Kimio Shinoda
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Hiroaki Shimizu
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Atsushi Kato
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-0856, Japan
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Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J Gastroenterol 2016; 22:2441-2459. [PMID: 26937133 PMCID: PMC4768191 DOI: 10.3748/wjg.v22.i8.2441] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/17/2015] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
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23
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Li S, Li J, Fei BY, Shao D, Pan Y, Mo ZH, Sun BZ, Zhang D, Zheng X, Zhang M, Zhang XW, Chen L. MiR-27a promotes hepatocellular carcinoma cell proliferation through suppression of its target gene peroxisome proliferator-activated receptor γ. Chin Med J (Engl) 2015; 128:941-7. [PMID: 25836616 PMCID: PMC4834012 DOI: 10.4103/0366-6999.154302] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background: MicroRNAs (miRNAs) function as essential posttranscriptional modulators of gene expression, and are involved in a wide range of physiologic and pathologic states, including cancer. Numerous miRNAs are deregulated in hepatocellular carcinoma (HCC). This study aimed to investigate the role of miR-27a in the development of HCC. Methods: The expression of MiR-27a was measured by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to examine changes in the viability of HepG2, Bel-7402, Bel-7404 hepatoma cell lines associated with up-regulation or down-regulation of miR-27a. A dual-luciferase activity assay was used to verify a target gene of miR-27a. Immunohistochemistry, qRT-PCR, Western blotting analysis, and cell cycle and apoptosis flow cytometric assays were used to elucidate the mechanism by which miR-27a modulates liver cancer cell proliferation. Results: The expression of miR-27a was significantly increased in HCC tissues and HepG2, Bel-7402, Bel-7404 hepatoma cell lines (P < 0.05). We also found that the down-regulation of miR-27a in HepG2 cells dramatically inhibited proliferation, blocked the G1 to S cell cycle transition and induced apoptosis (P < 0.05). In addition, miR-27a directly targeted the 3’-untranslated region of peroxisome proliferator-activated receptor γ (PPAR-γ), and ectopic miR-27a expression suppressed PPAR-γ expression on the mRNA and protein levels. The rosiglitazone-induced overexpression of PPAR-γ attenuated the effect of miR-27a in HCC cells. Conclusions: Our findings suggested that miRNA-27a promoted HCC cell proliferation by regulating PPAR-γ expression. MiR-27a may provide a potential therapeutic strategy for HCC treatment.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xue-Wen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130021, China
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Tarocchi M, Polvani S, Peired AJ, Marroncini G, Calamante M, Ceni E, Rhodes D, Mello T, Pieraccini G, Quattrone A, Luchinat C, Galli A. Telomerase activated thymidine analogue pro-drug is a new molecule targeting hepatocellular carcinoma. J Hepatol 2014; 61:1064-72. [PMID: 24862448 PMCID: PMC4309885 DOI: 10.1016/j.jhep.2014.05.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 04/22/2014] [Accepted: 05/11/2014] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although hepatectomy and transplantation have significantly improved survival, there is no effective chemotherapeutic treatment for HCC and its prognosis remains poor. Sustained activation of telomerase is essential for the growth and progression of HCC, suggesting that telomerase is a rational target for HCC therapy. Therefore, we developed a thymidine analogue pro-drug, acycloguanosyl-5'-thymidyltriphosphate (ACV-TP-T), which is specifically activated by telomerase in HCC cells and investigated its anti-tumour efficacy. METHODS First, we verified in vitro whether ACV-TP-T was a telomerase substrate. Second, we evaluated proliferation and apoptosis in murine (Hepa1-6) and human (Hep3B, HuH7, HepG2) hepatic cancer cells treated with ACV-TP-T. Next, we tested the in vivo treatment efficacy in HBV transgenic mice that spontaneously develop hepatic tumours, and in a syngeneic orthotopic murine model where HCC cells were implanted directly in the liver. RESULTS In vitro characterization provided direct evidence that the pro-drug was actively metabolized in liver cancer cells by telomerase to release the active form of acyclovir. Alterations in cell cycle and apoptosis were observed following in vitro treatment with ACV-TP-T. In the transgenic and orthotopic mouse models, treatment with ACV-TP-T reduced tumour growth, increased apoptosis, and reduced the proliferation of tumour cells. CONCLUSIONS ACV-TP-T is activated by telomerase in HCC cells and releases active acyclovir that reduces proliferation and induces apoptosis in human and murine liver cancer cells. This pro-drug holds a great promise for the treatment of HCC.
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Affiliation(s)
- Mirko Tarocchi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Simone Polvani
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Giada Marroncini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Massimo Calamante
- ProtEra S.r.l., University Scientific Campus, Sesto Fiorentino, Florence, Italy,ICCOM-CNR Florence, Italy
| | - Elisabetta Ceni
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | | | - Tommaso Mello
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | | | - Alessandro Quattrone
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Florence, Italy,Laboratory of Translational Genomics, Centre for Integrative Biology, University of Trento, Italy
| | - Claudio Luchinat
- Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, Florence, Italy,Department of Chemistry, University of Florence, Sesto Fiorentino, Florence, Italy,Giotto Biotech S.r.l., University Scientific Campus, Sesto Fiorentino, Florence, Italy
| | - Andrea Galli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
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Polvani S, Tarocchi M, Tempesti S, Galli A. Nuclear receptors and pathogenesis of pancreatic cancer. World J Gastroenterol 2014; 20:12062-12081. [PMID: 25232244 PMCID: PMC4161795 DOI: 10.3748/wjg.v20.i34.12062] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease.
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Tarocchi M, Polvani S, Marroncini G, Galli A. Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis. World J Gastroenterol 2014; 20:11630-11640. [PMID: 25206269 PMCID: PMC4155355 DOI: 10.3748/wjg.v20.i33.11630] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 03/05/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem with approximately 2 billion people that have been exposed to the virus. HBV is a member of a family of small, enveloped DNA viruses called hepadnaviruses, and has a preferential tropism for hepatocytes of mammals and birds. Epidemiological studies have proved a strong correlation between chronic hepatitis B virus infection and the development of hepatocellular carcinoma (HCC). HCC is the fifth most common malignancy with about 700000 new cases each year, and more than 50% of them arise in HBV carriers. A large number of studies describe the way in which HBV can contribute to HCC development. Multiple mechanisms have been proposed, including the accumulation of genetic damage due to immune-mediated hepatic inflammation and the induction of oxidative stress. There is evidence of the direct effects of the viral proteins HBx and HBs on the cell biology. Integration of HBV-DNA into the human genome is considered an early event in the carcinogenic process and can induce, through insertional mutagenesis, the alteration of gene expression and chromosomal instability. HBV has also epigenetic effects through the modification of the genomic methylation status. Furthermore, the virus plays an important role in the regulation of microRNA expression. This review will summarize the many mechanisms involved in HBV-related liver carcinogenesis.
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27
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Vacca M, D'Amore S, Graziano G, D'Orazio A, Cariello M, Massafra V, Salvatore L, Martelli N, Murzilli S, Sasso GL, Mariani-Costantini R, Moschetta A. Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. PLoS One 2014; 9:e104449. [PMID: 25116592 PMCID: PMC4130532 DOI: 10.1371/journal.pone.0104449] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Accepted: 07/09/2014] [Indexed: 12/12/2022] Open
Abstract
Background & Aims Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. Methods & Results We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car). In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF) analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ) as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells. Conclusions Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.
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Affiliation(s)
- Michele Vacca
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
- Unit of General Pathology, Aging Research Center (Ce.S.I.), “Gabriele D'Annunzio” University and Foundation, Chieti, Italy
- Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari, Bari, Italy
| | - Simona D'Amore
- National Cancer Institute, IRCCS Oncologico “Giovanni Paolo II”, Bari, Italy
| | - Giusi Graziano
- National Cancer Institute, IRCCS Oncologico “Giovanni Paolo II”, Bari, Italy
| | - Andria D'Orazio
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Marica Cariello
- National Cancer Institute, IRCCS Oncologico “Giovanni Paolo II”, Bari, Italy
| | - Vittoria Massafra
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Lorena Salvatore
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Nicola Martelli
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Stefania Murzilli
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Giuseppe Lo Sasso
- Fondazione Mario Negri Sud, Santa Maria Imbaro (Chieti), Chieti, Italy
| | - Renato Mariani-Costantini
- Unit of General Pathology, Aging Research Center (Ce.S.I.), “Gabriele D'Annunzio” University and Foundation, Chieti, Italy
| | - Antonio Moschetta
- Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari, Bari, Italy
- National Cancer Institute, IRCCS Oncologico “Giovanni Paolo II”, Bari, Italy
- * E-mail:
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Polvani S, Tarocchi M, Tempesti S, Mello T, Ceni E, Buccoliero F, D'Amico M, Boddi V, Farsi M, Nesi S, Nesi G, Milani S, Galli A. COUP-TFII in pancreatic adenocarcinoma: clinical implication for patient survival and tumor progression. Int J Cancer 2014; 134:1648-58. [PMID: 24122412 DOI: 10.1002/ijc.28502] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 08/10/2013] [Accepted: 09/06/2013] [Indexed: 12/16/2023]
Abstract
Despite the accumulating knowledge of alterations in pancreatic cancer molecular pathways, no substantial improvements in the clinical prognosis have been made and this malignancy continues to be a leading cause of cancer death in the Western World. The orphan nuclear receptor COUP-TFII is a regulator of a wide range of biological processes and it may exert a pro-oncogenic role in cancer cells; interestingly, indirect evidences suggest that the receptor could be involved in pancreatic cancer. The aim of this study was to evaluate the expression of COUP-TFII in human pancreatic tumors and to unveil its role in the regulation of pancreatic tumor growth. We evaluated COUP-TFII expression by immunohistochemistry on primary samples. We analyzed the effect of the nuclear receptor silencing in human pancreatic cancer cells by means of shRNA expressing cell lines. We finally confirmed the in vitro results by in vivo experiments on nude mice. COUP-TFII is expressed in 69% of tested primary samples and correlates with the N1 and M1 status and clinical stage; Kaplan-Meier and Cox regression analysis show that it may be an independent prognostic factor of worst outcome. In vitro silencing of COUP-TFII reduces the cell growth and invasiveness and it strongly inhibits angiogenesis, an effect mediated by the regulation of VEGF-C. In nude mice, COUP-TFII silencing reduces tumor growth by 40%. Our results suggest that COUP-TFII might be an important regulator of the behavior of pancreatic adenocarcinoma, thus representing a possible new target for pancreatic cancer therapy.
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Affiliation(s)
- Simone Polvani
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Firenze, Italy
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Chinthala Y, Kumar Domatti A, Sarfaraz A, Singh SP, Kumar Arigari N, Gupta N, Satya SK, Kotesh Kumar J, Khan F, Tiwari AK, Paramjit G. Synthesis, biological evaluation and molecular modeling studies of some novel thiazolidinediones with triazole ring. Eur J Med Chem 2013; 70:308-14. [DOI: 10.1016/j.ejmech.2013.10.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 09/24/2013] [Accepted: 10/03/2013] [Indexed: 10/26/2022]
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Wang T, Ning G, Bloomgarden Z. Diabetes and cancer relationships. J Diabetes 2013; 5:378-90. [PMID: 23574745 DOI: 10.1111/1753-0407.12057] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 03/10/2013] [Accepted: 03/24/2013] [Indexed: 12/29/2022] Open
Abstract
Diabetes and cancer are both heterogeneous and multifactorial diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that certain malignancies may be associated with diabetes, as well as with diabetes risk factors and, perhaps, with certain diabetes treatments. Numerous biological mechanisms could account for these relationships. Insulin-like growth factor (IGF)-1, IGF-2, IGF-1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. Although evidence from randomized controlled trials does not support or refute associations of diabetes and its treatments with either increased or reduced risk of cancer incidence or prognosis, consideration of malignancy incidence rates and the magnitude of the trials that would be required to address these issues explains why such studies may not be readily undertaken.
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Affiliation(s)
- Tiange Wang
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, Shanghai, China; Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; E-Institute of Shanghai Universities, Shanghai, China
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Lee NJ, Oh JH, Ban JO, Shim JH, Lee HP, Jung JK, Ahn BW, Yoon DY, Han SB, Ham YW, Hong JT. 4-O-methylhonokiol, a PPARγ agonist, inhibits prostate tumour growth: p21-mediated suppression of NF-κB activity. Br J Pharmacol 2013; 168:1133-45. [PMID: 23043610 DOI: 10.1111/j.1476-5381.2012.02235.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Revised: 08/22/2012] [Accepted: 09/05/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACH The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTS MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATION MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.
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Affiliation(s)
- N J Lee
- College of Pharmacy, Chungbuk National University, Chungbuk, South Korea
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Abstract
Cannabinoids exert antiproliferative effects in a wide range of tumoral cells, including hepatocellular carcinoma (HCC) cells. In this study, we examined whether the PPARγ-activated pathway contributed to the antitumor effect of two cannabinoids, Δ9-tetrahydrocannabinol (THC) and JWH-015, against HepG2 and HUH-7 HCC cells. Both cannabinoids increased the activity and intracellular level of PPARγ mRNA and protein, which was abolished by the PPARγ inhibitor GW9662. Moreover, genetic ablation with small interfering RNA (siRNA), as well as pharmacological inhibition of PPARγ decreased the cannabinoid-induced cell death and apoptosis. Likewise, GW9662 totally blocked the antitumoral action of cannabinoids in xenograft-induced HCC tumors in mice. In addition, PPARγ knockdown with siRNA caused accumulation of the autophagy markers LC3-II and p62, suggesting that PPARγ is necessary for the autophagy flux promoted by cannabinoids. Interestingly, downregulation of the endoplasmic reticulum stress-related protein tribbles homolog 3 (TRIB3) markedly reduced PPARγ expression and induced p62 accumulation, which was counteracted by overexpression of PPARγ in TRIB3-knocked down cells. Taken together, we demonstrate for the first time that the antiproliferative action of the cannabinoids THC and JWH-015 on HCC, in vitro and in vivo, are modulated by upregulation of PPARγ-dependent pathways.
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Vacca M, Degirolamo C, Massafra V, Polimeno L, Mariani-Costantini R, Palasciano G, Moschetta A. Nuclear receptors in regenerating liver and hepatocellular carcinoma. Mol Cell Endocrinol 2013; 368:108-19. [PMID: 22789748 DOI: 10.1016/j.mce.2012.06.025] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 06/28/2012] [Accepted: 06/29/2012] [Indexed: 12/22/2022]
Abstract
A comprehensive understanding of the pathways underlying hepatocyte turnover and liver regeneration is essential for the development of innovative and effective therapies in the management of chronic liver disease, and the prevention of hepatocellular carcinoma (HCC) in cirrhosis. Nuclear receptors (NRs) are master transcriptional regulators of liver development, differentiation and function. NRs have been implicated in the modulation of hepatocyte priming and proliferation in regenerating liver, chronic hepatitis and HCC development. In this review, we focus on NRs and their pathways regulating hepatocyte proliferation and liver regeneration, with a perspective view on NRs as candidate biomarkers and novel pharmacological targets in the management of liver disease and HCC.
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Affiliation(s)
- Michele Vacca
- Laboratory of Lipid Metabolism and Cancer, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy
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Kao CH, Sun LM, Chen PC, Lin MC, Liang JA, Muo CH, Chang SN, Sung FC. A population-based cohort study in Taiwan--use of insulin sensitizers can decrease cancer risk in diabetic patients? Ann Oncol 2013; 24:523-530. [PMID: 23110810 DOI: 10.1093/annonc/mds472] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The purpose of the study was to explore the possible association between the use of insulin sensitizers (thiazolidinediones, TZDs) and the risk of cancer in Taiwanese diabetic patients. PATIENTS AND METHODS From the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 22 910 diabetic patients newly diagnosed from 2001 to 2009 and 91 636 non-diabetic comparisons frequency matched with age, sex, and calendar year, excluding those with cancer at the baseline. Among the diabetics, 4159 patients were treated with TZDs and the rest of 18 752 patients were on other anti-diabetic medications (non-TZDs). RESULTS In comparison to the non-diabetes group, the non-TZDs group had an increased risk of developing cancer [the adjusted hazard ratio (HR): 1.20 and 95% confidence interval (CI) = 1.11-1.30]. The TZDs group had a HR of 1.18 (95% CI = 0.98-1.42). Analysis of site-specific cancer risks showed that both TZDs and non-TZDs groups with elevated risks of colorectal and pancreatic cancer. However, the non-TZDs group had an increased risk of liver cancer when comparing with TZD and non-diabetes groups. CONCLUSION This study suggests that patients with diabetes are at an elevated risk of cancer (especially in colorectal and pancreatic cancers), and the use of TZDs might decrease the liver cancer risk in diabetic patients. Further investigation using large samples and rigorous methodology is warranted.
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Affiliation(s)
- C-H Kao
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine; Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung.
| | - L-M Sun
- Department of Radiation Oncology, Zuoying Armed Forces General Hospital, Kaohsiung
| | - P-C Chen
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipe
| | - M-C Lin
- Department of Nuclear Medicine, E-DA Hospital, Kaohsiung
| | - J-A Liang
- Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine; Department of Radiation Oncology
| | - C-H Muo
- Management Office for Health Data; Department of Public Health, College of Public Health
| | - S-N Chang
- Department of Public Health, College of Public Health; The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - F-C Sung
- Department of Public Health, College of Public Health
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Bosetti C, Rosato V, Buniato D, Zambon A, La Vecchia C, Corrao G. Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis. Oncologist 2013; 18:148-56. [PMID: 23345544 DOI: 10.1634/theoncologist.2012-0302] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE To clarify and quantify the effect of thiazolidinediones (TZDs; e.g., pioglitazone, rosiglitazone) on the risk of bladder cancer, other selected cancers, and overall cancer in patients with type 2 diabetes, we performed a systematic review and meta-analysis of observational studies. METHODS A PubMed/MEDLINE search was conducted for studies published in English up to June 30, 2012. Random-effect models were fitted to estimate summary relative risks (RR). RESULTS Seventeen studies satisfying inclusion criteria (3 case-control studies and 14 cohort studies) were considered. Use of TZDs was not associated to the risk of cancer overall (summary RR: 0.96; 95% confidence interval [CI]: 0.91-1.01). A modest excess risk of bladder cancer was reported in pioglitazone (RR: 1.20; 95% CI: 1.07-1.34 from six studies) but not in rosiglitazone (RR: 1.08; 95% CI: 0.95-1.23 from three studies) users. The RRs of bladder cancer were higher for longer duration (RR: 1.42 for >2 years) and higher cumulative dose of pioglitazone (RR: 1.64 for >28,000 mg). Inverse relations were observed with colorectal cancer (RR: 0.93; 95% CI: 0.90-0.97 from six cohort studies) and liver cancer (RR: 0.65; 95% CI: 0.48-0.89 from four studies), whereas there was no association with pancreatic, lung, breast, and prostate cancers. CONCLUSIONS Adequate evidence excludes an overall excess cancer risk in TZD users within a few years after starting treatment. However, there is a modest excess risk of bladder cancer, particularly with reference to pioglitazone. Assuming that this association is real, the potential implications on the risk-benefit analysis of TZD use should be evaluated.
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Affiliation(s)
- Cristina Bosetti
- Department of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, 19 20156 Milano, Italy
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Chiu CC, Huang CC, Chen YC, Chen TJ, Liang Y, Lin SJ, Chen JW, Leu HB, Chan WL. Increased risk of gastrointestinal malignancy in patients with diabetes mellitus and correlations with anti-diabetes drugs: a nationwide population-based study in Taiwan. Intern Med 2013; 52:939-46. [PMID: 23648711 DOI: 10.2169/internalmedicine.52.8276] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
OBJECTIVE Although the major cause of morbidity and mortality in patients with diabetes mellitus (DM) is cardiovascular disease, DM is also associated with certain site-specific cancers. However, whether DM is associated with an increased risk of cancer of the digestive tract remains undetermined. A nationwide, population-based database in Taiwan was analyzed to explore the relationship between DM and cancer of the digestive organs. METHODS From 2000 to 2007, a study cohort consisting of 39,515 patients with newly diagnosed diabetes without a previous diagnosis of gastrointestinal (GI) cancer was identified from the National Health Insurance Research Database in Taiwan. A control cohort of 79,030 age- and sex-matched non-diabetic subjects was selected to compare the occurrence of GI malignancies between the two groups. The association between the incidence of GI cancers and the use of glucose-lowering therapies was also investigated. RESULTS During the 7-year follow-up period, GI cancers developed in 929 diabetic patients (2.35%) and 1,126 subjects (1.42%) in the comparison cohort. DM was associated with a 2.75-fold (95% confidence interval (CI), 2.51-3.02) higher risk of developing GI malignancy. Among GI cancers, the incidences of stomach (adjusted hazard ratio (HR), 1.49; 95% CI, 1.16-1.92), liver (adjusted HR, 2.65; 95% CI, 2.29-3.07), colon (adjusted HR, 1.58; 95% CI, 1.28-1.94) and pancreatic cancers (adjusted HR, 4.35; 95% CI, 2.93-6.47) were significantly increased in the patients with DM. An analysis of the effects of various glucose-lowering therapies in the diabetic patients revealed the use of α-glucosidase inhibitors to be associated with a lower risk of hepatic cancer (adjusted HR, 0.62; 95% CI, 0.4-0.94). Thiazolidinedione (TZD) treatment was associated with lower stomach (adjusted HR, 0.11; 95% CI, 0.02-0.82) and hepatic cancer risks (adjusted HR, 0.46; 95% CI, 0.29-0.73), while sulfonylurea use was associated with a lower colon cancer risk (adjusted HR, 0.74; 95% CI, 0.51-1.09) and a higher pancreatic cancer risk (adjusted HR, 2.36; 95% CI, 1.21-4.61). CONCLUSION Patients with DM have an increased risk of GI malignancy that may be affected by the use of different categories of glucose-lowering therapies.
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Affiliation(s)
- Chun-Chih Chiu
- Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taiwan
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Kimura O, Kondo Y, Shimosegawa T. PPAR Could Contribute to the Pathogenesis of Hepatocellular Carcinoma. PPAR Res 2012; 2012:574180. [PMID: 23316217 PMCID: PMC3533465 DOI: 10.1155/2012/574180] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 11/07/2012] [Accepted: 11/16/2012] [Indexed: 02/07/2023] Open
Abstract
Viral hepatitis with hepatitis C virus or hepatitis B virus and chronic liver disease such as alcoholic or nonalcoholic steatohepatitis are critical factors in the development of hepatocellular carcinoma (HCC). Furthermore, diabetes is known as an independent risk factor for HCC. Peroxisome proliferator-activated receptor (PPAR) is known to have an important role in fatty liver, and the mechanism of carcinogenesis has been clarified. PPAR controls ligand-dependent transcription, and three subtypes (α, δ, and γ) in humans are known. PPARs could contribute to the mechanisms of cell cycling, anti-inflammatory responses, and apoptosis. Therefore, to clarify the pathogenesis of HCC, we should examine PPAR signaling. In this paper, we have summarized the relevance of PPARs to the pathogenesis of HCC and cancer stem cells and possible therapeutic options through modifying PPAR signaling.
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Affiliation(s)
- Osamu Kimura
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-Machi, Aoba-ku, Sendai City, Miyagi 980-8574, Japan
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Cheung KF, Zhao J, Hao Y, Li X, Lowe AW, Cheng ASL, Sung JJY, Yu J. CITED2 is a novel direct effector of peroxisome proliferator-activated receptor γ in suppressing hepatocellular carcinoma cell growth. Cancer 2012; 119:1217-26. [PMID: 23212831 DOI: 10.1002/cncr.27865] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Revised: 08/13/2012] [Accepted: 09/19/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND Previous reports from these authors found that activation of peroxisome proliferator-activated receptor gamma (PPARγ) suppressed hepatocellular carcinoma (HCC). This study sought to identify the molecular target of PPARγ and characterize its antitumor effect in HCC. METHODS Optimal PPARγ binding activity was obtained using the PPARγ agonist rosiglitazone (100 μM) as determined by enzyme-linked immunosorbent assay. Under PPARγ activation, 114 PPARγ downstream targets associated with cancer development were identified by oligonucleotide microarray and Gene Ontology analysis. Among them, Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was the most prominent PPARγ-bound target, as determined by chromatin immunoprecipitation-polymerase chain reaction. RESULTS CITED2 messenger RNA and protein was significantly down-regulated in primary HCCs compared with their adjacent nontumor tissues. PPARγ induced expression of CITED2 in HCC cell lines after adenovirus-PPARγ transduction. The biological function of CITED2 was evaluated by loss- and gain-of-function assays. CITED2 knockdown in the hepatocyte cell line LO2 and HCC cell line Hep3B significantly increased cell viability and clonogenicity, and promoted G1 -S phase transition in both cell lines. In contrast, ectopic expression of CITED2 in HepG2 and BEL7404 HCC cell lines significantly suppressed cell growth. The tumor suppressive effect of CITED2 was associated with up-regulation of cyclin-dependent kinase inhibitors p15(INK4B) , p21(Wat1/Cip1) , p27(Kip1) , antiproliferative regulator interferon alpha 1, proapoptotic mediators including tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF25, caspase-8, granzyme A, and the tumor suppressor gene maspin. CITED2 was also associated with the down-regulation of cell cycle regulator cyclin D1, oncogene telomerase reverse transcriptase, and proinvasion/metastasis gene matrix metallopeptidase 2. CONCLUSIONS CITED2 is a direct effector of PPARγ for tumor suppression. Cancer 2013. © 2012 American Cancer Society.
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Affiliation(s)
- Kin-Fai Cheung
- Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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Qiu LP, Chen KP. Anti-HBV agents derived from botanical origin. Fitoterapia 2012; 84:140-57. [PMID: 23164603 DOI: 10.1016/j.fitote.2012.11.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2012] [Revised: 10/29/2012] [Accepted: 11/04/2012] [Indexed: 01/16/2023]
Abstract
There are 350,000 hepatitis B virus (HBV) carriers all over the world. Chronic HBV infection is at a high risk of developing liver cirrhosis and hepatocelluar carcinoma (HCC), and heavily threatened people's health. Two kinds of drugs approved by FDA for anti-HBV therapy are immunomodulators (interferon α, pegylated-interferon α) and nucleos(t)ide analogues (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate). These drugs have been proved to be far from being satisfactory due to their low specificity, side effects, and high rate of drug resistance. There is an urgent need to discover and develop novel effective anti-HBV drugs. With vast resources, various structures, diverse biological activities and action mechanisms, as well as abundant clinical experiences, botanical agents become a promising source of finding new anti-HBV drugs. This review summarizes the recent research and development of anti-HBV agents derived from botanical origin on their sources and active components, inhibitory effects and possible toxicities, as well as action targets and mechanisms, and also addresses the advantages and the existing shortcomings in the development of botanical inhibitors. This information may not only broaden the knowledge of anti-HBV therapy, and offer possible alternative or substitutive drugs for CHB patients, but also provides considerable information for developing new safe and effective anti-HBV drugs.
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Affiliation(s)
- Li-Peng Qiu
- Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu Province, 212013, China
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40
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Wu CW, Farrell GC, Yu J. Functional role of peroxisome-proliferator-activated receptor γ in hepatocellular carcinoma. J Gastroenterol Hepatol 2012; 27:1665-9. [PMID: 22742931 DOI: 10.1111/j.1440-1746.2012.07213.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Major risk factors of HCC include infection with hepatitis B or C viruses, alcohol and non-alcoholic fatty liver disease. HCC is difficult to diagnose at early stage, and has a very poor survival rate when diagnosed at a late stage. The majority of HCC-related deaths result from local invasion (to cause liver failure) or distant metastases. There is an urgent need to identify effective molecular targets for the treatment of the disease. As the target of an established class of therapeutic agent thiazolidinediones (TZDs), peroxisome-proliferator-activated receptor γ (PPARγ) has been widely studied for its role in the development of HCC. A substantial body of evidence based on in vitro and in vivo models indicates that the activation of PPARγ is able to inhibit HCC cell proliferation and tumor growth through inducing cell cycle arrest and apoptosis via the regulation of a panel of downstream effector molecules. PPARγ activation also induces an inhibitory effect on HCC metastasis. Meanwhile, there is new evidence suggesting that PPARγ inhibition could also be anti-tumorigenic. In the present review, we summarize the available information on the role of PPARγ in HCC development and spread, and discuss whether PPARγ activation by TZDs could play a role in the treatment of HCC, summarizing both in vitro and in vivo. Considering the available data, PPARγ seems to exert beneficial effects against HCC and may therefore represent as a therapeutic target.
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Affiliation(s)
- Chung-Wah Wu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong
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41
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PPARs Signaling and Cancer in the Gastrointestinal System. PPAR Res 2012; 2012:560846. [PMID: 23028383 PMCID: PMC3458283 DOI: 10.1155/2012/560846] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 07/23/2012] [Accepted: 08/07/2012] [Indexed: 12/27/2022] Open
Abstract
Nowadays, the study of the peroxisome proliferators activated receptors (PPARs) as potential targets for cancer prevention and therapy has gained a strong interest. From a biological point of view, the overall responsibility of PPARs in cancer development and progression is still controversial since several studies report both antiproliferative and tumor-promoting actions for these signaling molecules in human cancer cells and animal models. In this paper, we discuss PPARs functions in the context of different types of gastrointestinal cancer.
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Cariou B, Charbonnel B, Staels B. Thiazolidinediones and PPARγ agonists: time for a reassessment. Trends Endocrinol Metab 2012; 23:205-15. [PMID: 22513163 DOI: 10.1016/j.tem.2012.03.001] [Citation(s) in RCA: 312] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Revised: 03/05/2012] [Accepted: 03/06/2012] [Indexed: 12/20/2022]
Abstract
Thiazolidinediones (TZDs) are anti-diabetic drugs that act as insulin sensitizers and are used in the management of type 2 diabetes mellitus. TZDs, which are ligands for the transcription factor peroxisome proliferator-activated receptor PPARγ, have a wide spectrum of action, including modulation of glucose and lipid homeostasis, inflammation, atherosclerosis, bone remodeling and cell proliferation. Randomized clinical trials have demonstrated the efficacy and durability of the anti-hyperglycemic action of TZDs, and have suggested that the TZD pioglitazone also exerts cardioprotective action. However, the clinical use of TZDs is limited by the occurrence of several adverse events, including body-weight gain, congestive heart failure, bone fractures and possibly bladder cancer. Therefore, there is an unmet need for the development of new safer PPARγ-modulating drugs.
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Affiliation(s)
- Bertrand Cariou
- Unité Mixte de Recherche 1087, Institut National de la Santé et de la Recherche Médicale (INSERM), Nantes 44000, France.
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Polvani S, Tarocchi M, Galli A. PPARγ and Oxidative Stress: Con(β) Catenating NRF2 and FOXO. PPAR Res 2012; 2012:641087. [PMID: 22481913 PMCID: PMC3317010 DOI: 10.1155/2012/641087] [Citation(s) in RCA: 185] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 11/05/2011] [Accepted: 11/17/2011] [Indexed: 12/22/2022] Open
Abstract
Peroxisome-proliferator activator receptor γ (PPARγ) is a nuclear receptor of central importance in energy homeostasis and inflammation. Recent experimental pieces of evidence demonstrate that PPARγ is implicated in the oxidative stress response, an imbalance between antithetic prooxidation and antioxidation forces that may lead the cell to apoptotic or necrotic death. In this delicate and intricate game of equilibrium, PPARγ stands out as a central player devoted to the quenching and containment of the damage and to foster cell survival. However, PPARγ does not act alone: indeed the nuclear receptor is at the point of interconnection of various pathways, such as the nuclear factor erythroid 2-related factor 2 (NRF2), Wnt/β-catenin, and forkhead box proteins O (FOXO) pathways. Here we reviewed the role of PPARγ in response to oxidative stress and its interaction with other signaling pathways implicated in this process, an interaction that emerged as a potential new therapeutic target for several oxidative-related diseases.
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Affiliation(s)
- Simone Polvani
- Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
| | - Mirko Tarocchi
- Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
| | - Andrea Galli
- Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy
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Fröhlich E, Wahl R. Do antidiabetic medications play a specific role in differentiated thyroid cancer compared to other cancer types? Diabetes Obes Metab 2012; 14:204-13. [PMID: 21883805 DOI: 10.1111/j.1463-1326.2011.01491.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The risk for differentiated thyroid cancer, like for many other types of cancer, is increased in obese individuals and people with intermediate hyperglycaemia. The incidence of all cancers, with the exception of thyroid cancer, is also increased in type 2 diabetes mellitus patients. The review compares the prevalence of thyroid carcinoma and other cancers in obese, people with intermediate hyperglycaemia and patients with diabetes and summarizes mode of action and anti-tumourigenic effect of common antidiabetic medications. The over-expression of dipeptidyl peptidase IV in the tumours, not seen in the other cancer types, is suggested as a potential reason for the unique situation in thyroid cancer.
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Affiliation(s)
- E Fröhlich
- Internal Medicine, Department of Endocrinology, University of Tuebingen, Otfried-Muellerstrasse 10, Tuebingen, Germany
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45
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Lai SW, Chen PC, Liao KF, Muo CH, Lin CC, Sung FC. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study. Am J Gastroenterol 2012; 107:46-52. [PMID: 22085817 DOI: 10.1038/ajg.2011.384] [Citation(s) in RCA: 232] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Using population-based representative insurance claims data, the risk of developing hepatocellular carcinoma (HCC) among diabetes mellitus (DM) patients, as well as whether DM medications alter the risk of developing HCC were investigated. METHODS From the Taiwan National Health Insurance Research Database, 19,349 newly diagnosed DM patients 20 years and older and 77,396 comparison subjects without DM were identified from claims from 2000 to 2005. The incidences of HCC at the end of 2008 and the risks associated with hepatitis B and hepatitis C were determined. Whether metformin and thiazolidinediones reduce the risk of developing HCC was also measured. RESULTS The incidence of HCC was twice higher in the DM group compared with the non-DM group (21.0 vs. 10.4 per 10,000 person-years), with an adjusted hazard ratio (HR) of 1.73 (95% confidence interval (CI)=1.47-2.03) using multivariable Cox proportional hazard regression. Male sex, cirrhosis, hepatitis B, and hepatitis C were significant independent factors that predict HCC, with HRs of 2.32, 8.65, 2.52, and 5.61, respectively. In the stratified analysis, the HR increased to 72.4 (95% CI=42.9-122) among patients with DM, cirrhosis, and hepatitis C. HCC risk reduction was greater for diabetics taking metformin than those taking thiazolidinediones (51 vs. 44% reduction). CONCLUSIONS Comorbidity with cirrhosis and/or hepatitis appears to be associated with an extremely increased risk of developing HCC among DM patients. These high-risk patients should be closely monitored for HCC. The use of metformin or thiazolidinediones may reduce the risk of developing HCC.
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Affiliation(s)
- Shih-Wei Lai
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
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Methylation profile of single hepatocytes derived from hepatitis B virus-related hepatocellular carcinoma. PLoS One 2011; 6:e19862. [PMID: 21625442 PMCID: PMC3100314 DOI: 10.1371/journal.pone.0019862] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 04/05/2011] [Indexed: 12/21/2022] Open
Abstract
Background With the development of high-throughput screening, a variety of genetic alterations has been found in hepatocellular carcinoma (HCC). Although previous studies on HCC methylation profiles have focused on liver tissue, studies using isolated hepatocytes are rare. The heterogeneity of liver composition may impact the genuine methylation status of HCC; therefore, it is important to clarify the methylation profile of hepatocytes to aid in understanding the process of tumorigenesis. Methods and Findings The global methylation profile of single hepatocytes isolated from liver tissue of hepatitis B virus (HBV) related HCC (HBHC) was analyzed using Illumina Infinium Human Methylation27 BeadChips, and combined bisulfite restriction analysis (COBRA) and bisulfite sequencing were used to validate the 20 significant hypermethylated genes identified. In this study, we found many noteworthy differences in the genome-wide methylation profiles of single hepatocytes of HBHC. Unsupervised hierarchical clustering analysis showed that hepatocyte methylation profiles could be classified according to three cell types: hepatocytes of HCC, adjacent hepatocytes and normal hepatocytes. Among the 20 most hypermethylated genes in the hepatocytes of HBHC, 7 novel genes (WNK2, EMILIN2, TLX3, TM6SF1, TRIM58, HIST1H4Fand GRASP) were found to be hypermethylated in HBHC and hypomethylated in paired adjacent liver tissues; these findings have not been reported in previous studies on tissue samples. Conclusion The genome-wide methylation profile of purified single hepatocytes of HBHC was aided in understanding the process of tumorigenesis, and a series of novel methylated genes found in this study have the potential to be biomarkers for the diagnosis and prognosis of HBHC.
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