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Vasilogianni AM, Achour B, Al-Majdoub ZM, Peters SA, Barber J, Rostami-Hodjegan A. The quest to define cancer-specific systems parameters for personalized dosing in oncology. Expert Opin Drug Metab Toxicol 2025; 21:599-615. [PMID: 40042382 DOI: 10.1080/17425255.2025.2476560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 02/11/2025] [Accepted: 03/03/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Clinical trials in oncology initially recruit heterogeneous populations, without catering for all types of variability. The target cohort is often not representative, leading to variability in pharmacokinetics (PK). To address enrollment challenges in clinical trials, physiologically based pharmacokinetic models (PBPK) models can be used as a guide in the absence of large clinical studies. These models require patient-specific systems data relevant to the handling of drugs in the body for each type of cancer, which are scarce. AREAS COVERED This review explores system parameters affecting PK in cancer and highlights important gaps in data. Changes in drug-metabolizing enzymes (DMEs) and transporters have not been fully investigated in cancer. Their impaired expression can significantly affect capacity for drug elimination. Finally, the use of PBPK modeling for precision dosing in oncology is highlighted. Google Scholar and PubMed were mainly used for literature search, without date restriction. EXPERT OPINION Model-informed precision dosing is useful for dosing in sub-groups of cancer patients, which might not have been included in clinical trials. Systems parameters are not fully characterized in cancer cohorts, which are required in PBPK models. Generation of such data and application of cancer models in clinical practice should be encouraged.
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Affiliation(s)
- Areti-Maria Vasilogianni
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK
| | - Sheila Annie Peters
- Translational Quantitative Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, Germany
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co., Ingelheim am Rhein, Germany
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK
| | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, UK
- Certara Predictive Technologies (CPT), Simcyp Division, Sheffield, UK
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Qiao J, Yu Z, Zhou H, Wang W, Wu H, Ye J. The Pentose Phosphate Pathway: From Mechanisms to Implications for Gastrointestinal Cancers. Int J Mol Sci 2025; 26:610. [PMID: 39859324 PMCID: PMC11765532 DOI: 10.3390/ijms26020610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/27/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
The pentose phosphate pathway (PPP), traditionally recognized for its role in generating nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), has emerged as a critical metabolic hub with involvements in various gastrointestinal (GI) cancers. The PPP plays crucial roles in the initiation, development, and tumor microenvironment (TME) of GI cancers by modulating redox homeostasis and providing precursors for nucleotide biosynthesis. Targeting PPP enzymes and their regulatory axis has been a potential strategy in anti-GI cancer therapies. In this review, we summarize the regulatory mechanisms of PPP enzymes, elucidate the relationships between the PPP and TME's elements, and discuss the therapeutic potential of targeting the PPP in GI cancers.
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Affiliation(s)
- Jincheng Qiao
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; (J.Q.); (Z.Y.)
- Cancer Institute (A Key Laboratory for Cancer Prevention & Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Zhengchen Yu
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; (J.Q.); (Z.Y.)
- Cancer Institute (A Key Laboratory for Cancer Prevention & Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Han Zhou
- Cancer Institute (A Key Laboratory for Cancer Prevention & Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Wankun Wang
- Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China;
| | - Hao Wu
- Cancer Institute (A Key Laboratory for Cancer Prevention & Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;
| | - Jun Ye
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; (J.Q.); (Z.Y.)
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Wang S, Huang H, Hu X, Xiao M, Yang K, Bu H, Jiang Y, Huang Z. A Novel Amino Acid-Related Gene Signature Predicts Overall Survival in Patients With Hepatocellular Carcinoma. Cancer Rep (Hoboken) 2024; 7:e2131. [PMID: 39041652 PMCID: PMC11264112 DOI: 10.1002/cnr2.2131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/17/2024] [Accepted: 06/30/2024] [Indexed: 07/24/2024] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) is an extremely harmful malignant tumor in the world. Since the energy metabolism and biosynthesis of HCC cells are closely related to amino acids, it is necessary to further explore the relationship between amino acid-related genes and the prognosis of HCC to achieve individualized treatment. We herein aimed to develop a prognostic model for HCC based on amino acid genes. METHODS In this study, RNA-sequencing data of HCC patients were downloaded from the TCGA-LIHC cohort as the training cohort and the GSE14520 cohort as the validation cohort. Amino acid-related genes were derived from the Molecular Signatures Database. Univariate Cox and Lasso regression analysis were used to construct an amino acid-related signature (AARS). The predictive value of this risk score was evaluated by Kaplan-Meier (K-M) curve, receiver operating characteristic (ROC) curve, univariate and multivariate Cox regression analysis. Gene set variation analysis (GSVA) and immune characteristics evaluation were used to explore the underlying mechanisms. Finally, a nomogram was established to help the personalized prognosis assessment of patients with HCC. RESULTS The AARS comprises 14 amino acid-related genes to predict overall survival (OS) in HCC patients. HCC patients were divided into AARS-high group and AARS-low group according to the AARS scores. The K-M curve, ROC curve, and univariate and multivariate Cox regression analysis verified the good prediction efficiency of the risk score. Using GSVA, we found that AARS variants were concentrated in four pathways, including cholesterol metabolism, delayed estrogen response, fatty acid metabolism, and myogenesis metabolism. CONCLUSION Our results suggest that the AARS as a prognostic model based on amino acid-related genes is of great value in the prediction of survival of HCC, and can help improve the individualized treatment of patients with HCC.
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Affiliation(s)
- Shuyi Wang
- Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Nation Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaHunanChina
| | | | - Xingwang Hu
- Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Nation Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Meifang Xiao
- Department of Health Management CenterXiangya Hospital, Central South UniversityChangshaChina
| | - Kaili Yang
- Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Nation Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Haiyan Bu
- Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Nation Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Yupeng Jiang
- Department of OncologyThe Second Xiangya Hospital, Central South UniversityChangshaChina
| | - Zebing Huang
- Hunan Key Laboratory of Viral Hepatitis, Department of Infectious Diseases, Nation Clinical Research Center for Geriatric DisordersXiangya Hospital, Central South UniversityChangshaHunanChina
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Wu Q, Ge XL, Geng ZK, Wu H, Yang JY, Cao SR, Yang AL. HuaChanSu suppresses the growth of hepatocellular carcinoma cells by interfering with pentose phosphate pathway through down-regulation of G6PD enzyme activity and expression. Heliyon 2024; 10:e25144. [PMID: 38322888 PMCID: PMC10844274 DOI: 10.1016/j.heliyon.2024.e25144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 01/20/2024] [Accepted: 01/22/2024] [Indexed: 02/08/2024] Open
Abstract
HuaChanSu is active water extracts from the skin of Bufo bufo gargarizans Cantor. It has been already used to treat clinical cancers including HCC (Hepatocellular carcinoma, HCC), however, the molecular mechanisms under HuaChanSu's anti-cancer effects remain unclear. PPP (Pentose phosphate pathway, PPP), the major source of ribose and NADPH (Nicotinamide adenine dinucleotide phosphate, NADPH), is always over-activated and particularly critical for tumor cells growth. In this study, firstly, we illustrate that HuaChanSu restrains the growth of human hepatoma cells. More importantly, we demonstrate that the expression of G6PD (Glucose-6-phosphate dehydrogenase, G6PD), the first rate-limiting enzyme of the PPP, is restrained in human hepatoma cells after treatment with HuaChanSu. Additionally, our results show that G6PD enzyme activity and dimer formation are inhibited by HuaChanSu. Furthermore, we find that HuaChanSu could inhibit NADPH production and nucleotide level. In addition, we identify that expression of PLK1 (Polo-like kinase 1, PLK1) is also reduced in response to HuaChanSu, and knockdown of PLK1 restrains enzyme activity and dimer formation of G6PD, but has no effect on G6PD protein level. Subsequently, we demonstrate that inhibition of G6PD could restrain the proliferation of tumor cells and enhance the inhibitory effect of HuaChanSu on cell proliferation of human hepatoma cells. In conclusion, for the first time, our study reveals that HuaChanSu interferes with PPP via suppression of G6PD expression and enzyme activity to restrain growth of tumor cells, and these results provide a novel insight for the anti-hepatoma mechanisms of HuaChanSu and promote the innovation of the research model of TCM. Moreover, the development of drugs targeting abnormal tumor metabolism is currently a hot topic, our works provide theoretical support for further drug development from HuaChanSu, meanwhile, the revelation of the new molecular mechanism also provides a new perspective for the study of the pathogenesis of liver cancer. Short abstract HuaChanSu suppresses expression of G6PD, the first rate-limiting enzyme of the PPP, restrains G6PD enzyme activity and dimer formation via inhibition of PLK1, knockdown of G6PD could impair the growth of human hepatoma cells and increase the blocking effect of HuaChanSu on cell proliferation of cancer cells. In addition, HuaChanSu restrains NADPH production and nucleotide level, implying the suppression of PPP flux. Our study suggests that HuaChanSu interferes with PPP via G6PD inhibition to exert anti-hepatoma effects.
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Affiliation(s)
| | | | | | - Hao Wu
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Jing-yi Yang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Shi-rong Cao
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
| | - Ai-lin Yang
- School of Pharmacy, Binzhou Medical University, Yantai 264003, China
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Paluschinski M, Schira-Heinen J, Pellegrino R, Heij LR, Bednarsch J, Neumann UP, Longerich T, Stuehler K, Luedde T, Castoldi M. Uncovering Novel Roles of miR-122 in the Pathophysiology of the Liver: Potential Interaction with NRF1 and E2F4 Signaling. Cancers (Basel) 2023; 15:4129. [PMID: 37627157 PMCID: PMC10453129 DOI: 10.3390/cancers15164129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
MicroRNA miR-122 plays a pivotal role in liver function. Despite numerous studies investigating this miRNA, the global network of genes regulated by miR-122 and its contribution to the underlying pathophysiological mechanisms remain largely unknown. To gain a deeper understanding of miR-122 activity, we employed two complementary approaches. Firstly, through transcriptome analysis of polyribosome-bound RNAs, we discovered that miR-122 exhibits potential antagonistic effects on specific transcription factors known to be dysregulated in liver disease, including nuclear respiratory factor-1 (NRF1) and the E2F transcription factor 4 (E2F4). Secondly, through proteome analysis of hepatoma cells transfected with either miR-122 mimic or antagomir, we discovered changes in several proteins associated with increased malignancy. Interestingly, many of these proteins were reported to be transcriptionally regulated by NRF1 and E2F4, six of which we validated as miR-122 targets. Among these, a negative correlation was observed between miR-122 and glucose-6-phosphate dehydrogenase levels in the livers of patients with hepatitis B virus-associated hepatocellular carcinoma. This study provides novel insights into potential alterations of molecular pathway occurring at the early stages of liver disease, driven by the dysregulation of miR-122 and its associated genes.
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Affiliation(s)
- Martha Paluschinski
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
| | - Jessica Schira-Heinen
- Department of Neurology, Medical Faculty, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
- Molecular Proteomics Laboratory (MPL), Institute for Molecular Medicine, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
| | - Rossella Pellegrino
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (R.P.); (T.L.)
| | - Lara R. Heij
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Ulf P. Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (L.R.H.); (J.B.); (U.P.N.)
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany; (R.P.); (T.L.)
| | - Kai Stuehler
- Molecular Proteomics Laboratory (MPL), Institute for Molecular Medicine, Heinrich-Heine-University, 40225 Dusseldorf, Germany;
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital, Heinrich Heine University Dusseldorf, 40225 Dusseldorf, Germany; (M.P.); (T.L.)
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Zhang Q, Liu J, Lin H, Lin B, Zhu M, Li M. Glucose metabolism reprogramming promotes immune escape of hepatocellular carcinoma cells. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:519-536. [PMID: 37455832 PMCID: PMC10344893 DOI: 10.37349/etat.2023.00149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/13/2023] [Indexed: 07/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex process that plays an important role in its progression. Abnormal glucose metabolism in HCC cells can meet the nutrients required for the occurrence and development of liver cancer, better adapt to changes in the surrounding microenvironment, and escape the attack of the immune system on the tumor. There is a close relationship between reprogramming of glucose metabolism and immune escape. This article reviews the current status and progress of glucose metabolism reprogramming in promoting immune escape in liver cancer, aiming to provide new strategies for clinical immunotherapy of liver cancer.
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Affiliation(s)
- Qiuyue Zhang
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Jinchen Liu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Haifeng Lin
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou 570216, Hainan Province, China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou 570216, Hainan Province, China
- Institution of Tumor, Hainan Medical College, Haikou 570102, Hainan Province, China
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Integrated analysis of ferroptosis-related gene signature for overall survival prediction in Asian patients with hepatocellular carcinoma. Clin Transl Oncol 2023; 25:721-730. [PMID: 36319928 DOI: 10.1007/s12094-022-02977-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 10/07/2022] [Indexed: 01/05/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most prevalent types of cancers in Asia. Accumulating evidence suggests that ferroptosis is a non-apoptotic form of cell death, and has played an important role in cancer biology. METHODS Based on the manually curated ferroptosis-related gene set and TCGA-LIHC dataset of Asian patients, we used DESeq2, Kaplan-Meier analysis, and univariate Cox regression to identify differentially expressed ferroptosis-related genes with significantly prognostic capacity. A risk signature was constructed based on the selected genes for predicting the survival of HCC patients in Asia. The survival prediction accuracy was confirmed by the time-dependent receiver operating characteristic (ROC) curve analysis. Gene set variation analysis (GSVA) was used to explore the functional associations of the signature. Ferroptosis potential index (FPI) and xCell algorithm was applied to quantify ferroptosis and immune cell infiltration, respectively. Two independent datasets from the GEO and the ICGC database were used for external validation. RESULTS The ferroptosis-related signature could accurately predict the survival outcomes of HCC patients in Asian (p value < 0.0001). We showed that the signature was an independent factor and was beneficial in elevating risk stratification of current clinicopathologic features, such as the amount of alpha-fetoprotein (AFP) and residual tumor classification. Functional characterization showed that critical processes in tumorigenesis belonged to the high-risk groups, for example inflammatory response, which may be the main driver of HCC. The high-risk group had higher FPIs and infiltrations of macrophages and T-helper cells than the low-risk group. Furthermore, two independent cohorts confirmed the prognostic value of our signature. CONCLUSION Overall, our results demonstrated potential application of ferroptosis-related genes as independent biomarkers in Asian HCC patients. Targeting ferroptosis may be clinically useful beyond known clinicopathological factors and provide benefit in immunotherapy.
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Zong RQ, Zhang HY, Li XY, Li YR, Chen Y. Overexpressed Histocompatibility Minor 13 was Associated with Liver Hepatocellular Carcinoma Progression and Prognosis. Genet Res (Camb) 2022; 2022:7067743. [PMID: 36262249 PMCID: PMC9550386 DOI: 10.1155/2022/7067743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 12/03/2022] Open
Abstract
Among primary liver carcinoma cases, the proportion of liver hepatocellular carcinoma (LIHC) cases is 75%-85%. Current treatments for LIHC include chemotherapy, surgical excision, and liver transplantation, which are effective for early LIHC treatment. Nevertheless, the early symptoms of liver carcinoma are atypical, so a large proportion of LIHC patients are diagnosed at an advanced stage. Histocompatibility minor 13 (HM13), located in the endoplasmic reticulum, is responsible for catalysing the hydrolysis of some signal peptides after cleavage from the precursor protein. Here, we studied the role of HM13 in LIHC development through bioinformatics analysis. Database analysis showed that HM13 was of great significance for LIHC tumorigenesis. Compared to normal liver tissues, HM13 expression was increased to a greater extent in LIHC tissues. After analysis of Kaplan‒Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) datasets, we discovered that highly expressed HM13 exhibited an association with shorter overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS). We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to analyse HM13-related genes, and the data indicated that these genes obviously participated in rRNA processing, ribosome biogenesis, spliceosome, Huntington's disease, and ATP-dependent helicase activity. The Cell Counting Kit-8 (CCK-8) assay and Transwell assay showed that reducing HM13 expression hindered LIHC cell proliferation, migration, and invasion. In conclusion, these findings indicate that HM13 is a biomarker and is related to the poor prognosis of LIHC. Our results are conducive to discovering new targets for LIHC treatment.
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Affiliation(s)
- Rui-Qing Zong
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Hong-Yan Zhang
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xiao-Ying Li
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yi-ran Li
- Department of Intensive Care Medicine, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Ying Chen
- Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Zhang B, Tang B, Lv J, Gao J, Qin L. Systematic analyses to explore immune gene sets-based signature in hepatocellular carcinoma, in which IGF2BP3 contributes to tumor progression. Clin Immunol 2022; 241:109073. [PMID: 35817291 DOI: 10.1016/j.clim.2022.109073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 06/17/2022] [Accepted: 07/02/2022] [Indexed: 11/16/2022]
Abstract
Tumor immune microenvironment (TIME) is of critical importance for the development and therapeutic response of hepatocellular carcinoma (HCC). However, limited studies have investigated immune-related indicators for clinical supervision and decision. The current study aimed to develop an improved prognostic signature based on TIME. HCC patients from TCGA and ICGC database were classified into three subtypes (Immunity High, Immunity Medium and Immunity Low) according to ssGSEA scores of 29 immune gene sets. Differentially expressed immune-related genes (DE IRGs) between Immune High and Low groups were screened with an adjusted P < 0.05. Weighted gene co-expression network analysis (WGCNA) was used to establish gene co-expression modules of differentially expressed genes (DEGs) between tumor and normal tissues. 45 survival-related immune genes (SRIGs) were identified at points of intersection between hub genes and DE IRGs. By performing Cox regression and LASSO analysis, 3 of the 45 SRIGs were screened to establish a prognostic model. Patients with high risk scores exhibited worse survival outcome and poorer response to chemotherapy. Potential mechanisms of chemotherapy resistance also have been discussed. More significantly, high -risk patients showed increased immune cell infiltration and checkpoints, which suggested a benefit of immunotherapy. In addition, knockdown of IGF2BP3 was determined to significantly inhibit cell proliferation and migration in HCC. Our immune-related model may be an effective tool for precise diagnosis and treatment of HCC. It may help to select patients suitable for chemotherapy, and immunotherapy.
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Affiliation(s)
- Baohui Zhang
- Department of Physiology, School of Life Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China
| | - Bufu Tang
- Departmcent of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jiarui Lv
- Department of Physiology, School of Life Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China
| | - Jianyao Gao
- Department of Radiation Oncology, the First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ling Qin
- Department of Physiology, School of Life Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province 110122, PR China.
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Saad Alhar K, Afzal M, Kazmi I, Alzarea SI, Hadal Alot N, Khulaif Al S, Zafar A, K. Alruwai N. Protective Effect of Glucose-6-Phosphate Dehydrogenase and Dihydrofolate Reductase Against Diethylnitrosamine-Induced Hepatocellular Carcinoma in Rats. INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.354.362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Wu W, Yu F, Yu N, Zhu Y, Wu W, Gao P, Chen C. Glucose-6-phosphate dehydrogenase promotes the proliferation and migration of lung adenocarcinoma cells via the STAT3 signaling pathway. J Mol Histol 2022; 53:215-225. [PMID: 35028787 DOI: 10.1007/s10735-021-10045-7] [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: 01/19/2021] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, and the leading cause of cancer-related deaths worldwide. G6PD has been reported to enhance the progression of various tumors by regulating the intracellular redox state and mediating nucleic acid synthesis. However, the biological role and molecular mechanism of G6PD in LUAD remain largely unknown. In this study, we found that G6PD was significantly upregulated in LUAD specimens and cell lines, and that the high levels of G6PD expression were closely associated with a poor prognosis for LUAD patients. Moreover, we found that G6PD significantly promoted the proliferation and migration of LUAD cells in vitro, and overexpression of G6PD also play a role of facilitating tumorigenesis in in vivo experiments. Mechanistically, the STAT3 signaling pathway was significantly activated by G6PD-mediated LUAD progression. Overall, our results suggest that G6PD could serve as a novel prognostic marker and therapeutic target for treating LUAD.
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Affiliation(s)
- Weidong Wu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Fujian Provincial Key Laboratory of Cardiothoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Fengqiang Yu
- Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Nanding Yu
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Yong Zhu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Weihan Wu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Pengqiang Gao
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Chun Chen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Fujian Provincial Key Laboratory of Cardiothoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China. .,Department of Thoracic Surgery, Fujian Medical University Union Hospital, #29 Xinquan Road, Fuzhou, 350001, Fujian, China.
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System Analysis of ROS-Related Genes in the Prognosis, Immune Infiltration, and Drug Sensitivity in Hepatocellular Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6485871. [PMID: 34795841 PMCID: PMC8593590 DOI: 10.1155/2021/6485871] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with a poor prognosis. Reactive oxygen species (ROS) play an important role in tumors; however, the role of ROS-related genes is still unclear in HCC. Therefore, we analyzed the role of ROS-related genes in HCC via bioinformatics methods. Firstly, a prognosis model was constructed using LASSO Cox regression and multivariate analyses. We also investigated the potential function of the ROS-related genes and the correlation with immune infiltration, tumor stemness, and drug sensitivity. ICGC database was used for validation. Secondly, we further analyzed the role of 11 ROS-related genes in HCC. As a member of ROS gene family, the role of STK25 has remained unclear in HCC. We explored the biological function of STK25 using in vitro experiments. The present study was the first to construct a ROS-related prognostic model in HCC. The correlation of ROS-related genes with immune infiltration, tumor stemness, and drug sensitivity was dissected. Furthermore, we demonstrated that STK25 knockdown could increase the proliferation, migration, and invasion capacity of HCC cells.
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13
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Vasilogianni AM, Al-Majdoub ZM, Achour B, Peters SA, Rostami-Hodjegan A, Barber J. Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects. Br J Clin Pharmacol 2021; 88:1811-1823. [PMID: 34599518 PMCID: PMC9299784 DOI: 10.1111/bcp.15098] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 12/09/2022] Open
Abstract
Aims This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. Methods Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. Results Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. Conclusion This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer.
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Affiliation(s)
- Areti-Maria Vasilogianni
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK
| | - Zubida M Al-Majdoub
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK
| | - Brahim Achour
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK
| | | | - Amin Rostami-Hodjegan
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK.,Certara Inc (Simcyp Division), Sheffield, UK
| | - Jill Barber
- Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK
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14
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F. A. Abdelhameed R, Habib ES, Eltahawy NA, Hassanean HA, Ibrahim AK, Fahim JR, Sayed AM, Hendawy OM, Abdelmohsen UR, Ahmed SA. New glucose-6-phosphate dehydrogenase inhibitor from the Red Sea sponge Echinoclathria sp. Tetrahedron Lett 2021. [DOI: 10.1016/j.tetlet.2021.152986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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15
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Tenen DG, Chai L, Tan JL. Metabolic alterations and vulnerabilities in hepatocellular carcinoma. Gastroenterol Rep (Oxf) 2021; 9:1-13. [PMID: 33747521 PMCID: PMC7962738 DOI: 10.1093/gastro/goaa066] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 07/06/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Liver cancer is a serious disease. It is ranked as the cancer with the second highest number of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC), which arises from transformed hepatocytes, is the major subtype of liver cancer. It accounts for 85% of total liver-cancer cases. An important aspect of HCC that has been actively studied is its metabolism. With the liver as the primary site of numerous metabolic processes in the body, it has been shown that the metabolism of HCC cells is highly dysregulated compared to that of normal hepatocytes. It is therefore crucial to understand the metabolic alterations caused by HCC and the underlying mechanisms for these alterations. This deeper understanding will allow diagnostic and therapeutic advancements in the treatment of HCC. In this review, we will summarize the current literature in HCC metabolic alterations, induced vulnerabilities, and potential therapeutic interventions.
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Affiliation(s)
- Daniel G Tenen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, USA
| | - Li Chai
- Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Justin L Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Experimental Drug Development Centre, Agency for Science, Technology and Research (A*STAR), Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
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16
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Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12113318. [PMID: 33182674 PMCID: PMC7696782 DOI: 10.3390/cancers12113318] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 11/05/2020] [Accepted: 11/08/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) represents an important health problem. At the moment, systemic therapies offered only modest clinical benefits. Thus, HCC represents a cancer extremely difficult to treat, and therapeutic breakthroughs are urgently needed. Metabolic reprogramming of neoplastic cells has been recognized as one of the core hallmarks of cancer. Experimental animal models represent an important tool that allows to investigate metabolic changes underlying HCC development and progression. In the present review, we characterize available rodent models of hepatocarcinogenesis. Moreover, we discuss the possibility that pharmacological targeting of Warburg metabolism may represent an additional tool to improve already available therapeutic approaches for HCC. Abstract Hepatocellular carcinoma (HCC) is one the most frequent and lethal human cancers. At present, no effective treatment for advanced HCC exist; therefore, the overall prognosis for HCC patients remains dismal. In recent years, a better knowledge of the signaling pathways involved in the regulation of HCC development and progression, has led to the identification of novel potential targets for therapeutic strategies. However, the obtained benefits from current therapeutic options are disappointing. Altered cancer metabolism has become a topic of renewed interest in the last decades, and it has been included among the core hallmarks of cancer. In the light of growing evidence for metabolic reprogramming in cancer, a wide number of experimental animal models have been exploited to study metabolic changes characterizing HCC development and progression and to further expand our knowledge of this tumor. In the present review, we discuss several rodent models of hepatocarcinogenesis, that contributed to elucidate the metabolic profile of HCC and the implications of these changes in modulating the aggressiveness of neoplastic cells. We also highlight the apparently contrasting results stemming from different animal models. Finally, we analyze whether these observations could be exploited to improve current therapeutic strategies for HCC.
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17
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Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways. ACTA ACUST UNITED AC 2020; 1:735-747. [DOI: 10.1038/s43018-020-0086-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 05/27/2020] [Indexed: 12/11/2022]
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18
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Su X, Gao C, Feng X, Jiang M. miR-613 suppresses migration and invasion in esophageal squamous cell carcinoma via the targeting of G6PD. Exp Ther Med 2020; 19:3081-3089. [PMID: 32256796 PMCID: PMC7086187 DOI: 10.3892/etm.2020.8540] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 01/17/2020] [Indexed: 12/20/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common cancer in China and has a high mortality rate. MicroRNAs (miRs) are a family of post-transcriptional regulators, which negatively regulate target gene expression. miR-613 has been revealed to be a diagnostic and prognostic biomarker in ESCC. However, the role of miR-613 in ESCC remains unclear. In the present study, miR-613 expression was identified to be reduced in tumor tissues in comparison with corresponding adjacent normal tissues. TargetScan and a dual-luciferase reporter assay verified glucose-6-phosphate dehydrogenase (G6PD) as a direct target of miR-613. In contrast with miR-613, G6PD expression was increased in tumor tissues compared with matched healthy tissues. Furthermore, overexpression of miR-613 inhibited cell migration and invasion of Eca109 cells compared with controls, while G6PD overexpression reversed the inhibition induced by miR-613, as determined by wound healing and Transwell assays. In addition, miR-613 overexpression decreased the mRNA and protein expression of G6PD, matrix metalloproteinase (MMP)2 and MMP9, and reduced the phosphorylation of signal transducer and activator of transcription 3 (STAT3) compared with controls, while G6PD reversed the effects of miR-613. However, miR-613 and G6PD did not affect the expression of STAT3. In conclusion, the aforementioned results suggest that miR-613 targets G6PD to suppress ESCC cell migration and invasion through reduced MMP2 and MMP9 expression and inactivation of the STAT3 signaling pathway. Thus, the present study may provide a new molecular foundation for treatment of ESCC.
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Affiliation(s)
- Xiangyu Su
- Department of Oncology, Zhongda Hospital, The Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210009, P.R. China
- Clinical Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Chanchan Gao
- Department of Oncology, Zhongda Hospital, The Affiliated Hospital of Southeast University, Nanjing, Jiangsu 210009, P.R. China
- Clinical Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Xiaoyao Feng
- Department of Radiation Oncology, General Hospital of Eastern Theater Command, Nanjing, Jiangsu 210002, P.R. China
| | - Ming Jiang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, P.R. China
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19
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Palafox MA, Chalanchi SM, Isasi J, Premkumar R, Franklin Benial AM, Rastogi VK. Effect of bromine atom on the different tautomeric forms of microhydrated 5-bromouracil, in the DNA:RNA microhelix and in the interaction with human proteins. J Biomol Struct Dyn 2020; 38:5443-5463. [DOI: 10.1080/07391102.2019.1704878] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- M. Alcolea Palafox
- Facultad de Ciencias Químicas, Departamento de Química-Fisica, Universidad Complutense de Madrid, Madrid, Spain
| | - S. M. Chalanchi
- Department of Chemistry, University of Sistan and Baluchestan, Zahedan, Iran
| | - J. Isasi
- Facultad de Ciencias Químicas, Departamento de Química Inorgánica, Universidad Complutense de Madrid, Madrid, Spain
| | - R. Premkumar
- PG and Research Department of Physics, N.M.S.S.V.N. College, Madurai, Tamil Nadu, India
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20
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Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol 2019; 16:748-766. [PMID: 31666728 DOI: 10.1038/s41575-019-0217-8] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
Primary liver cancer (PLC) is the fourth most frequent cause of cancer-related death. The high mortality rates arise from late diagnosis and the limited accuracy of diagnostic and prognostic biomarkers. The liver is a major regulator, orchestrating the clearance of toxins, balancing glucose, lipid and amino acid uptake, managing whole-body metabolism and maintaining metabolic homeostasis. Tumour onset and progression is frequently accompanied by rearrangements of metabolic pathways, leading to dysregulation of metabolism. The limitation of current therapies targeting PLCs, such as hepatocellular carcinoma and cholangiocarcinoma, points towards the importance of deciphering this metabolic complexity. In this Review, we discuss the role of metabolic liver disruptions and the implications of these processes in PLCs, emphasizing their clinical relevance and value in early diagnosis and prognosis and as putative therapeutic targets. We also describe system biology approaches able to reconstruct the metabolic complexity of liver diseases. We also discuss whether metabolic rearrangements are a cause or consequence of PLCs, emphasizing the opportunity to clinically exploit the rewired metabolism. In line with this idea, we discuss circulating metabolites as promising biomarkers for PLCs.
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Affiliation(s)
- Letizia Satriano
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Monika Lewinska
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Pedro M Rodrigues
- Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
| | - Jesus M Banales
- Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesper B Andersen
- Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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21
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Baig MH, Adil M, Khan R, Dhadi S, Ahmad K, Rabbani G, Bashir T, Imran MA, Husain FM, Lee EJ, Kamal MA, Choi I. Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy. Semin Cancer Biol 2019; 56:1-11. [DOI: 10.1016/j.semcancer.2017.12.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/22/2017] [Accepted: 12/08/2017] [Indexed: 12/16/2022]
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22
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Zhao J, Zhang X, Guan T, Dai Q, He W, Zhang H, Wang Y, Wang B, Peng Z, Hu X, Qi D, Yang X, Zhang Y, Ma X. The association between low glucose-6-phosphate dehydrogenase activity level and hepatitis B virus infection among pre-pregnant reproductive-age Chinese females. Sci Rep 2019; 9:3865. [PMID: 30846733 PMCID: PMC6405931 DOI: 10.1038/s41598-019-40354-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 02/14/2019] [Indexed: 01/18/2023] Open
Abstract
The relationship between females with low glucose-6-phosphate dehydrogenase activity level (LG6PD) and HBV infection is unclear. We conducted a cross sectional study of 124 406 reproductive-age Chinese females who participated in the National Free Pre-conception Check-up Projects to investigate the risk of HBV infection among females with LG6PD and its effect on liver enzyme. Based on HBV serological test results, the participants were divided into the susceptible, immunized, and HBV infected groups. The multivariable-adjusted odds ratios (ORs) for HBV infection in LG6PD participants were 1.71 (95% confidence interval (CI): 1.45-2.01) and 1.41 (95% CI: 1.23-1.62), respectively with the susceptible and immunized participants as references, compared to those without LG6PD. Participants with HBV infection only and combined with HBV infection and LG6PD had 184% and 249% significantly higher risks of elevated alanine transaminase (ALT) (susceptible participants as reference). If the immunized participants were used as reference, significant higher odds of elevated ALT occurred (3.48 (95% CI: 3.18-3.80), 4.28 (95% CI: 2.92-6.28)). Thus, reproductive-age females with LG6PD had a higher prevalence of HBV infection, and LG6PD might exacerbate ALT elevation in HBV infected females. Our findings underscore the need to explore collaborative management approaches for these two diseases among reproductive-age females for maternal and child health.
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Affiliation(s)
- Jun Zhao
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Xu Zhang
- Department of medical record management, The Affiliated YanAn Hospital of Kunming Medical University, Yunnan, China
| | - Ting Guan
- Shenzhen Health Development Research Center, Guangdong, China
| | - Qiaoyun Dai
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Wenshan He
- Shenzhen Health Development Research Center, Guangdong, China
| | - Hongguang Zhang
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Yuanyuan Wang
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Bei Wang
- School of Public Health, Southeast University, Jiangsu, China
| | - Zuoqi Peng
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Xuhuai Hu
- Shenzhen Health Development Research Center, Guangdong, China
| | - Daxun Qi
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Xueying Yang
- National Research Institute for Family Planning, Beijing, China.,National Human Genetic Resources Center, Beijing, China
| | - Yue Zhang
- National Research Institute for Family Planning, Beijing, China.,Graduate School of Peking Union Medical College, Beijing, China
| | - Xu Ma
- National Research Institute for Family Planning, Beijing, China. .,National Human Genetic Resources Center, Beijing, China. .,Graduate School of Peking Union Medical College, Beijing, China.
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23
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Choudhary I, Lee H, Pyo MJ, Heo Y, Chae J, Yum SS, Kang C, Kim E. Proteomic Investigation to Identify Anticancer Targets of Nemopilema nomurai Jellyfish Venom in Human Hepatocarcinoma HepG2 Cells. Toxins (Basel) 2018; 10:E194. [PMID: 29748501 PMCID: PMC5983250 DOI: 10.3390/toxins10050194] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 04/24/2018] [Accepted: 04/27/2018] [Indexed: 12/30/2022] Open
Abstract
Nemopilema nomurai is a giant jellyfish that blooms in East Asian seas. Recently, N. nomurai venom (NnV) was characterized from a toxicological and pharmacological point of view. A mild dose of NnV inhibits the growth of various kinds of cancer cells, mainly hepatic cancer cells. The present study aims to identify the potential therapeutic targets and mechanism of NnV in the growth inhibition of cancer cells. Human hepatocellular carcinoma (HepG2) cells were treated with NnV, and its proteome was analyzed using two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI/TOF/MS). The quantity of twenty four proteins in NnV-treated HepG2 cells varied compared to non-treated control cells. Among them, the amounts of fourteen proteins decreased and ten proteins showed elevated levels. We also found that the amounts of several cancer biomarkers and oncoproteins, which usually increase in various types of cancer cells, decreased after NnV treatment. The representative proteins included proliferating cell nuclear antigen (PCNA), glucose-regulated protein 78 (GRP78), glucose-6-phosphate dehydrogenase (G6PD), elongation factor 1γ (EF1γ), nucleolar and spindle-associated protein (NuSAP), and activator of 90 kDa heat shock protein ATPase homolog 1 (AHSA1). Western blotting also confirmed altered levels of PCNA, GRP78, and G6PD in NnV-treated HepG2 cells. In summary, the proteomic approach explains the mode of action of NnV as an anticancer agent. Further characterization of NnV may help to unveil novel therapeutic agents in cancer treatment.
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Affiliation(s)
- Indu Choudhary
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
| | - Hyunkyoung Lee
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
| | - Min Jung Pyo
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
| | - Yunwi Heo
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
| | - Jinho Chae
- Marine Environmental Research and Information Laboratory, Gunpo 15850, Korea.
| | - Seung Shic Yum
- South Sea Environmental Research Center, Korea Institute of Ocean Science and Technology (KIOST), Geoje 53201, Korea.
- Faculty of Marine Environmental Science, University of Science and technology (UST), Geoje 53201, Korea.
| | - Changkeun Kang
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
- Institutes of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea.
| | - Euikyung Kim
- College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea.
- Institute of Animal Medicine, Gyeongsang National University, Jinju 52828, Korea.
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Abstract
PURPOSE OF REVIEW Glucose 6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway. G6PD is the main source of the essential cellular reductant, NADPH. The purpose of this review is to describe the biochemistry of G6PD and NADPH, cellular factors that regulate G6PD, normal physiologic roles of G6PD, and the pathogenic role altered G6PD/NADPH plays in kidney disease. RECENT FINDINGS NADPH is required for many essential cellular processes such as the antioxidant system, nitric oxide synthase, cytochrome p450 enzymes, and NADPH oxidase. Decreased G6PD activity and, as a result, decreased NADPH level have been associated with diabetic kidney disease, altered nitric oxide production, aldosterone-mediated endothelial dysfunction, and dialysis-associated anemia. Increased G6PD activity is associated with all cancers including kidney cancer. Inherited G6PD deficiency is the most common mutation in the world that is thought to be a relatively mild disorder primarily associated with anemia. Yet, intriguing studies have shown an increased prevalence of diabetes mellitus in G6PD-deficient people. It is not known if G6PD-deficient people are at more risk for other diseases. SUMMARY Much more research needs to be done to determine the role of altered G6PD activity (inherited or acquired) in the pathogenesis of kidney disease.
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25
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Sheng X, Huang T, Qin J, Yang L, Sa ZQ, Li Q. Identification of the Differential Expression Profiles of Serum and Tissue Proteins During Rat Hepatocarcinogenesis. Technol Cancer Res Treat 2018; 17:1533034618756785. [PMID: 29478368 PMCID: PMC5833169 DOI: 10.1177/1533034618756785] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of hepatocellular carcinoma is complex and not fully known yet. This study aims to screen and identify the differentially expressed proteins in peripheral blood and liver tissue samples from rat hepatocellular carcinoma and to further clarify the pathogenesis and discover the specific tumor markers and molecular targets of hepatocellular carcinoma. The hepatocellular carcinoma model of Wistar rats were induced by chemical carcinogen. The serum and liver tissue samples were obtained after induction for 2, 4, 8, 14, 18, and 21 weeks. The results showed that the clusterin (IPI00198667), heat shock protein a8 (IPI00208205), and N-myc downstream-regulated gene-2 (IPI00382069) being closely related to hepatocarcinogenesis were eventually identified from the 30 different proteins. As the time progressed, the serum levels of clusterin and heat shock protein a8 increased gradually during induced liver cancer in rats. However, the serum N-myc downstream-regulated gene 2 level in induced liver cancer in rats underwent biphasic changes, and the serum N-myc downstream-regulated gene 2 level decreased at the 8th week, increased at the 14th week, and then decreased significantly. Statistical difference occurred in protein expression of clusterin and heat shock protein a8 in liver tissues at the different time points. In the liver tissues, the N-myc downstream-regulated gene 2 level decreased gradually at the 8th week, increased gradually at the 14th week, and then decreased significantly after 14 weeks. The study demonstrated that heat shock protein a8, clusterin, and N-myc downstream-regulated gene 2 participated in the process of abnormal cell division, proliferation, and carcinogenesis of liver cells during hepatocarcinogenesis.
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MESH Headings
- Animals
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Immunohistochemistry
- Liver/metabolism
- Liver/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Proteome
- Proteomics/methods
- Rats
- Transcriptome
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Affiliation(s)
- Xia Sheng
- 1 Department of pathology, Affiliated to the Third Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Tao Huang
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Jianmin Qin
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
- 3 Department of general surgery, Affiliated to the Third Hospital, Second Military Medical University, Shanghai, P.R. China
| | - Lin Yang
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Zhong-Qiu Sa
- 2 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
| | - Qi Li
- 4 Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, P.R. China
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Kitayama K, Yashiro M, Morisaki T, Miki Y, Okuno T, Kinoshita H, Fukuoka T, Kasashima H, Masuda G, Hasegawa T, Sakurai K, Kubo N, Hirakawa K, Ohira M. Pyruvate kinase isozyme M2 and glutaminase might be promising molecular targets for the treatment of gastric cancer. Cancer Sci 2017; 108:2462-2469. [PMID: 29032577 PMCID: PMC5715358 DOI: 10.1111/cas.13421] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 10/04/2017] [Accepted: 10/04/2017] [Indexed: 12/19/2022] Open
Abstract
The aim of this study was to analyze the significance of glucose metabolism-related enzymes in the proliferation of gastric cancer under hypoxia. Four hypoxia-resistant gastric cancer cell lines and four parent cell lines were used. Reverse transcription-PCR was used to evaluate the mRNA expression levels of the following metabolism-related enzymes: pyruvate kinase isozyme M2 (PKM2), glutaminase (GLS), enolase 1 (ENO1), glucose-6-phosphate dehydrogenase (G6PDH), and PKM1. The effects of these enzymes on the proliferation of gastric cancer cells were examined using siRNAs, shikonin as a PKM2 inhibitor, or BPTES as a GLS inhibitor, in vitro and in vivo. Levels of both PKM2 and GLS mRNA were significantly high in all hypoxia-resistant cell lines, compared with those of their parent cells. Knockdown of PKM2 and GLS significantly decreased the proliferation of all hypoxia-resistant cells. The combination of siPKM2 and siGLS significantly decreased proliferation compared with treatment by siPKM2 or siGLS alone. The knockdown of ENO1, G6PDH, or PKM1 did not decrease the proliferation of all hypoxia-resistant cells. Combination treatment using shikonin and BPTES inhibited the proliferation of all hypoxia-resistant cancer cells more than that by either agent alone. The in vivo study indicated that the tumor size treated by the combination of shikonin and BPTES was significantly smaller than that of vehicle-treated group. These findings suggested that PKM2 and GLS might play important roles in the proliferation of hypoxic gastric cancer cells. A combination of PKM2 and GLS inhibitors could be therapeutically promising for the treatment of gastric cancer.
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Affiliation(s)
- Kishu Kitayama
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
- Molecular Oncology and TherapeuticsOsaka City University Graduate School of MedicineOsakaJapan
| | - Masakazu Yashiro
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
- Molecular Oncology and TherapeuticsOsaka City University Graduate School of MedicineOsakaJapan
- Cancer Center for Translational ResearchOsaka City University Graduate School of MedicineOsakaJapan
| | - Tamami Morisaki
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Yuichiro Miki
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
- Molecular Oncology and TherapeuticsOsaka City University Graduate School of MedicineOsakaJapan
| | - Tomohisa Okuno
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
- Molecular Oncology and TherapeuticsOsaka City University Graduate School of MedicineOsakaJapan
| | - Haruhito Kinoshita
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Tatsunari Fukuoka
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Hiroaki Kasashima
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Go Masuda
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Tsuyoshi Hasegawa
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Katsunobu Sakurai
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Naoshi Kubo
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Kosei Hirakawa
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
| | - Masaichi Ohira
- Department of Surgical OncologyOsaka City University Graduate School of MedicineOsakaJapan
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Soukupova J, Malfettone A, Hyroššová P, Hernández-Alvarez MI, Peñuelas-Haro I, Bertran E, Junza A, Capellades J, Giannelli G, Yanes O, Zorzano A, Perales JC, Fabregat I. Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism. Sci Rep 2017; 7:12486. [PMID: 28970582 PMCID: PMC5624948 DOI: 10.1038/s41598-017-12837-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 09/14/2017] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profile of hepatocellular carcinoma (HCC) cells that show differences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells is characterized by reduced mitochondrial respiration, without significant differences in glycolytic activity. Concomitantly, enhanced glutamine anaplerosis and biosynthetic use of TCA metabolites were proved through analysis of metabolite levels, as well as metabolic fluxes from U-13C6-Glucose and U-13C5-Glutamine. This correlated with increase in glutaminase 1 (GLS1) expression, whose inhibition reduced cell migration. Experiments where TGF-β function was activated with extracellular TGF-β1 or inhibited through TGF-β receptor I silencing showed that TGF-β induces a switch from oxidative metabolism, coincident with a decrease in OCR and the upregulation of glutamine transporter Solute Carrier Family 7 Member 5 (SLC7A5) and GLS1. TGF-β also regulated the expression of key genes involved in the flux of glycolytic intermediates and fatty acid metabolism. Together, these results indicate that autocrine activation of the TGF-β pathway regulates oxidative metabolism in HCC cells.
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Affiliation(s)
- Jitka Soukupova
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
| | - Andrea Malfettone
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
| | - Petra Hyroššová
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
- Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - María-Isabel Hernández-Alvarez
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Irene Peñuelas-Haro
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
| | - Esther Bertran
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
| | - Alexandra Junza
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain
- Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Jordi Capellades
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain
- Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Gianluigi Giannelli
- National Institute of Gastroenterology IRCCS "S. De Bellis", Castellana Grotte Bari, Italy
| | - Oscar Yanes
- Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain
- Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
| | - José Carlos Perales
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
- Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain.
- Department of Physiological Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
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Kowalik MA, Columbano A, Perra A. Emerging Role of the Pentose Phosphate Pathway in Hepatocellular Carcinoma. Front Oncol 2017; 7:87. [PMID: 28553614 PMCID: PMC5425478 DOI: 10.3389/fonc.2017.00087] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 04/19/2017] [Indexed: 12/30/2022] Open
Abstract
In recent years, there has been a revival of interest in metabolic changes of cancer cells as it has been noticed that malignant transformation and metabolic reprogramming are closely intertwined. The pentose phosphate pathway (PPP) is one of the fundamental components of cellular metabolism crucial for cancer cells. This review will discuss recent findings regarding the involvement of PPP enzymes in several types of cancer, with a focus on hepatocellular carcinoma (HCC). We will pay considerable attention to the involvement of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Subsequently, we discuss the inhibition of the PPP as a potential therapeutic strategy against cancer, in particular, HCC.
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Affiliation(s)
- Marta Anna Kowalik
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy
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Shen S, Gong J, Yang Y, Qin S, Huang L, She S, Yang M, Ren H, Hu H. Molecular mechanism of C-reaction protein in promoting migration and invasion of hepatocellular carcinoma cells in vitro. Int J Oncol 2017; 50:1289-1298. [PMID: 28350119 DOI: 10.3892/ijo.2017.3911] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/07/2017] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of most common malignant cancers and is the second leading cause of cancer related deaths. The prognosis and survival of patients are closely related to the degree of tumor metastasis. The mechanism of HCC metastasis is still unclear. In the present study, we investigated the molecular mechanism of C-reaction protein in promoting migration and invasion of hepatocellular carcinoma cells in vitro. We estimated that CRP is overexpressed in liver cancer tissues and that it promotes invasion and metastasis of HCC in vitro. In the present study, we employed iTRAQ-based mass spectrometry to analyze the HepG2 secretory proteins of CRP siRNA-treated cells and negative control siRNA-treated cells. We identified 109 differentially expressed proteins after silencing CRP, of which 45 were upregulated and 64 were downregulated. Some of the differentially expressed proteins were confirmed by western blot analysis and real-time quantitative PCR. Furthermore, we found that knockdown of CRP substantially abrogates HIF-1α expression levels, the luciferase activity of HIF-1α and ERK and Akt phosphorylation in HepG2 cells. The present study provides a novel mechanism by which CRP promotes the proliferation, migration, invasion and metastasis of hepatocellular carcinoma cells. Inhibition of CRP suppressed migration, invasion and healing of hepatoma carcinoma cells by decreasing HIF-1α activity and CTSD.
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Affiliation(s)
- Shasha Shen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Jiaojiao Gong
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Yixuan Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Si Qin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Lifan Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Sha She
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Min Yang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
| | - Huaidong Hu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China
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Fang Z, Jiang C, Feng Y, Chen R, Lin X, Zhang Z, Han L, Chen X, Li H, Guo Y, Jiang W. Effects of G6PD activity inhibition on the viability, ROS generation and mechanical properties of cervical cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2245-54. [PMID: 27217331 DOI: 10.1016/j.bbamcr.2016.05.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 05/17/2016] [Accepted: 05/19/2016] [Indexed: 10/21/2022]
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been revealed to be involved in the efficacy to anti-cancer therapy but the mechanism remains unclear. We aimed to investigate the anti-cancer mechanism of G6PD deficiency. In our study, dehydroepiandrosterone (DHEA) and shRNA technology were used for inhibiting the activity of G6PD of cervical cancer cells. Peak Force QNM Atomic Force Microscopy was used to assess the changes of topography and biomechanical properties of cells and detect the effects on living cells in a natural aqueous environment. Flow cytometry was used to detect the apoptosis and reactive oxygen species (ROS) generation. Scanning electron microscopy was used to observe cell morphology. Moreover, a laser scanning confocal microscope was used to observe the alterations in cytoskeleton to explore the involved mechanism. When G6PD was inhibited by DHEA or RNA interference, the abnormal Young's modulus and increased roughness of cell membrane were observed in HeLa cells, as well as the idioblasts. Simultaneously, G6PD deficiency resulted in decreased HeLa cells migration and proliferation ability but increased ROS generation inducing apoptosis. What's more, the inhibition of G6PD activity caused the disorganization of microfilaments and microtubules of cytoskeletons and cell shrinkage. Our results indicated the anti-cervix cancer mechanism of G6PD deficiency may be involved with the decreased cancer cells migration and proliferation ability as a result of abnormal reorganization of cell cytoskeleton and abnormal biomechanical properties caused by the increased ROS. Suppression of G6PD may be a promising strategy in developing novel therapeutic methods for cervical cancer.
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Affiliation(s)
- Zishui Fang
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Chengrui Jiang
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Yi Feng
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Rixin Chen
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Xiaoying Lin
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Zhiqiang Zhang
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Luhao Han
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Xiaodan Chen
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Hongyi Li
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Yibin Guo
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China
| | - Weiying Jiang
- Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen University, University and Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education Guangzhou, 510080, China.
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31
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Kuzu M, Aslan A, Ahmed I, Comakli V, Demirdag R, Uzun N. Purification of glucose-6-phosphate dehydrogenase and glutathione reductase enzymes from the gill tissue of Lake Van fish and analyzing the effects of some chalcone derivatives on enzyme activities. FISH PHYSIOLOGY AND BIOCHEMISTRY 2016; 42:483-491. [PMID: 26676512 DOI: 10.1007/s10695-015-0153-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 10/26/2015] [Indexed: 06/05/2023]
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase (GR) are metabolically quite important enzymes. Within this study, these two enzymes were purified for the first time from the gills of Lake Van fish. In the purifying process, ammonium sulfate precipitation and 2',5'-ADP Sepharose 4B affinity column chromatography techniques for glucose-6-phosphate dehydrogenase, temperature degradation and 2',5'-ADP Sepharose 4B affinity column chromatography for glutathione reductase enzyme were used. The control of the enzyme purity and determination of molecular weight were done with sodium dodecyl sulfate polyacrylamide gel electrophoresis. K(M) and V(max) values were determined with Lineweaver-Burk plot. Besides, the effects of some chalcone derivatives on the purified enzymes were analyzed. For the ones showing inhibition effect, % activity-[I] figures were drawn and IC50 values were determined. K(i) value was calculated by using Cheng-Prusoff equation.
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Affiliation(s)
- Muslum Kuzu
- Faculty of Pharmacy, University of Ağrı İbrahim Çeçen, 04100, Ağrı, Turkey.
| | - Abdulselam Aslan
- Department of Nutrition and Dietetics, University of Ağrı İbrahim Çeçen, Ağrı, Turkey
| | - Ishtiaq Ahmed
- Karlsruhe Institute of Technology, Karlsruhe, Germany
| | - Veysel Comakli
- Department of Nutrition and Dietetics, University of Ağrı İbrahim Çeçen, Ağrı, Turkey
| | - Ramazan Demirdag
- Department of Nutrition and Dietetics, University of Ağrı İbrahim Çeçen, Ağrı, Turkey
| | - Naim Uzun
- Faculty of Pharmacy, University of Ağrı İbrahim Çeçen, 04100, Ağrı, Turkey
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Blanquer-Rosselló MDM, Oliver J, Sastre-Serra J, Valle A, Roca P. Leptin regulates energy metabolism in MCF-7 breast cancer cells. Int J Biochem Cell Biol 2016; 72:18-26. [PMID: 26772821 DOI: 10.1016/j.biocel.2016.01.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/14/2015] [Accepted: 01/05/2016] [Indexed: 01/12/2023]
Abstract
Obesity is known to be a poorer prognosis factor for breast cancer in postmenopausal women. Among the diverse endocrine factors associated to obesity, leptin has received special attention since it promotes breast cancer cell growth and invasiveness, processes which force cells to adapt their metabolism to satisfy the increased demands of energy and biosynthetic intermediates. Taking this into account, our aim was to explore the effects of leptin in the metabolism of MCF-7 breast cancer cells. Polarographic analysis revealed that leptin increased oxygen consumption rate and cellular ATP levels were more dependent on mitochondrial oxidative metabolism in leptin-treated cells compared to the more glycolytic control cells. Experiments with selective inhibitors of glycolysis (2-DG), fatty acid oxidation (etomoxir) or aminoacid deprivation showed that ATP levels were more reliant on fatty acid oxidation. In agreement, levels of key proteins involved in lipid catabolism (FAT/CD36, CPT1, PPARα) and phosphorylation of the energy sensor AMPK were increased by leptin. Regarding glucose, cellular uptake was not affected by leptin, but lactate release was deeply repressed. Analysis of pyruvate dehydrogenase (PDH), lactate dehydrogenase (LDH) and pyruvate carboxylase (PC) together with the pentose-phosphate pathway enzyme glucose-6 phosphate dehydrogenase (G6PDH) revealed that leptin favors the use of glucose for biosynthesis. These results point towards a role of leptin in metabolic reprogramming, consisting of an enhanced use of glucose for biosynthesis and lipids for energy production. This metabolic adaptations induced by leptin may provide benefits for MCF-7 growth and give support to the reverse Warburg effect described in breast cancer.
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Affiliation(s)
- Mª Del Mar Blanquer-Rosselló
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d́Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, edificio S., E-07120 Palma de Mallorca, Illes Balears, Spain
| | - Jordi Oliver
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d́Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, edificio S., E-07120 Palma de Mallorca, Illes Balears, Spain
| | - Jorge Sastre-Serra
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d́Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, edificio S., E-07120 Palma de Mallorca, Illes Balears, Spain
| | - Adamo Valle
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d́Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, edificio S., E-07120 Palma de Mallorca, Illes Balears, Spain.
| | - Pilar Roca
- Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d́Investigació en Ciències de la Salut (IUNICS), Palma de Mallorca, Illes Balears, Spain; Ciber Fisiopatología Obesidad y Nutrición (CB06/03) Instituto Salud Carlos III, Madrid, Spain; Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, edificio S., E-07120 Palma de Mallorca, Illes Balears, Spain
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Niu JX, Meng XK, Ren JJ. Studied microRNA gene expression in human hepatocellular carcinoma by microRNA microarray techniques. World J Gastroenterol 2015; 21:12605-12611. [PMID: 26640336 PMCID: PMC4658614 DOI: 10.3748/wjg.v21.i44.12605] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 07/26/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023] Open
Abstract
AIM: To achieve a better understanding of the molecular mechanisms of microRNA expression changes involved in hepatocellular carcinoma.
METHODS: In this research process, patients were not treated with antivirals, immunosuppressants or immunomodulators for at least 6 mo before collecting serum. The study population was composed of 35 outpatient hepatitis B virus (HBV) cases and 12 healthy control cases from the Affiliated Hospital of Inner Mongolia Medical University (Inner Mongolia, China) from July 2013 to April 2014. The 35 HBV cases were divided into two groups: a hepatocirrhosis group with 20 cases and a liver cancer group with 15 cases. All 35 cases carried HBsAg. The diagnostic criteria followed the European Association for the Study of the Liver 2012 (EASL2012) standards. MicroRNA (miRNA) was extracted from a control group of patients, a group with hepatocirrhosis and a group with liver cancer and its quality was analyzed using the human V2 microRNA expression beadchip. Cluster analysis and a radar chart were then applied to the miRNA changes.
RESULTS: The miRNA-qualified rate of human serum samples was 93%. The concentration of a single sample was > 200 ng/μL and the volume was > 5 μL. All miRNA serum samples were uncontaminated by the genome. The Mann-Whitney test showed significant differences in miRNA between each group, with a detection P-value of < 0.05. Illumina software was set up with Diff Score set to ± 13, meaning that P = 0.001.There were significant changes in miRNA expression between the three groups. miRNA-183 was the most up-regulated, followed by miRNA-373. miRNA-129 and miRNA-188 were both strongly down-regulated and miRNA-378 was down-regulated a small amount. The liver cancer group had greater changes, which indicated that changes in miRNA expression levels were caused by hepatocirrhosis. The liver cancer disease course then further increased these changes. In the pentagon created by these five miRNAs, three groups showed significant deviation. The liver cancer group had a bigger deviation trend. The chart indicated that miRNA expression changes occurred in the hepatocirrhosis group, which increased in the liver cancer disease course and were irreversible.
CONCLUSION: There was a significant relationship between the irreversible up-regulation of miRNA-183/373 and down-regulation of miRNA-129/188/378 and incidences of hepatocirrhosis and liver cancer.
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Wang X, Li X, Zhang X, Fan R, Gu H, Shi Y, Liu H. Glucose-6-phosphate dehydrogenase expression is correlated with poor clinical prognosis in esophageal squamous cell carcinoma. Eur J Surg Oncol 2015; 41:1293-9. [PMID: 26329784 DOI: 10.1016/j.ejso.2015.08.155] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 07/30/2015] [Accepted: 08/04/2015] [Indexed: 01/22/2023] Open
Abstract
Increasing evidence has demonstrated that glucose-6-phosphate dehydrogenase (G6PD), a key metabolic enzyme, participating in pentose phosphate pathway (PPP), is tightly associated with development and progression of a variety of tumors. Here, we reported expression of G6PD and its association with the prognosis of the patients with esophageal squamous cell carcinoma (ESCC). The results revealed significantly elevated G6PD mRNA and protein expressions in ESCC tissues compared with normal tissues (P < 0.05). Furthermore, high G6PD expression was tightly associated with histological grade, TNM staging and lymph node metastasis (P < 0.05), but not related to the patients' age and gender (P > 0.05). Importantly, the survival time of G6PD-positive patients was markedly lower than that of G6PD-negative patients (P < 0.05). Most notably, Cox multivariate assay demonstrated that G6PD was an independent prognostic factor for the patients with ESCC. In conclusion, G6PD may be a novel predictor for the prognosis of the patients with ESCC.
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Affiliation(s)
- Xin Wang
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China
| | - XiaoJuan Li
- School of Basic Medical Sciences, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, PR China
| | - XiaQing Zhang
- Laboratory for Cell Biology, School of Life Sciences of Zhengzhou University, Zhengzhou, Henan, 450001, PR China
| | - RuiTai Fan
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China
| | - Hao Gu
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China
| | - YongGang Shi
- Department of Radiotherapy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, PR China
| | - HongTao Liu
- Laboratory for Cell Biology, School of Life Sciences of Zhengzhou University, Zhengzhou, Henan, 450001, PR China.
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G6PD downregulation triggered growth inhibition and induced apoptosis by regulating STAT3 signaling pathway in esophageal squamous cell carcinoma. Tumour Biol 2015; 37:781-9. [DOI: 10.1007/s13277-015-3861-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 07/28/2015] [Indexed: 10/23/2022] Open
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