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1
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Jiang J, Hu Y, Fang D, Luo J. Glutamine synthetase and hepatocellular carcinoma. Clin Res Hepatol Gastroenterol 2023; 47:102248. [PMID: 37979911 DOI: 10.1016/j.clinre.2023.102248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/02/2023] [Accepted: 11/15/2023] [Indexed: 11/20/2023]
Abstract
Glutamine synthetase (GS) is an enzyme that converts ammonia and glutamate to glutamine using adenosine triphosphate. GS is expressed in the brain, kidney, and liver tissues under normal physiological conditions. GS is involved in abnormal lipid metabolism of the liver by catalyzing de novo synthesis of glutamine, thereby inducing liver inflammation. Metabolic dysfunction-associated steatotic liver diseases (MASLD), such as Metabolic Associated Fatty Liver Disease and Metabolic Associated Steato Hepatitis, are considered risk factors for HCC. GS may also be involved in the development and progression of hepatocellular carcinoma (HCC) through other signaling pathways, including the rapamycin (mTOR) and Wnt/β-catenin signaling pathways. Furthermore, the correct combination of HSP70, GPC3, and GS can improve the accuracy and precision of HCC diagnosis. However, the prognostic value of GS in different HCC populations remains controversial. The expression of GS affects the sensitivity of HCC cells to radiotherapy and chemotherapy. In addition, immunotherapy has been approved for the treatment of advanced HCC. This article delves into the development and application of GS in HCC, laying a theoretical foundation for the subsequent exploration of GS as a potential target for treating HCC.
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Affiliation(s)
- Jinghua Jiang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Yiting Hu
- Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University, Shulan International Medical College, Hangzhou, Zhejiang, China
| | - Dazhang Fang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - JianSheng Luo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China.
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Ye Y, Yu B, Wang H, Yi F. Glutamine metabolic reprogramming in hepatocellular carcinoma. Front Mol Biosci 2023; 10:1242059. [PMID: 37635935 PMCID: PMC10452011 DOI: 10.3389/fmolb.2023.1242059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 08/03/2023] [Indexed: 08/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal disease with limited management strategies and poor prognosis. Metabolism alternations have been frequently unveiled in HCC, including glutamine metabolic reprogramming. The components of glutamine metabolism, such as glutamine synthetase, glutamate dehydrogenase, glutaminase, metabolites, and metabolite transporters, are validated to be potential biomarkers of HCC. Increased glutamine consumption is confirmed in HCC, which fuels proliferation by elevated glutamate dehydrogenase or upstream signals. Glutamine metabolism also serves as a nitrogen source for amino acid or nucleotide anabolism. In addition, more glutamine converts to glutathione as an antioxidant in HCC to protect HCC cells from oxidative stress. Moreover, glutamine metabolic reprogramming activates the mTORC signaling pathway to support tumor cell proliferation. Glutamine metabolism targeting therapy includes glutamine deprivation, related enzyme inhibitors, and transporters inhibitors. Together, glutamine metabolic reprogramming plays a pivotal role in HCC identification, proliferation, and progression.
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Affiliation(s)
- Yanyan Ye
- Department of Ultrasound, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bodong Yu
- The Second Clinical Medical College of Nanchang University, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hua Wang
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
| | - Fengming Yi
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Clinical and Translational Cancer Research, Nanchang, China
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Jot K, Urs AB, Kumar P. Does Loss of Immunohistochemical Expression of Glypican 3 in Oral Squamous Cell Carcinoma Play a Role in the Wnt/β-catenin Signaling Pathway? Appl Immunohistochem Mol Morphol 2021; 29:693-699. [PMID: 34091531 DOI: 10.1097/pai.0000000000000955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 05/10/2021] [Indexed: 11/25/2022]
Abstract
Glypican 3 (GPC3) is a cell membrane protein and plays a dual role, as a tumor suppressor and oncogene, depending on its structure. It is known to regulate the Wnt/β-catenin signaling pathway and affect cell growth and proliferation. β-catenin plays a major oncogenic role in progression of oral squamous cell carcinoma (OSCC); thus, this study aimed to explore the relationship between β-catenin and GPC3 in OSCC. Immunoexpression of GPC3 and β-catenin was evaluated semiquantitatively in tumor tissue (n=80) and normal oral mucosa tissue (n=20). For GPC3, the percentage of stained cells and the staining intensity were assessed. For β-catenin, the percentage of stained cells, localization, and intensity of staining were assessed at the tumor-invasive front. The Pearson correlation was used to determine the correlation between the GPC3 and β-catenin immunoreactivity. Significantly decreased expression of GPC3 (P=0.008) and a highly significant difference in the case of localization of β-catenin (P=0.0001) were observed in OSCC when compared with normal oral mucosa. Cytoplasmic expression with a shift of β-catenin expression to the nucleus was seen in OSCC in comparison with primarily membranous and membranous and cytoplasmic staining in normal mucosa. A significant difference was observed with respect to localization of stain, with β-catenin staining moving to the nuclear compartment with an increase in the tumor grade (P=0.011). No correlation was observed between β-catenin and GPC3 expression in OSCC cases. It is concluded that loss of expression of GPC3 in OSCC compared with normal oral mucosa indicates that it plays the role of a tumor suppressor gene in OSCC and its expression is therefore silenced in OSCC.
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Affiliation(s)
- Kiran Jot
- Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, New Delhi, Delhi, India
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Kerdput V, Nilbu-Nga C, Kaewnoonual N, Itharat A, Pongsawat S, Pradidarcheep W. Therapeutic efficacy of a Dioscorea membranacea extract in a rat model of hepatocellular carcinoma: Histopathological aspects. J Tradit Complement Med 2021; 11:400-408. [PMID: 34522634 PMCID: PMC8427478 DOI: 10.1016/j.jtcme.2021.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 01/03/2021] [Accepted: 02/01/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is most common in adults and has a high mortality rate because of a lack of effective treatment options. We investigated the effect of a medicinal plant as a potential source of drugs against HCC. The rhizomes of Dioscorea membranacea Pierre (DM), Hua-Khao-Yen in Thai, are commonly used as ingredients for alternative treatment of cancer in Thailand. In this study, the anticancer effects of DM extract in HCC-bearing rats were evaluated with respect to gross morphology, histopathology, and leakage of liver enzymes. In untreated HCCs, typical features of liver cancer, including hepatic nodules, thick-cell cords, and pseudoglandular cell arrangements, were observed. In addition, the HCCs showed abnormal reticulin patterns and a high glypican3 expression. In HCC-bearing rats treated with DM the cancer areas and reticulin expression were significantly reduced compared to the untreated group (p < 0.01). Sorafenib, the standard drug to treat HCC, reduced the cancer area further, but increased leakage of liver enzymes and decreased serum albumin concentration, indicating liver toxicity. These findings suggest that DM has an anticancer effect on HCCs in an animal model in vivo with potentially less severe side effects than sorafenib. Therefore, further studies of DM’s mechanism of action in HCC should be carried out.
DM exerted a mitigating effect on histopathology and membrane damage of HCC in rats. Its effect was similar to that of the standard drug sorafenib. It reduced the volume of cancer nodules without the serious hepatotoxic side effects seen after SF treatment.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- DEN, diethylnitrosamine
- DM, Dioscorea membranacea
- GGT, γ-glutamyltransferase
- GPC3, glypican3
- HCC, hepatocellular carcinoma
- Hua-Khao-Yen
- Liver cancer
- PBS, phosphate-buffered saline
- Reticulin
- SF, sorafenib
- TAA, thioacetamide
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- Traditional medicine
- glypican3
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Affiliation(s)
- Vichununt Kerdput
- Biomedical Science Program, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
| | - Cheng Nilbu-Nga
- Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
| | - Nattpawit Kaewnoonual
- Anatomy Unit, Department of Medical Science, Faculty of Science, Rangsit University, Pathumthani, Thailand
| | - Arunporn Itharat
- Center of Excellence in Applied Thai Traditional Medicine Research, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Suriya Pongsawat
- Department of Pathology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
| | - Wisuit Pradidarcheep
- Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
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Nia A, Dhanasekaran R. Genomic Landscape of HCC. CURRENT HEPATOLOGY REPORTS 2020; 19:448-461. [PMID: 33816052 PMCID: PMC8015384 DOI: 10.1007/s11901-020-00553-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/23/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a leading cause of cancer related mortality in the world and it has limited treatment options. Understanding the molecular drivers of HCC is important to develop novel biomarkers and therapeutics. PURPOSE OF REVIEW HCC arises in a complex background of chronic hepatitis, fibrosis and liver regeneration which lead to genomic changes. Here, we summarize studies that have expanded our understanding of the molecular landscape of HCC. RECENT FINDINGS Recent technological advances in next generation sequencing (NGS) have elucidated specific genetic and molecular programs involved in hepatocarcinogenesis. We summarize the major somatic mutations and epigenetic changes have been identified in NGS-based studies. We also describe promising molecular therapies and immunotherapies which target specific genetic and epigenetic molecular events. SUMMARY The genomic landscape of HCC is incredibly complex and heterogeneous. Promising new developments are helping us decipher the molecular drivers of HCC and leading to new therapies.
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Dysregulation of glutaminase and glutamine synthetase in cancer. Cancer Lett 2019; 467:29-39. [DOI: 10.1016/j.canlet.2019.09.011] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/11/2019] [Accepted: 09/19/2019] [Indexed: 12/20/2022]
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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Wang BM, Li N. Effect of the Wnt/β-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma cells after transcatheter arterial chemoembolization in rats. J Cell Biochem 2018; 119:4050-4060. [PMID: 29232009 DOI: 10.1002/jcb.26576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 12/01/2017] [Indexed: 12/16/2022]
Abstract
This study aims to investigate the influence of the Wnt/β-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma (HCC) cells after transcatheter arterial chemoembolization (TACE) in rat models. A total of 80 rats were grouped into sham, TACE, Wnt-C59, and TACE + Wnt-C59 groups (n = 20). Ten days after model establishment, 10 rats in each group were executed to perform pathological examination and follow-up experiment, and the remaining 10 rats in each group were reared to observe the survival condition. RT-qPCR and Western blotting were applied to determine the expressions of Wnt1, β-catenin, cyclin D1, c-met, vimentin, E-cadherin, and vascular endothelial growth factor (VEGF). ELISA was performed to measure the serum alpha-fetoprotein (AFP) content of rats. Flow cytometry was used to evaluate cell apoptosis rate and transwell assay to examine cell migration and invasion. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed increased apoptosis and survival time (the TACE + Wnt-C59 group > the Wnt-C59 group). Compared with the sham group, the TACE + Wnt-C59 groups showed decreased cancer tissue weight and expressions of Wnt1, β-catenin, cyclin D1, vimentin, c-met, and VEGF, but increased E-cadherin expression. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed decreased AFP level, migration, and invasion (the TACE + Wnt-C59 group < the Wnt-C59 group). These findings indicate inhibition of the Wnt/β-catenin signaling pathway improves therapeutic effect on TACE via suppressing migration, invasion, and promoting apoptosis of transplanted HCC cells in rats.
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Affiliation(s)
- Bao-Ming Wang
- Interventional Department, The Fourth Affiliated Hospital of China Medical University, Shenyang, P. R. China
| | - Nuo Li
- Department of Gastroenterology, The Fourth Affiliated Hospital of China Medical University, Shenyang, P. R. China
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