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Meng Z, Tan B, Wang M, Zhu J, Qu C, Cheng Z. Development of a Cyclic TMTP1-Based PET Probe for Visualization of Hepatocellular Carcinoma. ACS Med Chem Lett 2025; 16:617-624. [PMID: 40236552 PMCID: PMC11995206 DOI: 10.1021/acsmedchemlett.5c00008] [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: 01/06/2025] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/17/2025] Open
Abstract
TMTP1 is a tumor-homing peptide that selectively targets highly metastatic tumor cells with XPNPEP2 identified as its potential targeting receptor. Although TMTP1-based molecular probes have been explored for imaging tumors such as hepatocellular carcinoma (HCC), their clinical translation has been hampered by factors including suboptimal tumor uptake and rapid systemic clearance. To study possible solution for addressing these challenges, a cyclic TMTP1 based positron emission tomography (PET) probe, [68Ga]Ga-DOTA-cTMTP1, was designed, synthesized, and evaluated for imaging HCC in small animal models. [68Ga]Ga-DOTA-cTMTP1 demonstrated favorable aqueous solubility, with a log D 7.4 value of -3.28 ± 0.05, and it exhibited excellent in vitro stability in phosphate buffered saline (PBS) and fetal bovine serum (FBS). Biodistribution studies revealed a certain level of tumor accumulation (0.98 ± 0.14%ID/g at 30 min) and retention (0.40 ± 0.11%ID/g at 120 min). Impressively, [68Ga]Ga-DOTA-cTMTP1 maintained high tumor-to-liver contrast over time, with ratios of 2.65 ± 0.45 at 30 min, 2.37 ± 0.07 at 60 min, and 2.14 ± 0.20 at 120 min. It also displayed capability of clear visualization of small HCC foci (<4 mm) in transgenic c-Myc liver tumor mice models, with tumor/liver ratios 2.20 ± 0.10 at 30 min, 2.26 ± 0.11 at 60 min, and 2.55 ± 0.44 at 120 min, respectively. Overall, this study highlights that [68Ga]Ga-DOTA-cTMTP1 has favorable pharmacokinetic and in vivo tumor imaging profile, and it is a highly promising probe for visualization of HCC microlesions. Development of PET probes based on cyclic TMTP1 is a promising approach for discovering novel imaging probes.
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Affiliation(s)
- Zihan Meng
- Shandong
First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- Shandong
Laboratory of Yantai Drug Discovery, Bohai
Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Boyu Tan
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School of
Biomedical Engineering, ShanghaiTech University, Shanghai 201210, China
- School of
Life Science and Technology, ShanghaiTech
University, Shanghai 201210, China
| | - Min Wang
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
| | - Jiamin Zhu
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
| | - Chunrong Qu
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
| | - Zhen Cheng
- Shandong
First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China
- State Key
Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy
of Sciences, Shanghai 201203, China
- Shandong
Laboratory of Yantai Drug Discovery, Bohai
Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
- School
of
Pharmacy, University of Chinese Academy
of Sciences, No. 19A
Yuquan Road, Beijing 100049, China
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2
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El-Serag HB, Duong H, Luster M, Kanwal F, Hill DD, Burroughs M, Hernandez C, Haber BA, Larsen LM, Marcinak JF, Wegrzyn LR, Kramer JR. Risk of Hepatocellular Cancer in U.S. Patients With Compensated Cirrhosis Treated With Direct-Acting Antivirals Versus Interferon. Aliment Pharmacol Ther 2025; 61:1226-1237. [PMID: 39921230 DOI: 10.1111/apt.18525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/07/2024] [Accepted: 01/18/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Few studies have examined the risk of de novo hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-infected patients with cirrhosis who received interferon (IFN)-free direct-acting antiviral (DAA) therapy relative to patients who received IFN-containing therapy or remained untreated. AIMS To estimate the risk of de novo HCC with DAA treatment in cirrhotic HCV patients compared to no anti-HCV treatment and those treated with IFN-based therapy. METHODS We identified patients with chronic HCV infection and compensated cirrhosis in the US Department of Veterans Affairs healthcare system treated with IFN (2005 to 2013) or DAAs (2013 to 2017). We compared the risk of de novo HCC for patients treated with DAAs, IFN-containing regimens or no treatment after accounting for differences in demographics, alcohol and drug abuse, comorbidities, laboratory values, healthcare utilisation, prior HCV treatment and HCC surveillance. RESULTS A total of 53,847 patients contributed to untreated time, 27,147 patients contributed to DAA-treated time (15,641 contributed to both untreated and DAA-treated times) and 6809 patients contributed to IFN-treated time. HCC risk associated with DAA treatment was significantly lower than untreated [adjusted HR: 0.70 (95% CI: 0.65-0.74)]. The risk of HCC was not significantly different for patients treated with DAA compared with those treated with IFN [adjusted HR: 0.98 (95% CI: 0.87-1.10)]. CONCLUSIONS The study shows a reduced risk of de novo HCC among patients with chronic HCV-related compensated cirrhosis who received DAA treatment compared to that of untreated patients. There were no differences in HCC risk between DAA-treated and IFN-treated patients.
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Affiliation(s)
- Hashem B El-Serag
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Hao Duong
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Michelle Luster
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | | | | | | | | | | | | | | | - Jennifer R Kramer
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
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3
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Anwar J, Arslan HM, Sarfraz Z, Shuroog J, Abdelhakeem A, Saeed A, Saeed A. Immunotherapy Responses in Viral Hepatitis-Induced HCC: A Systematic Review and Meta-Analysis. Curr Oncol 2024; 31:7204-7225. [PMID: 39590162 PMCID: PMC11592516 DOI: 10.3390/curroncol31110532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/03/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with poor prognosis, often linked to hepatitis B (HBV) and C (HCV) infections. This meta-analysis evaluates the efficacy of immunotherapy in HCC, particularly in cases arising from viral hepatitis. Methods: In adherence to PRISMA Statement 2020 guidelines, the immunotherapeutic outcomes comprised objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Data were analyzed from randomized controlled trials up to April 2024 using the fixed-effects models in R (V.4.3.3.) and RevMan (Cochrane). Results: This study included 9 trials with 5316 patients. The ORR was slightly higher in the viral group at 27.93% compared to 24.07% in the non-viral group, though this difference was not significant (p = 0.15). Viral HCC patients exhibited a median PFS of 7.3 months (IQR: 6.2-8.4) compared to 5.8 months (IQR: 5.48-6.13) in non-viral patients, a significant improvement (p = 0.005). Similarly, median OS was longer in the viral group at 16.8 months (IQR: 12.99-20.61) versus 15.2 months (IQR: 13.25-17.15) for non-viral HCC, which was also significant (p < 0.0001). The median OS for viral HCC was 16.8 months (IQR: 14.11-19.49 months), with HBV patients experiencing slightly higher survival at 17.15 months (IQR: 14.3-20 months) compared to 16.8 months (IQR: 12.99-20.61 months) for HCV patients; this difference was not statistically significant (p = 0.89). Conclusions: Immunotherapy shows potential in treating HCC, with significantly better outcomes in viral HCC, particularly HBV-associated cases. The heterogeneity highlights the need for personalized treatment approaches based on the viral background of HCC patients. Further research should aim to optimize these therapies to improve survival rates.
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Affiliation(s)
- Junaid Anwar
- Department of Medicine, Baptist Hospitals of Southeast Texas, Beaumont, TX 77701, USA;
| | - Hafiz Muhammad Arslan
- Department of Medicine, Lincoln Medical and Mental Health Center, Bronx, NY 10451, USA;
| | - Zouina Sarfraz
- Department of Medicine, Fatima Jinnah Medical University, Lahore 54000, Pakistan;
| | - Juwairiya Shuroog
- Department of Medicine, TidalHealth Peninsula Regional, Salisbury, MD 21801, USA;
| | - Ahmed Abdelhakeem
- Department of Medicine, Division of Hematology & Oncology, Mayo Clinic College of Medicine and Science, Jacksonville, FL 32224, USA;
| | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA
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Ali MH, Talha M, Hussain SA. The Role of Hepatic Stellate Cells and the Gas6/Axl Axis in Liver Fibrosis and Hepatocellular Carcinoma. J Clin Exp Hepatol 2024; 14:101400. [PMID: 38601748 PMCID: PMC11002857 DOI: 10.1016/j.jceh.2024.101400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 03/14/2024] [Indexed: 04/12/2024] Open
Affiliation(s)
- Mohammad Haris Ali
- Shaikh Khalifa Bin Zayed Al-Nahyan Medical and Dental College, Lahore, Pakistan
| | - Muhammad Talha
- Shaikh Khalifa Bin Zayed Al-Nahyan Medical and Dental College, Lahore, Pakistan
| | - Syed A.S. Hussain
- Shaikh Khalifa Bin Zayed Al-Nahyan Medical and Dental College, Lahore, Pakistan
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Zhang L, Cui TX, Li XZ, Liu C, Wang WQ. Diagnostic and prognostic role of LINC01767 in hepatocellular carcinoma. World J Hepatol 2024; 16:932-950. [PMID: 38948436 PMCID: PMC11212654 DOI: 10.4254/wjh.v16.i6.932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a primary contributor to cancer-related mortality on a global scale. However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs are emerging markers for HCC diagnosis, prognosis, and therapeutic target. No study of LINC01767 in HCC was published. AIM To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time. METHODS DESeq2 Package was used to analyze different gene expressions. Receiver operating characteristic curves assessed the diagnostic performance. Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis. The least absolute shrinkage and selection operator (LASSO)-Cox was used to identify the prediction model. Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction, next generation sequencing was performed following LINC01767 over expression (GSE243371), and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out. In vitro experiment in Huh7 cell was carried out. RESULTS LINC01767 was down-regulated in HCC with a log fold change = 1.575 and was positively correlated with the cancer stemness. LINC01767 was a good diagnostic marker with area under the curve (AUC) [0.801, 95% confidence interval (CI): 0.751-0.852, P = 0.0106] and an independent predictor for overall survival (OS) with hazard ratio = 1.899 (95%CI: 1.01-3.58, P = 0.048). LINC01767 nomogram model showed a satisfied performance. The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways. LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC > 0.75. LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line; the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 in vitro. CONCLUSION LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.
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Affiliation(s)
- Li Zhang
- Department of Thyroid and Breast Surgery, The Affiliated People Hospital of Second Medical University, Weifang 266010, Shandong Province, China
| | - Tong-Xing Cui
- Department of General Surgery, Qingdao Municipal Hospital Group, Qingdao 266237, Shandong Province, China
| | - Xiang-Zhi Li
- School of Life Sciences, Shandong University (Qingdao), Qingdao 26637, Shandong Province, China
| | - Chong Liu
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - Wen-Qin Wang
- School of Life Sciences, Shandong University (Qingdao), Qingdao 26637, Shandong Province, China.
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Zhou XQ, Li YP, Dang SS. Precision targeting in hepatocellular carcinoma: Exploring ligand-receptor mediated nanotherapy. World J Hepatol 2024; 16:164-176. [PMID: 38495282 PMCID: PMC10941735 DOI: 10.4254/wjh.v16.i2.164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 02/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality. Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages, but it is often ineffective and suffers from problems such as multidrug resistance, rapid drug clearance, nonspecific targeting, high side effects, and low drug accumulation in tumor cells. In response to these limitations, recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC. This review focuses on recent advances in nanoparticle-based targeted drug delivery systems, with special attention to various receptors overexpressed on HCC cells. These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC. We comprehensively summarize the current understanding of these receptors, their role in nanoparticle targeting, and the impact of such targeted therapies on HCC. By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies, more effective and precise treatment of HCC can be achieved.
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Affiliation(s)
- Xia-Qing Zhou
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Ya-Ping Li
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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7
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Abou-Shanab AM, Gaser OA, Salah RA, El-Badri N. Application of the Human Amniotic Membrane as an Adjuvant Therapy for the Treatment of Hepatocellular Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1470:129-146. [PMID: 38036871 DOI: 10.1007/5584_2023_792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related morbidity and mortality worldwide. Current therapeutic approaches suffer significant side effects and lack of clear understanding of their molecular targets. Recent studies reported the anticancer effects, immunomodulatory properties, and antiangiogenic effects of the human amniotic membrane (hAM). hAM is a transparent protective membrane that surrounds the fetus. Preclinical studies showed pro-apoptotic and antiproliferative properties of hAM treatment on cancer cells. Herein, we present the latest findings of the application of the hAM in combating HCC tumorigenesis and the underlying molecular pathogenies and the role of transforming growth factor-beta (TGFβ), P53, WNT/beta-catenin, and PI3K/AKT pathways. The emerging clinical applications of hAM in cancer therapy provide evidence for its diverse and unique features and suitability for the management of a wide range of pathological conditions.
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Affiliation(s)
- Ahmed M Abou-Shanab
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, Egypt
| | - Ola A Gaser
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, Egypt.
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Huang X, Lian YE, Qiu L, Yu X, Zhan Z, Zhang Z, Zhang X, Lin H, Xu S, Chen J, Bai Y, Li L. Detection of fibrotic changes in the progression of liver diseases by label-free multiphoton imaging. JOURNAL OF BIOPHOTONICS 2023; 16:e202300153. [PMID: 37403400 DOI: 10.1002/jbio.202300153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/02/2023] [Accepted: 06/28/2023] [Indexed: 07/06/2023]
Abstract
Collagen fibers play an important role in the progression of liver diseases. The formation and progression of liver fibrosis is a dynamic pathological process accompanied by morphological changes in collagen fibers. In this study, we used multiphoton microscopy for label-free imaging of liver tissues, allowing direct detection of various components including collagen fibers, tumors, blood vessels, and lymphocytes. Then, we developed a deep learning classification model to automatically identify tumor regions, and the accuracy reaches 0.998. We introduced an automated image processing method to extract eight collagen morphological features from various stages of liver diseases. Statistical analysis showed significant differences between them, indicating the potential use of these quantitative features for monitoring fibrotic changes during the progression of liver diseases. Therefore, multiphoton imaging combined with automatic image processing method would hold a promising future in rapid and label-free diagnosis of liver diseases.
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Affiliation(s)
- Xingxin Huang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Yuan-E Lian
- Department of Pathology, The Affiliated Union Hospital of Fujian Medical University, Fuzhou, China
| | - Lida Qiu
- College of Physics and Electronic Information Engineering, Minjiang University, Fuzhou, China
| | - XunBin Yu
- Department of Pathology, Fujian Provincial Hospital, Fuzhou, China
| | - Zhenlin Zhan
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Zheng Zhang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Xiong Zhang
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Hongxin Lin
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Shuoyu Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianxin Chen
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
| | - Yannan Bai
- Shengli Clinical Medical College of Fujian Medical University, Department of Hepatobiliary and Pancreatic Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Lianhuang Li
- Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, China
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You J, Xia H, Huang Z, He R, Zhao X, Chen J, Liu S, Xu Y, Cui Y. Research progress of circulating non-coding RNA in diagnosis and treatment of hepatocellular carcinoma. Front Oncol 2023; 13:1204715. [PMID: 37546394 PMCID: PMC10400719 DOI: 10.3389/fonc.2023.1204715] [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: 04/12/2023] [Accepted: 06/28/2023] [Indexed: 08/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor that carries a significant risk of morbidity and mortality. This type of cancer is prevalent in Asia due to the widespread presence of risk factors. Unfortunately, HCC often goes undetected until it has reached an advanced stage, making early detection and treatment critical for better outcomes. Alpha-fetoprotein (AFP) is commonly used in clinical practice for diagnosing HCC, but its sensitivity and specificity are limited. While surgery and liver transplantation are the main radical treatments, drug therapy and local interventions are better options for patients with advanced HCC. Accurately assessing treatment efficacy and adjusting plans in a timely manner can significantly improve the prognosis of HCC. Non-coding RNA gene transcription products cannot participate in protein production, but they can regulate gene expression and protein function through the regulation of transcription and translation processes. These non-coding RNAs have been found to be associated with tumor development in various types of tumors. Noncoding RNA released by tumor or blood cells can circulate in the blood and serve as a biomarker for diagnosis, prognosis, and efficacy assessment. This article explores the unique role of circulating noncoding RNA in HCC from various perspectives.
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Affiliation(s)
- Junqi You
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Haoming Xia
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Ziyue Huang
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Risheng He
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Xudong Zhao
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jiali Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Sidi Liu
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Xu
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yunfu Cui
- Department of Pancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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10
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Sun L, Zhou H, Zhao X, Zhang H, Wang Y, Li G. Small RNA sequencing identified miR-3180 as a potential prognostic biomarker for Chinese hepatocellular carcinoma patients. Front Genet 2023; 14:1102171. [PMID: 37051592 PMCID: PMC10083302 DOI: 10.3389/fgene.2023.1102171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 03/10/2023] [Indexed: 03/28/2023] Open
Abstract
MicroRNAs (miRNAs) and their target genes are aberrantly expressed in many cancers and are linked to carcinogenesis and metastasis, especially among hepatocellular carcinoma (HCC) patients. This study sought to identify new biomarkers related to HCC prognosis using small RNA sequencing from the tumor and matched normal adjacent tissue of 32 patients with HCC. Eight miRNAs were downregulated and 61 were upregulated more than twofold. Of these, five miRNAs, hsa-miR-3180, hsa-miR-5589-5p, hsa-miR-490-5p, hsa-miR-137, and hsa-miR-378i, were significantly associated with 5-year overall survival (OS) rates. Differential upregulation of hsa-miR-3180 and downregulation of hsa-miR-378i in tumor samples supported the finding that low and high concentrations of hsa-miR-3180 (p = 0.029) and hsa-miR-378i (p = 0.047), respectively, were associated with higher 5-year OS. Cox regression analyses indicated that hsa-miR-3180 (HR = 0.08; p = 0.013) and hsa-miR-378i (HR = 18.34; p = 0.045) were independent prognostic factors of poor survival. However, high hsa-miR-3180 expression obtained larger AUCs for OS and progression-free survival (PFS) and had better nomogram prediction than hsa-miR-378i. These findings indicate that hsa-miR-3180 may be associated with HCC progression and could serve as a potential biomarker for this disease.
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Affiliation(s)
- Libo Sun
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Hansheng Zhou
- Department of Pharmacy, Linyi People’s Hospital, Linyi, Shandong, China
| | - Xiaofei Zhao
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Haitao Zhang
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yan Wang
- CAS Key Lab of Mental Health, Institute of Psychology, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Yan Wang, ; Guangming Li,
| | - Guangming Li
- General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yan Wang, ; Guangming Li,
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Drott J, Björnsson B, Sandström P, Berterö C. Experiences of Symptoms and Impact on Daily Life and Health in Hepatocellular Carcinoma Patients: A Meta-synthesis of Qualitative Research. Cancer Nurs 2022; 45:430-437. [PMID: 35025775 PMCID: PMC9584044 DOI: 10.1097/ncc.0000000000001044] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND The incidence of hepatocellular cancer (HCC) has continually increased. To achieve optimal supportive cancer care for HCC patients, it is important to consider patients' experiences and preferences. OBJECTIVE This meta-synthesis aims to critically interpret how patients with HCC experience symptoms and the impact of the disease on daily life and health. METHODS Searches were performed in the following bibliographic databases: PubMed, CINAHL, Web of Science, Scopus, PsycINFO, and Cochrane Library. In addition, searches were performed using Open Gray to identify relevant studies in the gray literature. The search was limited to studies published in English from 2009 to 2019. Five studies (124 participants) were identified, appraised, and ultimately interpreted and synthesized. RESULTS Receiving an HCC diagnosis was overwhelming and affected the patients' entire lives. Three themes were identified based on the meta-synthesis: (1) disrupted life, (2) living with uncertainty, and (3) a changed body. Patients with HCC experience disrupted lives because of the cancer's effect on health and multidimensional symptoms. CONCLUSION Available research on the experiences of HCC patients is limited. This meta-synthesis of available studies shows that being given a diagnosis of HCC is an overwhelming event. Our study findings show that an HCC diagnosis affected the individual's entire life. IMPLICATIONS FOR PRACTICE It is important to identify the patients' physical, psychological, social, and existential needs during the investigation of their condition, during any curative treatment, and at the palliative stage of the disease.
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Sharifi H, Safarpour H, Moossavi M, Khorashadizadeh M. Identification of Potential Prognostic Markers and Key Therapeutic Targets in Hepatocellular Carcinoma Using Weighted Gene Co-Expression Network Analysis: A Systems Biology Approach. IRANIAN JOURNAL OF BIOTECHNOLOGY 2022; 20:e2968. [PMID: 36381283 PMCID: PMC9618018 DOI: 10.30498/ijb.2022.269817.2968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND As the most prevalent form of liver cancer, hepatocellular carcinoma (HCC) ranks the fifth highest cause of cancer-related death worldwide. Despite recent advancements in diagnostic and therapeutic techniques, the prognosis for HCC is still unknown. OBJECTIVES This study aimed to identify potential genes contributing to HCC pathogenicity. MATERIALS AND METHODS To this end, we examined the GSE39791 microarray dataset, which included 72 HCC samples and 72 normal samples. An investigation of co-expression networks using WGCNA found a highly conserved blue module with 665 genes that were strongly linked to HCC. RESULTS APOF, NAT2, LCAT, TTC36, IGFALS, ASPDH, and VIPR1 were the blue module's top 7 hub genes. According to the results of hub gene enrichment, the most related issues in the biological process and KEGG were peroxisome organization and metabolic pathways, respectively. In addition, using the drug-target network, we discovered 19 FDA-approved medication candidates for different reasons that might potentially be employed to treat HCC patients through the modulation of 3 hub genes of the co-expression network (LCAT, NAT2, and VIPR1). Our findings also demonstrated that the 3 scientifically validated miRNAs regulated the co-expression network by the VIPR1 hub gene. CONCLUSION We found co-expressed gene modules and hub genes linked with HCC advancement, offering insights into the mechanisms underlying HCC progression as well as some potential HCC treatments.
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Affiliation(s)
- Hengameh Sharifi
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Hossein Safarpour
- Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Maryam Moossavi
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohsen Khorashadizadeh
- Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran,
Cellular & Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran,
3Department of Medical Biotechnology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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13
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Dat VHX, Nhung BTH, Chau NNB, Cuong PH, Hieu VD, Linh NTM, Quoc NB. Identification of potential microRNA groups for the diagnosis of hepatocellular carcinoma (HCC) using microarray datasets and bioinformatics tools. Heliyon 2022; 8:e08987. [PMID: 35243101 PMCID: PMC8873536 DOI: 10.1016/j.heliyon.2022.e08987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/19/2021] [Accepted: 02/15/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third cause of cancer-related death worldwide. Potential microRNAs have been reported as biomarkers for early detection of HCC as well as novel molecular targets for HCC treatment. Various tissue expression profiles of miRNAs using three microarray datasets from groups in Asia (2), Europe, America (GSE147892, GSE21362, GSE74618, GSE40744) and multiple bioinformatics tools were integrated to determine the most significant miRNA groups to assist in the diagnosis of HCC. Statistical analyses identified at least 30 miRNAs with 17 up-regulated and 13 down-regulated in HCC-related tumor tissues. All the miRNAs also showed relevance to the hallmarks of cancer such as cell proliferation, invasion, metastasis, angiogenesis, metabolism, epithelial-mesenchymal transition and apoptosis. Expression levels of miRNAs observed in the European group showed up-regulation at 5–37% compared to both Asian and American groups. Interestingly, four miRNAs divided into two groups as miR-182-5p/miR-1269a and miR-199a/miR-422a were the most promising for diagnosis of HCC patients from healthy controls, with AUC values of 0.902 and 0.892, respectively. Results provided evidence of the correlation between potential miRNAs and HCC that could be useful for disease diagnosis based on in-depth analyses of large case numbers and cohort studies.
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Affiliation(s)
- Vo Hoang Xuan Dat
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam
| | - Bui Thi Huyen Nhung
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam
| | | | | | - Vo Duc Hieu
- Ho Chi Minh City Oncology Hospital, Viet Nam
| | | | - Nguyen Bao Quoc
- Faculty of Biological Sciences, Nong Lam University, Ho Chi Minh City, Viet Nam.,Research Institute of Biotechnology and Environment, Nong Lam University, Ho Chi Minh City, Viet Nam
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14
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Bai W, Cheng L, Xiong L, Wang M, Liu H, Yu K, Wang W. Identification of Prognostic Genes in Hepatocellular Carcinoma. Int J Gen Med 2022; 15:2895-2904. [PMID: 35300146 PMCID: PMC8923701 DOI: 10.2147/ijgm.s347535] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/11/2022] [Indexed: 12/05/2022] Open
Abstract
Background Previous studies have demonstrated the important role of tumor stem cells (TSCs) in the development of hepatocellular carcinoma (HCC); however, TSC-related genetic markers have not been investigated. Aim The aim of the present study was to identify stem cell-related signature genes to predict the prognosis of HCC, using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Methods In total, 423 liver HCC tissue samples, including 373 tumor and 50 adjacent normal tissue samples from TCGA, and 115 primary tumor and 52 adjacent non-tumor tissue samples from the GEO GSE76427 database, were used in the present study. The non-negative matrix factorization (NMF) algorithm, t-distributed stochastic neighbor embedding (t-SNE) algorithm and Cox regression analysis were combined for model construction and validation. Results Overall, six clusters were identified using the NMF and t-SNE algorithms with 470 stem cell-related genes. The results demonstrated that patients in cluster 5 had the worst prognosis. For multivariate Cox survival analysis, 15 genes with optimal lambda values were chosen and eight genes were incorporated into the final regression model using the optimal Akaike information criterion value. Validation of the risk model using the aforementioned eight signature genes demonstrated the models strong reliability and stable predictive performance. Conclusion The results of the present study indicated that the eight-gene (Hes family BHLH transcription factor 5, KIT ligand, methyltransferase-like 3, proteasome 26S subunit non-ATPase 1, Ras-related protein Rab-10, treacle ribosome biogenesis factor 1, YTH N6-methyladenosine RNA binding protein 2 and Zinc Finger CCCH-Type Containing 13) signature constructed by the model may be reliable in predicting the prognosis of patients with HCC.
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Affiliation(s)
- Wenhui Bai
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Li Cheng
- Department of Intensive Care Unit, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Liangkun Xiong
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Maoming Wang
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Hao Liu
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Kaihuan Yu
- Department of Hepatobiliary Surgery, Eastern Campus, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
| | - Weixing Wang
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China
- Correspondence: Weixing Wang; Kaihuan Yu, Email ;
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15
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Ratnasari N, Lestari P, Renovaldi D, Raditya Ningsih J, Qoriansas N, Wardana T, Hakim S, Signa Aini Gumilas N, Indrarti F, Triwikatmani C, Bayupurnama P, Setyo Heriyanto D, Astuti I, Mubarika Harjana S. Potential plasma biomarkers: miRNA-29c, miRNA-21, and miRNA-155 in clinical progression of Hepatocellular Carcinoma patients. PLoS One 2022; 17:e0263298. [PMID: 35157721 PMCID: PMC8843218 DOI: 10.1371/journal.pone.0263298] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
This study evaluated differences in the clinical appearance of patients with hepatocellular carcinoma (HCC) based on plasma level and regulation of microRNAs (miRNA-29c, miRNA-21, and miRNA-155). The observational-analytical study with a cross-sectional design was conducted on 36 HCC patients and 36 healthy controls. The blood samples were collected from 2 Province Hospitals (Dr. Sardjito Hospital and Prof. Dr. Margono Soekarjo Hospital) for HCC and the Blood Bank Donor of the Indonesian Red Cross for 36 healthy controls. These blood samples were treated as follows: plasma isolation, RNA isolation, cDNA synthesis, quantification by qRT-PCR using a sequence-specific forward primer, and normalization of miRNA using housekeeping-stably miRNA-16. There were only 27 HCC patients with complete clinical variables (neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), platelet count, albumin, C-reactive protein (CRP), and cholinesterase (ChE)) that were able to analyses for regulation miRNAs based on its fold change expression miRNA target. All 27 HCC subjects were follow-up until 3-years of monitoring for their overall survival. The miRNA plasma expression was analyzed by Bio-Rad CFX 96 Manager software to determine the cycle of quantification, followed by the calculation of expression levels using Livak's methods. Data were analyzed using STATA 11.0, with a significant value of p<0.05. The miRNAs expression of HCC subjects were lower than that healthy control subjects in miRNA-29c (down-regulation 1.83-fold), higher than that healthy control subjects in miRNA 21 and miRNA-155 (up-regulation, 1.74-fold; 1.55-fold) respectively. NLR, CRP, ChE, and platelet count showed a significant difference in miRNA-29c regulation, though neutrophil count showed a significant difference in miRNA-21 and miRNA-155 regulation (p<0.05). Conclusion: Plasma biomarkers: miRNA-21 and miRNA-155 might be potential biomarkers as onco-miR in HCC subjects, while miRNA-29c might act as a tumor suppressor. Significant evidence was identified with clinical progression based on the regulation of miRNAs, which was consistent with miRNA -29c.
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Affiliation(s)
- Neneng Ratnasari
- Gastroenterology-Hepatology Division of Internal Medicine, Department Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada/ Dr. Sardjito General Hospital, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Puji Lestari
- Graduate School of Biotechnology Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, Indonesia
| | - Dede Renovaldi
- Graduate School of Biotechnology Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, Indonesia
| | - Juwita Raditya Ningsih
- Graduate School of Biotechnology Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, Indonesia
| | - Nanda Qoriansas
- Graduate School of Biotechnology Universitas Gadjah Mada, Daerah Istimewa Yogyakarta, Indonesia
| | - Tirta Wardana
- Department Biomedicine, School of Dentistry, Faculty of Medicine Jenderal Soedirman University, Jawa Tengah, Indonesia
| | - Suharno Hakim
- Internal Medicine Department Dr. Margono Soekarjo Hospital/Faculty of Medicine Universitas Jendral Soedirman, Jawa Tengah, Indonesia
| | - Nur Signa Aini Gumilas
- Histology Department Faculty of Medicine Universitas Jendral Soedirman, Jawa Tengah, Indonesia
| | - Fahmi Indrarti
- Gastroenterology-Hepatology Division of Internal Medicine, Department Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada/ Dr. Sardjito General Hospital, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Catharina Triwikatmani
- Gastroenterology-Hepatology Division of Internal Medicine, Department Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada/ Dr. Sardjito General Hospital, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Putut Bayupurnama
- Gastroenterology-Hepatology Division of Internal Medicine, Department Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada/ Dr. Sardjito General Hospital, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Didik Setyo Heriyanto
- Anatomic Pathology Department, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Indwiani Astuti
- Pharmacology and Therapy Department, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
| | - Sofia Mubarika Harjana
- Histology and Cell Biology Department, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Daerah Istimewa Yogyakarta, Indonesia
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16
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ARID1A Is a Prognostic Biomarker and Associated with Immune Infiltrates in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2022; 2022:3163955. [PMID: 35028302 PMCID: PMC8752298 DOI: 10.1155/2022/3163955] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/16/2021] [Accepted: 12/18/2021] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE ARID1A has been discovered as a potential cancer biomarker. But its role in hepatocellular carcinoma (HCC) is subject to considerable dispute. METHODS The relationship between ARID1A and clinical factors was investigated. Clinicopathological variables related to overall survival in HCC subjects were identified using Cox and Kaplan-Meier studies. The connection between immune infiltrating cells and ARID1A expression was investigated using the tumor Genome Atlas (TCGA) dataset for gene set enrichment analysis (GSEA). Finally, a cell experiment was used to confirm it. RESULTS The gender and cancer topography (T) categorization of HCC were linked to increased ARID1A expression. Participants with advanced levels of ARID1A expression had a worse prognosis than someone with lower levels. ARID1A was shown to be a risk indicator of overall survival on its own. ARID1A expression is inversely proportional to immune cell infiltration. In vitro, decreasing ARID1A expression substantially slowed the cell cycle and decreased HCC cell proliferation, migration, and invasion. CONCLUSION The expression of ARID1A could be used to predict the outcome of HCC. It is closely related to tumor immune cell infiltration.
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17
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Salah RA, Nasr MA, El-Derby AM, Abd Elkodous M, Mohamed RH, El-Ekiaby N, Osama A, Elshenawy SE, Hamad MHM, Magdeldin S, Gabr MM, Abdelaziz AI, El-Badri NS. Hepatocellular carcinoma cell line-microenvironment induced cancer-associated phenotype, genotype and functionality in mesenchymal stem cells. Life Sci 2022; 288:120168. [PMID: 34826437 DOI: 10.1016/j.lfs.2021.120168] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 12/21/2022]
Abstract
Mesenchymal stromal cells (MSCs) have shown promise in liver cancer treatment. However, when MSCs are recruited to hepatic site of injury, they acquire cancerous promoting phenotype. AIMS To assess the influence of Hepatocellular carcinoma (HCC) microenvironment on human adipose MSCs (hA-MSCs) and predict hA-MSCs intracellular miRNAs role. MATERIALS AND METHODS After indirect co-culturing with Huh-7 cells, hA-MSCs were characterized via cell cycle profile, proliferation and migration potentials by MTT and scratch assays respectively. Functional enrichment analysis of deregulated proteins and miRNA targets was also analyzed. KEY FINDINGS Co-cultured hA-MSCs could acquire a cancer-associated phenotype as shown by upregulation of CAF, cancer markers, and downregulation of differentiation markers. Migration of these cancer-associated cells was increased concomitantly with upregulation of adhesion molecules, but not epithelial to mesenchymal transition markers. Co-cultured cells showed increased proliferation confirmed by downregulation in cell percentage in G0/G1, G2/M and upregulation in S phases of cell cycle. Upregulation of miR-17-5p and 615-5p in co-cultured hA-MSCs was also observed. Functional enrichment analysis of dysregulated proteins in co-cultured hA-MSCs, including our selected miRNAs targets, showed their involvement in development of cancer-associated characteristics. SIGNIFICANCE This study suggests an interaction between tumor cells and surrounding stromal components to generate cancer associated phenotype of some CAF-like characteristics, known to favor cancer progression. This sheds the light on the use of hA-MSCs in HCC therapy. hA-MSCs modulation may be partially achieved via dysregulation of intracellular miR17-5P and 615-5p expression, suggesting an important role for miRNAs in HCC pathogenesis, and as a possible therapeutic candidate.
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Affiliation(s)
- Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | - Rania Hassan Mohamed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Nada El-Ekiaby
- School of Medicine NewGiza University (NGU), Cairo, Egypt
| | - Aya Osama
- Proteomics and metabolomics Research Program, Basic Research Department, Children Cancer Hospital Egypt, 57357 Cairo, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt
| | | | - Sameh Magdeldin
- Proteomics and metabolomics Research Program, Basic Research Department, Children Cancer Hospital Egypt, 57357 Cairo, Egypt; Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Mahmoud M Gabr
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | | | - Nagwa S El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Egypt.
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18
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Cai H, Zheng Y, Wen Z, Yang Y, Yang S, Zhang Q. LncRNA AIRN influences the proliferation and apoptosis of hepatocellular carcinoma cells by regulating STAT1 ubiquitination. Arch Pharm Res 2021; 44:414-426. [PMID: 33759138 DOI: 10.1007/s12272-021-01317-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 03/06/2021] [Indexed: 01/11/2023]
Abstract
Long non-coding RNAs (LncRNAs) have been implicated in the pathogenesis of various human diseases. In this study, we probed into the role and potential mechanisms of the antisense of IGF2R non-protein coding RNA (LncRNA AIRN) in the progression of hepatocellular carcinoma (HCC). Using a quantitative real-time polymerase chain reaction, we corroborated that LncRNA AIRN expression was raised in the HCC tissues and cells. The bioinformatic analysis revealed that a potential interaction between LncRNA AIRN and STAT1, which was verified by the RNA pull-down and RNA immunoprecipitation. In the cycloheximide-chase assay, the knockdown of LncRNA AIRN enhanced the stability of STAT1 protein. In the immunoprecipitation assay, the knockdown of LncRNA AIRN restrained the cullin 4A (CUL4A)-mediated ubiquitination of STAT1 protein. The cell transfection, MTT and flow cytometry assays expounded that the LncRNA AIRN/STAT1 axis was bound up with the regulation of the proliferation and apoptosis of HCC cells. The in vivo experiments corroborated that the knockdown of LncRNA AIRN restrained the tumor growth of HCC. Our data expounded that the knockdown of LncRNA AIRN restrained HCC cell proliferation and boosted cell apoptosis by restraining the CUL4A-mediated ubiquitination of STAT1 protein.
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Affiliation(s)
- Huajie Cai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Yihu Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Zhengde Wen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Yingnan Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Shouzhang Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nan Bai Xiang Street, Ouhai District, Wenzhou, 325000, Zhejiang Province, China.
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Peng Z, Gong Y, Liang X. Role of FAT1 in health and disease. Oncol Lett 2021; 21:398. [PMID: 33777221 PMCID: PMC7988705 DOI: 10.3892/ol.2021.12659] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 02/25/2021] [Indexed: 01/15/2023] Open
Abstract
FAT atypical cadherin 1 (FAT1), which encodes a protocadherin, is one of the most frequently mutated genes in human cancer. Over the past 20 years, the role of FAT1 in tissue growth and in the development of diseases has been extensively studied. There is definitive evidence that FAT1 serves a substantial role in the maintenance of organs and development, and its expression appears to be tissue-specific. FAT1 activates a variety of signaling pathways through protein-protein interactions, including the Wnt/β-catenin, Hippo and MAPK/ERK signaling pathways, which affect cell proliferation, migration and invasion. Abnormal FAT1 expression may lead to the development of tumors and may affect prognosis. Therefore, FAT1 may have potential in tumor therapy. The structural and functional changes mediated by FAT1, its tissue distribution and changes in FAT1 expression in human diseases are described in the present review, which provides further insight for understanding the role of FAT1 in development and disease.
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Affiliation(s)
- Zizhen Peng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yanyu Gong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoqiu Liang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China
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20
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Djokic M, Cemazar M, Bosnjak M, Dezman R, Badovinac D, Miklavcic D, Kos B, Stabuc M, Stabuc B, Jansa R, Popovic P, Smid LM, Sersa G, Trotovsek B. A Prospective Phase II Study Evaluating Intraoperative Electrochemotherapy of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:3778. [PMID: 33333941 PMCID: PMC7765454 DOI: 10.3390/cancers12123778] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/09/2020] [Accepted: 12/14/2020] [Indexed: 12/17/2022] Open
Abstract
The aim of this clinical study was to investigate the effectiveness and long-term safety of electrochemotherapy as an emerging treatment for HCC in patients not suitable for other treatment options. A prospective phase II clinical study was conducted in patients with primary HCC who were not suitable for other treatment options according to the Barcelona Clinic Liver Cancer classification. A total of 24 patients with 32 tumors were treated by electrochemotherapy. The procedure was effective, feasible, and safe with some procedure-related side effects. The responses of the 32 treated nodules were: 84.4% complete response (CR), 12.5% partial response (PR), and 3.1% stable disease (SD). The treatment was equally effective for nodules located centrally and peripherally. Electrochemotherapy provided a durable response with local tumor control over 50 months of observation in 78.0% of nodules. The patient responses were: 79.2% CR and 16.6% PR. The median progression-free survival was 12 months (range 2.7-50), and the overall survival over 5 years of observation was 72.0%. This prospective phase II clinical study showed that electrochemotherapy was an effective, feasible, and safe option for treating HCC in patients not suitable for other treatment options.
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Affiliation(s)
- Mihajlo Djokic
- Clinical Department of Abdominal Surgery, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia; (M.D.); (D.B.)
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
| | - Maja Cemazar
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (M.B.)
- Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia
| | - Masa Bosnjak
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (M.B.)
| | - Rok Dezman
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - David Badovinac
- Clinical Department of Abdominal Surgery, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia; (M.D.); (D.B.)
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
| | - Damijan Miklavcic
- Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, SI-1000 Ljubljana, Slovenia; (D.M.); (B.K.)
| | - Bor Kos
- Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, SI-1000 Ljubljana, Slovenia; (D.M.); (B.K.)
| | - Miha Stabuc
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Borut Stabuc
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Department of Gastroenterology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Rado Jansa
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Department of Gastroenterology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Peter Popovic
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Institute of Radiology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Lojze M. Smid
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
- Clinical Department of Gastroenterology, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Gregor Sersa
- Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia; (M.C.); (M.B.)
- Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia
| | - Blaz Trotovsek
- Clinical Department of Abdominal Surgery, University Medical Centre Ljubljana, Zaloska 7, SI-1000 Ljubljana, Slovenia; (M.D.); (D.B.)
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, SI-1000 Ljubljana, Slovenia; (R.D.); (M.S.); (B.S.); (R.J.); (P.P.); (L.M.S.)
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Vidal RIDO, Vidal EIDO, Pereira BDB, Assane CC, Ribeiro A, do Nascimento EM, Romeiro FG, Ribeiro Filho J. Risk Factors for Hepatocellular Carcinoma Recurrence and Survival after Liver Transplantation in Patients with HCV-Related Cirrhosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:1487593. [PMID: 33134370 PMCID: PMC7591978 DOI: 10.1155/2020/1487593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 10/05/2020] [Indexed: 12/25/2022]
Abstract
PURPOSE We aimed to identify prognostic factors for survival and recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) for patients with HCC and hepatitis C virus-related cirrhosis (HCV-cirrhosis). METHODS This retrospective cohort study followed all adult patients with HCV-cirrhosis who underwent LT because of HCC or had incidental HCC identified through pathologic examination of the explanted liver at a university hospital in Rio de Janeiro, Brazil, over 11 years (1998-2008). We used Cox regression models to assess the following risk factors regarding HCC recurrence or death after LT: age, Model for End-stage Liver Disease score, Child-Pugh classification, alpha-fetoprotein (AFP), whether patients had undergone locoregional treatment before transplantation, the number of packed red blood cell units (PRBCU) transfused during surgery, the number and size of HCC lesions in the explanted liver, and the presence of microvascular invasion and necrotic areas within HCC lesions. RESULTS Seventy-six patients were followed up for a median (interquartile range (IQR)) of 4.4 (0.7-6.6) years. Thirteen (17%) patients had HCC recurrence during the follow-up period, and 26 (34%) died. The median survival time was 6.6 years (95% CI: 2.4-12.0), and the 5-year survival was 52.5% (95% CI: 42.3-65.0%). The final regression model for overall survival included four variables: age (hazard ratio (HR): 1.02, 95% CI: 0.96-1.08, P = 0.603), transplantation waiting time (HR: 1.00, 95% CI: 1.00-1.00, P = 0.190), preoperative AFP serum levels (HR: 1.01, 95% CI: 1.00-1.02, P = 0.006), and whether >4 PRBCU were transfused during surgery (HR: 1.15, 95% CI: 1.05-1.25, P = 0.001). The final cause-specific Cox regression model for HCC recurrence included only microvascular invasion (HR: 14.86, 95% CI: 4.47-49.39, P < 0.001). CONCLUSION In this study of LT for HCV-cirrhosis, preoperative AFP levels and the number of PRBCU transfused during surgery were associated with overall survival, whereas microvascular invasion with HCC recurrence.
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Affiliation(s)
- Raphael Iglesias de Oliveira Vidal
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
| | - Edison Iglesias de Oliveira Vidal
- Internal Medicine Department, Botucatu Medical School, Sao Paulo State University (UNESP), Av. Prof. Mario Rubens Guimaraes Montenegro, S/N, Botucatu, SP, Brazil 18618-687
| | - Basilio de Bragança Pereira
- Preventive Medicine Department, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Cidade Universitária, Ilha do Fundão, P.O. Box: 68507, Rio de Janeiro, RJ, Brazil 21941-972
| | - Cachimo Combo Assane
- Department of Mathematics and Informatics, Faculty of Sciences, Universidade Eduardo Mondlane, Av. Julius Nyerere/Campus 3453, P.O. Box 257, Maputo, Mozambique
| | - Alexandre Ribeiro
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
| | - Emilia Matos do Nascimento
- Centro Universitário da Zona Oeste, UEZO-Unidade de Engenharia de Produção, Engenharia de Produção, Avenida Manuel Caldeira de Alvarenga, Campo Grande, Rio de Janeiro, RJ, Brazil 23070-200
| | - Fernando Gomes Romeiro
- Internal Medicine Department, Botucatu Medical School, Sao Paulo State University (UNESP), Av. Prof. Mario Rubens Guimaraes Montenegro, S/N, Botucatu, SP, Brazil 18618-687
| | - Joaquim Ribeiro Filho
- Department of Surgery, Faculty of Medicine, Federal University of Rio de Janeiro (UFRJ), Rua Rodolpho Paulo Rocco, 255-Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ, Brazil 21941-902
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22
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Cao S, Zhu S, Yin W, Xu H, Wu J, Wang Q. Relevance of EGFR Between Serum VEGF and MMP-9 in Primary Hepatocellular Carcinoma Patients with Transarterial Chemoembolization. Onco Targets Ther 2020; 13:9407-9417. [PMID: 33061427 PMCID: PMC7520140 DOI: 10.2147/ott.s257271] [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: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 12/19/2022] Open
Abstract
Objective The aim of this study was to estimate the relevance of the epidermal growth factor receptor (EGFR) between serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) in primary hepatocellular carcinoma (HCC) patients with transarterial chemoembolization (TACE). Methods The pre-treatment and post-treatment concentrations of the serum VEGF and MMP‑9 were detected with Luminex assay in 80 EGFR-negative patients and 59 EGFR-positive patients who received TACE therapy with different chemotherapeutic drugs. Results The serum concentration of MMP-9 in the EGFR-positive patients with primary HCC was significantly higher than that in the EGFR-negative patients (P < 0.05). In EGFR-positive patients with primary HCC, differences in stage, metastasis, and differentiation were significant (P < 0.05). Serum VEGF level significantly decreased at the second course of treatment in the EGFR-negative patients from the P group (P < 0.05), while serum MMP-9 level significantly decreased at the second course of treatment in the EGFR-negative patients from the E group (P < 0.05). Serum VEGF level in the EGFR-positive patients among three groups slightly decreased at the first, second and third courses of treatments; however, the differences were not significant (P > 0.05). Serum MMP-9 level in the EGFR-positive patients among three groups showed mild decrease at the first and second courses of treatments; however, the decreases at the third course of treatment were significant (P < 0.05). Conclusion Serum VEGF and MMP-9 are potential biomarkers for the treatment monitoring of EGFR-positive and -negative patients after TACE therapy with different chemotherapeutic drugs.
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Affiliation(s)
- Shengya Cao
- Department of Clinical laboratory, Xuzhou Cancer Hospital, Xuzhou, Jiangsu 221005, People's Republic of China
| | - Shuo Zhu
- Department of Hepatobiliary Surgery, Xuzhou Cancer Hospital, Xuzhou, Jiangsu 221005, People's Republic of China
| | - Wei Yin
- Department of Clinical laboratory, Xuzhou Cancer Hospital, Xuzhou, Jiangsu 221005, People's Republic of China
| | - Heng Xu
- Laboratory of Pharmaceutical Chemistry, Jiangsu Province Institute of Materia Medica, Nanjing Tech University, Nanjing, Jiangsu 210000, People's Republic of China
| | - Jianzhong Wu
- Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210000, People's Republic of China
| | - Qiang Wang
- Department of Clinical laboratory, Xuzhou Cancer Hospital, Xuzhou, Jiangsu 221005, People's Republic of China.,Department of Radiotherapy, Xuzhou Cancer Hospital, Xuzhou, Jiangsu 221005, People's Republic of China
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23
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Fernandes GDS, Campos D, Ballalai A, Palhares R, da Silva MRA, Palhares DMF, Neto BHF, Barros FMDR, Gil RDA, Chagas A, Carrilho FJ. Epidemiological and Clinical Patterns of Newly Diagnosed Hepatocellular Carcinoma in Brazil: the Need for Liver Disease Screening Programs Based on Real-World Data. J Gastrointest Cancer 2020; 52:952-958. [PMID: 32918274 PMCID: PMC8376733 DOI: 10.1007/s12029-020-00508-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Purpose Describe sociodemographic and clinical characteristics of patients with hepatocellular carcinoma (HCC) and establish their history in the Brazilian public health system. Methods Retrospective observational study was conducted using the database from the Department of Informatics of the Unified Health System (DataSUS). Patients with at least one claim of HCC between July/2011 and June/2016 were included. A record linkage methodology was performed to obtain longitudinal data across different databases. Demographic and clinical data were evaluated, including the time elapsed between diagnosis of HCC risk-factors and the cancer development. Data was analyzed using descriptive statistics. Results A total of 28,822 HCC cases were identified between July/2011 and June/2016. Mean age was 59.7 years (SD = 14.7), and most patients were men (55.9%). The highest relative number of HCC cases was detected in the south of Brazil (> 20 cases/100,000 inhabitants). About 86.5% of the patients had diagnosis of HCC without previous liver diseases. Only 8% had diagnosis of chronic viral hepatitis and 3.5% cirrhosis. About 76% were diagnosed at an advanced stage, and only 11% of the patients had early stage HCC. Approximately 58% of patients with previous underlying liver diseases were diagnosed at early stages, compared with only 24% of patients without prior record of underlying diseases. Conclusion The diagnosis of HCC in the Brazilian public health is usually made in patients with no previous diagnosis of liver disease and in advanced stages, when no curative treatment is available and survival rates are low. Public health policies are key for the screening and monitoring liver disease and, consequently, HCC.
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Affiliation(s)
- Gustavo Dos Santos Fernandes
- Centro de Oncologia, Hospital Sírio-Libanês, SGAS 613/614, Conjunto E, Lote 95, Brasilia, DF, CEP 70200730, Brazil. .,Sociedade Brasileira de Oncologia Clínica, Sao Paulo, SP, Brazil.
| | | | | | | | - Mario R A da Silva
- Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel M F Palhares
- Centro de Oncologia, Hospital Sírio-Libanês, SGAS 613/614, Conjunto E, Lote 95, Brasilia, DF, CEP 70200730, Brazil
| | - Ben-Hur F Neto
- Consultant Surgeon at Diagnósticos da América SA (DASA) e Associação Brasileira de Linfoma e Leucemia (ABRALE), Sao Paulo, SP, Brazil
| | | | - Roberto de A Gil
- Serviço de Oncologia Clínica do INCA e Oncoclínica Centro de Tratamento Oncológico, Rio de Janeiro, RJ, Brazil
| | - Aline Chagas
- Hospital das Clínicas da Faculdade de Medicina da USP e Instituto do Câncer do Estado de São Paulo (ICESP), Sao Paulo, SP, Brazil
| | - Flair José Carrilho
- Hospital das Clínicas da Faculdade de Medicina da USP e Instituto do Câncer do Estado de São Paulo (ICESP), Sao Paulo, SP, Brazil
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Patel SS, Tripathi R, Chavda VK, Savjani JK. Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property. Anticancer Agents Med Chem 2020; 20:998-1008. [DOI: 10.2174/1871520620666200415100614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 10/25/2019] [Accepted: 02/18/2020] [Indexed: 12/11/2022]
Abstract
Background:
Numerous studies suggest that non-steroidal anti-inflammatory drugs reduce cancer
cell proliferation, progression, angiogenesis, apoptosis, and invasiveness.
Objective:
The current study focuses on the evaluation of novel mefenamic acid derivatives for the treatment of
hepatocellular carcinoma.
Methods:
Derivatives were subjected to molecular modeling for prediction of pharmacological activity using
software, followed by synthesis and in vitro assay. In in vivo study, disease was induced with N-Nitrosodiethylamine
followed by 2-acetylaminofluorene orally for 2 weeks. After 12 weeks of induction, treatment was given for a
period of one week. At the end of the treatment, determination of liver weight, a number of nodules, biochemical
parameters, immunohistochemistry, histopathology, and gene expression studies, were carried out.
Results:
Based on molecular docking score for PDGF-α (Platelet-Derived Growth Factor) and IC50 values in
HepG2 cell line study, JS-PFA was selected for the in vivo study where JS-PFA showed a statistically significant
reduction in a number of nodules and liver weight. Protective role of JS-PFA has been observed in tumorspecific
markers like α-fetoprotein, carcinoembryonic antigen, and lactate dehydrogenase levels. The JS-PFA
has shown a significant reduction in PDGF-α levels as well as liver markers and total bilirubin levels. Histopathological
analysis also showed a protective effect. The results of immunohistochemical analysis of P53 and
down-regulation of vascular endothelial growth factor and matrix metalloproteinases-9 genes suggest that derivative
inhibits PDGF mediated tumor growth and leads to apoptosis, inhibition of angiogenesis, and metastasis.
Conclusion:
The effectiveness of JS-PFA in our studies suggests targeting PDGF by COX 2 inhibitor can serve
as a novel treatment strategy for the treatment of HCC.
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Affiliation(s)
- Snehal S. Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Richa Tripathi
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Vishal K. Chavda
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
| | - Jignasa K. Savjani
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad-382 481, Gujarat, India
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Tomas K, Oguz S, Topaloglu S, Calik A, Arslan M, Dinç H, Ozdemir F, Kucukaslan H, Cobanoglu U, Karabulut E, ÖZtÜRk MH. Is it Rational to Perform Liver Resection for Patients with Intermediate and Advanced Stages of Hepatocellular Carcinoma? Am Surg 2020. [DOI: 10.1177/000313482008600427] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study aimed to investigate clinical characteristics of hepatocellular carcinoma and the outcome of our aggressive treatment policy which follows the Barcelona Clinic Liver Cancer (BCLC) guidance. In this study, we retrospectively analyzed data of 102 patients who were treated for hepatocellular carcinoma between January 2007 and October 2016. Male predominance (81.4%) and a median age of 61 years were observed. Cirrhosis was evident in 88.2 per cent of patients. Viral hepatitis (77.5%) was the most common underlying etiology. The majority of our patients (71.6%) were in BCLC B and C stages. Liver resection was performed in 53.4 per cent of patients in those stages. Transarterial chemoembolization was the leading interventional treatment. Overall survival rates at three and five years were 75 per cent and 75 per cent in BCLC 0, 69 per cent and 58 per cent in BCLC A, 50 per cent and 41 per cent in BCLC B, and 11 per cent and 11 per cent in BCLC C, respectively. The BCLC treatment algorithm should consider the role of liver resection also for intermediate stages.
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Affiliation(s)
- Kadir Tomas
- Department of Surgery, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Sukru Oguz
- Department of Radiology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Serdar Topaloglu
- Department of Surgery, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Adnan Calik
- Department of Surgery, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Mehmet Arslan
- Department of Gastroenterology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Hasan Dinç
- Department of Radiology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Feyyaz Ozdemir
- Department of Oncology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Hakan Kucukaslan
- Department of Surgery, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Umit Cobanoglu
- Department of Pathology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Erdem Karabulut
- Department of Biostatistics, Hacettepe University, Ankara, Turkey
| | - Mehmet Halil ÖZtÜRk
- Department of Radiology, School of Medicine, Karadeniz Technical University, Trabzon, Turkey
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Zhao J, Zhang X, Fang L, Pan H, Shi J. Association between IL28B Polymorphisms and Outcomes of Hepatitis B Virus Infection: A meta-analysis. BMC MEDICAL GENETICS 2020; 21:88. [PMID: 32357928 PMCID: PMC7195703 DOI: 10.1186/s12881-020-01026-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/14/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Interleukin (IL) 28B polymorphisms encoding pro-inflammatory and anti-inflammatory cytokines trigger diverse clinical outcome of hepatitis virus infection. However, there is controversy concerning the association of IL28B polymorphisms with the outcome of hepatitis B virus (HBV) infection, with several studies obtaining inconsistent results. We performed a meta-analysis to evaluate the role of 3 single nucleotide polymorphisms (SNPs) rs12979860, rs12980275 and rs8099917 in the progression of HBV infection, overall and by ethnicity. METHODS Searched PubMed, Embase and Wiley Online Library electronic databases using 'interleukin 28B', 'IL 28B', 'IL 28B polymorphism', 'hepatitis B virus', 'HBV', and performed meta- analysis for rs12979860, rs12980275 and rs8099917 in Asian and Caucasian populations under the dominant recessive and allele model. RESULTS Eighteen studies were found in total and used for this meta-analysis, including 5587 cases and 4295 controls. The IL28B polymorphism rs12979860 had no association with HBV persistence (CC vs CT + TT: OR = 0.86, 95% CI = 0.76-1.00; TT vs CT + CC: OR = 1.14, 95% CI = 0.76-1.70; T vs C: OR = 1.03, 95% CI = 0.94-1.13). Similarly, neither rs12980275 nor rs8099917 had associations with HBV persistence (rs12980275 in AA vs AG + AA: OR = 1.15, 95% CI = 0.96-1.38; rs8099917 in TT vs GT + GG: OR = 1.15, 95% CI = 0.96-1.39). There was also no significant association of IL28B polymorphisms with persistent HBV infection in Asians or Chinese. There was no evidence of an association of rs12979860 with the HBV-related hepatocellular carcinoma susceptibility (T vs C: OR = 1.53, 95% CI = 0.96-2.43). CONCLUSION IL28B polymorphisms had no association with the outcome of HBV infection overall, nor in the Asians and the Chinese. These 3 SNPs might not be relevant to the development of HBV infection.
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Affiliation(s)
- Jingyu Zhao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Xinyue Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Liwei Fang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Hong Pan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Jun Shi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China.
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Dinges SS, Hohm A, Vandergrift LA, Nowak J, Habbel P, Kaltashov IA, Cheng LL. Cancer metabolomic markers in urine: evidence, techniques and recommendations. Nat Rev Urol 2020; 16:339-362. [PMID: 31092915 DOI: 10.1038/s41585-019-0185-3] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Urinary tests have been used as noninvasive, cost-effective tools for screening, diagnosis and monitoring of diseases since ancient times. As we progress through the 21st century, modern analytical platforms have enabled effective measurement of metabolites, with promising results for both a deeper understanding of cancer pathophysiology and, ultimately, clinical translation. The first study to measure metabolomic urinary cancer biomarkers using NMR and mass spectrometry (MS) was published in 2006 and, since then, these techniques have been used to detect cancers of the urological system (kidney, prostate and bladder) and nonurological tumours including those of the breast, ovary, lung, liver, gastrointestinal tract, pancreas, bone and blood. This growing field warrants an assessment of the current status of research developments and recommendations to help systematize future research.
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Affiliation(s)
- Sarah S Dinges
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Haematology and Oncology, CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Annika Hohm
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Diagnostic and Interventional Neuroradiology, University Hospital of Würzburg, Würzburg, Germany
| | - Lindsey A Vandergrift
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Johannes Nowak
- Department of Diagnostic and Interventional Radiology, University Hospital of Würzburg, Würzburg, Germany
| | - Piet Habbel
- Department of Haematology and Oncology, CCM, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Igor A Kaltashov
- Department of Chemistry, University of Massachusetts-Amherst, Amherst, MA, USA.
| | - Leo L Cheng
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. .,Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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O'Keefe-Markman C, Lea KD, McCabe C, Hyshka E, Bubela T. Social values for health technology assessment in Canada: a scoping review of hepatitis C screening, diagnosis and treatment. BMC Public Health 2020; 20:89. [PMID: 31959155 PMCID: PMC6971980 DOI: 10.1186/s12889-020-8190-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/09/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Health care system decision makers face challenges in allocating resources for screening, diagnosis and treatment of hepatitis C. Approximately 240,000 individuals are infected with the hepatitis C virus (HCV) in Canada. Populations most affected by HCV include Indigenous people, people who inject drugs, immigrants and homeless or incarcerated populations as well as those born between 1946 and 1965. Curative but expensive drug regimens of novel direct acting antivirals (DAAs) are available. We aim to identify social values from academic literature for inclusion in health technology assessments. METHODS We conducted a scoping review of academic literature to identify and analyze the social values and evidence-based recommendations for screening, diagnosis and treatment of HCV in Canada. After applying inclusion/exclusion criteria, we abstracted: type of intervention(s), population(s) affected, study location, screening methods, diagnostics and treatments. We then abstracted and applied qualitative codes for social values. We extracted social value statements and clustered them into one of 4 categories: (1) equity and justice, (2) duty to provide care, (3) maximization of population benefit, and (4) individual versus community interests. RESULTS One hundred and eighteen articles met our inclusion criteria on screening, diagnosis and treatment of HCV in Canada. Of these, 54 (45.8%) discussed screening, 4 (3.4%) discussed diagnosis and 60 (50.8%) discussed treatment options. Most articles discussed the general population and other non-vulnerable populations. Articles that discussed vulnerable populations focused on people who inject drugs. We coded 1243 statements, most of which fell into the social value categories of equity and justice, duty to provide care and maximization of population benefit. CONCLUSION The academic literature identified an expanded set of social values to be taken into account by resource allocation decision makers in financially constrained environments. In the context of hepatitis C, authors called for greater consideration of equity and justice and the duty to provide care in making evidence-based recommendations for screening, diagnosis and treatment for different populations and in different settings that also account for individual and community interests.
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Affiliation(s)
| | - Kristina Dawn Lea
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Christopher McCabe
- Institute of Health Economics, Edmonton, AB, Canada
- Department of Emergency Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Elaine Hyshka
- School of Public Health, University of Alberta, Edmonton, AB, Canada
- Inner City Health and Wellness, Royal Alexandra Hospital, Edmonton, AB, Canada
| | - Tania Bubela
- Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
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Huang CC, Hwang JM, Tsai JH, Chen JH, Lin H, Lin GJ, Yang HL, Liu JY, Yang CY, Ye JC. Aqueous Ocimum gratissimum extract induces cell apoptosis in human hepatocellular carcinoma cells. Int J Med Sci 2020; 17:338-346. [PMID: 32132869 PMCID: PMC7053345 DOI: 10.7150/ijms.39436] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 11/10/2019] [Indexed: 01/30/2023] Open
Abstract
Treatment of advanced hepatocellular carcinoma (HCC) has exhibited a poor overall survival rate of only six to ten months, and the urgency of the development of more effective novel agents is ever present. In this line of research, we aimed to investigate the effects and inhibitive mechanisms of aqueous Ocimum gratissimum leaf extract (OGE), the extract of Ocimum gratissimum, which is commonly used as a therapeutic herb for its numerous pharmacological properties, on malignant HCC cells. Our results showed that OGE decreased the cell viability of HCC SK-Hep1 and HA22T cells in a dose-dependent manner (from 400 to 800 µg/mL), while there is little effect on Chang liver cells. Moreover, cell-cycle analysis shows increased Sub-G1 cell count in SK-Hep1 and HA22T cells which is not observed in Chang liver cells. These findings raise suspicion that the OGE-induced cell death may be mediated through proteins that regulate cell cycle and apoptosis in SK-Hep1 and HA22T cells, and further experimentation revealed that OGE treatment resulted in a dose-dependent decrease in caspase 3 and PARP expressions and in CDK4and p-ERK1/2expressions. Moreover, animal tests also exhibited decreased HCC tumor growth by OGE treatment. We therefore suggest that the inhibition of cell viability and tumor growth induced by OGE may be correlated to the alteration of apoptosis-related proteins.
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Affiliation(s)
- Chen-Cheng Huang
- Institute of Molecular Biology College of Life Science, National Chung Hsing University, Taichung, Taiwan
- Division of Chest Medicine, Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan
| | - Jin-Ming Hwang
- School of Applied Chemistry, Chung-Shan Medical University, Taichung 40201, Taiwan
| | - Jen-Hsiang Tsai
- Basic Medical Science Education Center, College of Medicine and Health, Fooyin University, Kaohsiung, Taiwan
| | - Jing Huei Chen
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Ho Lin
- Department of Life Science, National Chung Hsing University, Taichung, Taiwan
| | - Geng-Jhih Lin
- Department of Life Science, National Chung Hsing University, Taichung, Taiwan
| | - Hsin-Ling Yang
- Institute of Nutrition, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan
| | - Jer-Yuh Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chiou-Ying Yang
- Institute of Molecular Biology College of Life Science, National Chung Hsing University, Taichung, Taiwan
| | - Je-Chiuan Ye
- Department of Bachelor's Degree Program for Indigenous Peoples in Senior Health and Care Management, National Taitung University, Taitung, Taiwan
- Master Program in Biomedical Science, National Taitung University, Taitung, Taiwan
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30
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Cheng KC, Wang CJ, Chang YC, Hung TW, Lai CJ, Kuo CW, Huang HP. Mulberry fruits extracts induce apoptosis and autophagy of liver cancer cell and prevent hepatocarcinogenesis in vivo. J Food Drug Anal 2020; 28:84-93. [DOI: 10.1016/j.jfda.2019.06.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/15/2019] [Accepted: 06/04/2019] [Indexed: 12/13/2022] Open
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Long noncoding RNA AURKAPS1 potentiates malignant hepatocellular carcinoma progression by regulating miR-142, miR-155 and miR-182. Sci Rep 2019; 9:19645. [PMID: 31873123 PMCID: PMC6927972 DOI: 10.1038/s41598-019-56036-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/05/2019] [Indexed: 01/17/2023] Open
Abstract
The mitotic serine/threonine kinase aurora kinase-A (AURKA) has been identified as carcinogenic in hepatocellular carcinoma (HCC). AURKAPS1, a long non-coding RNA (lncRNA), is the pseudo-gene of AURKA, which play important roles in the cancer. Its underlying functions and mechanisms in liver cancer progression remain largely unknown. The mRNA expression of AURKAPS1 in HCC tumor tissues was significantly higher, which is associated with tumor size and TNM stage. The high expression of AURKAPS1 promotes cell movement, migration and invasion. AURKAPS1 can increases the protein expression of RAC1, promotes the activation of ERK, and enhance the formation of membrane ruffles by binding with miR-182, miR-155 and miR-142 competively. Thus, AURKAPS1 could be a useful marker, and the combination of AURKAPS1/miRNAs (miR-142, miR-155 and miR-182) may be a new theoretical basis for the treatment of HCC.
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32
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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33
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Su X, Su J, He H, Zhan Y, Liu H. Hsa_circ_0070269 inhibits hepatocellular carcinoma progression through modulating miR-182/NPTX1 axis. Biomed Pharmacother 2019; 120:109497. [PMID: 31606623 DOI: 10.1016/j.biopha.2019.109497] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 12/21/2022] Open
Abstract
Circular RNAs (circRNAs) have recently been shown to play critical roles in tumorigenesis. However, the roles of circRNAs in hepatocellular carcinoma (HCC) remain largely unknown. In the present study, we identified a novel circRNA (hsa_circ_0070269) was significantly decreased in HCC tissues and cell lines, low hsa_circ_0070269 expression was positively associated with advanced tumor stage, lymph node metastasis, and poor overall survival. Hsa_circ_0070269 overexpression suppressed proliferation and invasion of HCC cells in vitro and reduced tumor growth in vivo. Mechanistically, hsa_circ_0070269 increased NPTX1 expression via sponging miR-182 in HCC cells, which inhibited aggressive tumor behavior. Taken together, our findings suggest that hsa_circ_0070269 might play an important role in HCC development via miR-182/NPTX1 axis, therefore could serve as a potential therapeutic target for HCC treatment.
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Affiliation(s)
- Xiaotong Su
- Department of General Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471000, Henan, PR China.
| | - Jutong Su
- Luoyang Central Blood Station, Luoyang, 471000, Henan, PR China
| | - Hua He
- Department of General Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471000, Henan, PR China
| | - Yong Zhan
- Department of General Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471000, Henan, PR China
| | - Haichao Liu
- Department of General Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471000, Henan, PR China
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34
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Jin Y, Wong YS, Goh BKP, Chan CY, Cheow PC, Chow PKH, Lim TKH, Goh GBB, Krishnamoorthy TL, Kumar R, Ng TP, Chong SS, Tan HH, Chung AYF, Ooi LLPJ, Chang JPE, Tan CK, Lee CGL. Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma. Sci Rep 2019; 9:10464. [PMID: 31320713 PMCID: PMC6639394 DOI: 10.1038/s41598-019-46872-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3rd cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.
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Affiliation(s)
- Yu Jin
- Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Ye Shen Wong
- Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Brian K P Goh
- Department of Hepato-pancreato-biliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Chung Yip Chan
- Department of Hepato-pancreato-biliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Peng Chung Cheow
- Department of Hepato-pancreato-biliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - Pierce K H Chow
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.,Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Tony K H Lim
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - George B B Goh
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
| | | | - Rajneesh Kumar
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore.,Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Tze Pin Ng
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Samuel S Chong
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Laboratory Medicine, National University Hospital, Singapore, Singapore
| | - Hwee Huang Tan
- Blood Services Group, Health Sciences Authority, Singapore, Singapore
| | - Alexander Y F Chung
- Department of Hepato-pancreato-biliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore
| | - London Lucien P J Ooi
- Department of Hepato-pancreato-biliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore.,Duke-NUS Graduate Medical School, Singapore, Singapore
| | - Jason P E Chang
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore
| | - Chee Kiat Tan
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore.
| | - Caroline G L Lee
- Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore, Singapore. .,Duke-NUS Graduate Medical School, Singapore, Singapore. .,Department of Biochemistry, National University of Singapore, Singapore, Singapore.
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35
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Xing H, Qiu H, Ding X, Han J, Li Z, Wu H, Yan C, Li H, Han R, Zhang H, Li C, Wang M, Wu M, Shen F, Zheng Y, Yang T. Clinical performance of α-L-fucosidase for early detection of hepatocellular carcinoma. Biomark Med 2019; 13:545-555. [PMID: 31140827 DOI: 10.2217/bmm-2018-0414] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Aim: To evaluate the diagnostic performance of serum AFU for early stage hepatocellular carcinoma (HCC). Methods: Concentration of AFU and AFP were measured in 512 patients. The performance was compared for AFU and AFP alone or in combination. Results: The area under the curve (AUC) for AFU was 0.68, with a sensitivity of 56.1% and specificity of 69.2% at the cut-off value of 24 U/l; whereas the AUC for AFP was 0.83, with a sensitivity of 58.2% and specificity of 85.2% at cut-off value of 20 ng/ml. The AUC of AFU alone or the combination with AFP were lower than that of AFP alone. Conclusion: AFU is a suboptimal biomarker for early detection of HCC.
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Affiliation(s)
- Hao Xing
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Haibo Qiu
- Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Xuemei Ding
- Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Jun Han
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Zhenli Li
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Han Wu
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Cunling Yan
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, PR China
| | - Huijun Li
- Department of Laboratory Medicine, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, PR China
| | - Ruilin Han
- Department of Clinical Laboratory, Peking University First Hospital, Beijing, PR China
| | - Han Zhang
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Chao Li
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Mingda Wang
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Mengchao Wu
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
| | - Yijie Zheng
- Medical Scientific Affairs, Abbott Diagnostics, Shanghai, PR China
| | - Tian Yang
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China
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Hussein NAEM, El-Toukhy MAEF, Kazem AH, Ali MES, Ahmad MAER, Ghazy HMR, El-Din AMG. Protective and therapeutic effects of cannabis plant extract on liver cancer induced by dimethylnitrosamine in mice. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2014.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Affiliation(s)
- Neveen Abd El Moneim Hussein
- Applied Medical Chemistry, Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Mervat Abd El-Fattah El-Toukhy
- Applied Medical Chemistry, Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Amany Hussein Kazem
- Department of Pathology, Medical Research Institute, University of Alexandria, Alexandria, Egypt
| | - Mahmoud El-Said Ali
- Toxicology Department, Forensic Science College, Naif Arab University for Security Sciences, Saudi Arabia
| | | | - Hossam Mahmoud Rashad Ghazy
- Applied Medical Chemistry, Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Ahmed Mohamed Gamal El-Din
- Applied Medical Chemistry, Applied Medical Chemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
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Li Q, Liu XP, Wang DW, Shen YM, Jia Q, Liu WT. Brachytherapy using elastin-like polypeptide with different concentrations of 131I for treatment of VX2 liver tumor in rabbits. Shijie Huaren Xiaohua Zazhi 2019; 27:485-493. [DOI: 10.11569/wcjd.v27.i8.485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Brachytherapy is a targeted radiation therapy for cancer. The elastin-like peptide (ELP) is a genetically engineered peptide that has unique advantages such as self-assembly, temperature responsiveness, and non-immunogenicity, which make it possible to become the carrier of the radionuclide 131I.
AIM To evaluate the effectiveness of brachytherapy in a rabbit model of VX2 liver tumor using elastin-like polypeptide as a radionuclide 131I carrier and compare the effectiveness of 131I-ELP at different radioactive concentrations to provide evidence for its clinical application.
METHODS ELP as a carrier was labeled with 131I by the iodogen method, and different concentrations of 131I-ELP were prepared. Under ultrasound guidance, different concentrations of 131I-ELP and ELP solution were randomly injected into 15 rabbits with VX2 liver tumor for brachytherapy and blank control observation. The rabbits were divided into the following groups: high-dose radiation group (injection with 100 mCi/mL 131I-ELP; group H, n = 5); low-dose radiation group (injection with 50 mCi/mL 131I-ELP; group L, n = 5); and blank control group (injection with ELP solution; group C, n = 5). Periodic biochemical and sonographic examinations were performed to assess the therapeutic efficacy after treatment. Single-photon emission computed tomography/computed tomography (SPECT/CT) was additionally performed in the treatment groups. The natural survival time of animals in the three groups was determined. In addition, histopathological examination was performed.
RESULTS The survival time of animals was the longest in group H (61.4 d ± 10.50 d) and the shortest (39.2 d ± 5.63 d) in group C. The survival time of animals in group L was 52.6 d ± 8.85 d. Significant differences were observed in the survival time among the three groups (P < 0.05). At 7 and 14 d after treatment, SPECT/CT showed that 131I-ELP was continuously localized in liver tumors in groups H and L. The tumor growth rates in groups H and L were significantly lower than that in group C (P < 0.05). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) at 14 d after treatment in groups H and L were significantly lower than those in group C (P < 0.05). At 7 d after treatment, ALT level in group L was significantly lower than that in group H (P < 0.05). At 14 d after treatment, AST value in group L was significantly lower than that in group H (P < 0.05), suggesting that group L is better than group H with regard to ameliorating ALT and AST levels (P < 0.05). There were no significant differences in Hb or RBC levels between the three groups at 7 and 14 d after treatment. Histopathological examination showed that normal tissues around the tumor in group H were destroyed; proliferation of cord-like fibers, expansion of hepatic sinus, and dilatation of small bile ducts in the portal area were observed. In group L, no radioactive damage was observed in normal liver tissues around the tumor.
CONCLUSION 131I-ELP brachytherapy has curative effects in inhibiting tumor growth. 131I-ELP at a radiation dose of 100 mCi/mL inhibits tumor growth better than 131I-ELP at a radiation dose of 50 mCi/mL; however, the higher dose causes greater radiation damage to normal liver tissues around the tumor.
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Affiliation(s)
- Qian Li
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin-Pei Liu
- Department of Gastroenterology, the Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Duo-Wei Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yi-Ming Shen
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Qiang Jia
- Department of Nuclear Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wen-Tian Liu
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Qin Z, Xiang C, Zhong F, Liu Y, Dong Q, Li K, Shi W, Ding C, Qin L, He F. Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. J Exp Clin Cancer Res 2019; 38:154. [PMID: 30971297 PMCID: PMC6458711 DOI: 10.1186/s13046-019-1131-1] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 03/08/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Metabolic reprogramming is one of the hallmarks of cancer cells. The pentose phosphate pathway (PPP), a branch of glycolysis, is an important metabolic pathway for the survival and biosynthesis of cancer cells. Transketolase (TKT) is a key enzyme in the non-oxidative phase of PPP. The mechanistic details of TKT in hepatocellular carcinoma (HCC) development remain unclear. METHODS TKT level and subcellular location were examined in HCC cell lines and tissue samples. We established the TKT overexpression and knocking-down stable cells in HCC cell lines. Proliferation, migration, viability and enzyme activity assays in vitro, tumor growth and metastasis assays in vivo were employed to test the effects of TKT on HCC development. GFP-tagged TKT truncations and mutants were used to locate the nuclear localization sequence (NLSs) of TKT. Cross-linking co-IP/MS was applied to identify the interaction proteins of nuclear TKT. RESULTS We showed that TKT increased the proliferation and migration of HCC cells, as well as the viability under oxidative stress in vitro and accelerated the growth and metastasis of HCC cells in vivo. We found as a key enzyme of PPP, TKT could promote the proliferation, cell cycle, migration and viability by regulating the metabolic flux. Moreover, it was firstly reported that unlike other key enzymes in PPP, TKT showed a strong nuclear localization in HCC cells. We found not only high TKT expression, but also its nuclear localization was a prediction for poor prognosis of HCC patients. We further identified the nuclear localization sequences (NLS) for TKT and demonstrated the NLS mutations decreased the pro-tumor function of TKT independent of the enzyme activity. Cross-linking Co-IP/MS showed that nuclear TKT interacted with kinases and transcriptional coregulators such as EGFR and MAPK3, which are associated with cell activation or stress response processes. EGF treatment significantly increased the viability and proliferation of HCC cells in the enzyme-inactivating mutation TKT-D155A overexpression cells but not in the NLS-D155A double mutant group, which could be blocked by EGFR inhibitor erlotinib treatment. CONCLUSIONS Our research suggests that in addition to the metabolic manner, TKT can promote the development of HCC in a non-metabolic manner via its nuclear localization and EGFR pathway.
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Affiliation(s)
- Zhaoyu Qin
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032 China
| | - Chan Xiang
- Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030 China
| | - Fan Zhong
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032 China
| | - Yang Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032 China
| | - Qiongzhu Dong
- Department of Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200040 China
| | - Kai Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, 102206 China
| | - Wenhao Shi
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, 102206 China
| | - Chen Ding
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032 China
| | - Lunxiu Qin
- Department of Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai, 200040 China
| | - Fuchu He
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032 China
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing, 102206 China
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Madduru D, Ijaq J, Dhar S, Sarkar S, Poondla N, Das PS, Vasquez S, Suravajhala P. Systems Challenges of Hepatic Carcinomas: A Review. J Clin Exp Hepatol 2019; 9:233-244. [PMID: 31024206 PMCID: PMC6477144 DOI: 10.1016/j.jceh.2018.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is ubiquitous in its prevalence in most of the developing countries. In the era of systems biology, multi-omics has evinced an extensive approach to define the underlying mechanism of disease progression. HCC is a multifactorial disease and the investigation of progression of liver cirrhosis becomes much extensive with cultivating omics approaches. We have performed a comprehensive review about such challenges in multi-omics approaches that are concerned to identify the immunological, genetics and epidemiological factors associated with HCC.
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Affiliation(s)
- Dhatri Madduru
- Department of Biochemistry, Osmania University, Hyderabad 500007, TG, India
- Bioclues.org
| | - Johny Ijaq
- Department of Genetics and Biotechnology, Osmania University, Hyderabad 500007, TG, India
- Bioclues.org
| | | | | | | | - Partha S. Das
- Bioclues.org
- Patient MD, Chicago, IL 60640-5710, United States
| | - Silvia Vasquez
- Bioclues.org
- Instituto Peruano de Energía Nuclear, Avenida Canadá 1470, Lima, Peru
| | - Prashanth Suravajhala
- Bioclues.org
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle 302001, RJ, India
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40
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Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 2019; 128:184-194. [PMID: 30611768 DOI: 10.1016/j.micpath.2019.01.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
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Kaltenecker D, Themanns M, Mueller KM, Spirk K, Golob-Schwarzl N, Friedbichler K, Kenner L, Haybaeck J, Moriggl R. STAT5 deficiency in hepatocytes reduces diethylnitrosamine-induced liver tumorigenesis in mice. Cytokine 2018; 124:154573. [PMID: 30377054 DOI: 10.1016/j.cyto.2018.10.014] [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: 08/23/2018] [Revised: 10/03/2018] [Accepted: 10/18/2018] [Indexed: 02/06/2023]
Abstract
Chronic liver diseases and the development of hepatocellular carcinoma are closely linked and pose a major medical challenge as treatment options are limited. Animal studies have shown that genetic deletion of the signal transducer and activator of transcription (STAT) 5 in liver is associated with higher susceptibility to fatty liver disease, fibrosis and cancer, indicating a protective role of hepatic STAT5 in mouse models of chronic liver disease. To investigate the role of STAT5 in the etiology of liver cancer in more detail, we applied the chemical carcinogen diethylnitrosamine (DEN) to mice harboring a hepatocyte-specific deletion of Stat5 (S5KO). At 8 months after DEN injections, tumor formation in S5KO was significantly reduced. This was associated with diminished tumor frequency and less aggressive liver cancer progression. Apoptosis and inflammation markers were not changed in S5KO livers suggesting that the reduced tumor burden was not due to impaired inflammatory response. Despite reduced mRNA expression of the DEN bio-activator cytochrome P450 2e1 (Cyp2e1) in S5KO livers, protein levels were similar. Yet, delayed tumor formation in S5KO mice coincided with decreased activation of c-Jun N-terminal Kinase (JNK). Taken together, while STAT5 has a protective role in fatty liver-associated liver cancer, it exerts oncogenic functions in DEN-induced liver cancer.
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Affiliation(s)
- Doris Kaltenecker
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Madeleine Themanns
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Kristina M Mueller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Katrin Spirk
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
| | - Nicole Golob-Schwarzl
- Center for Biomarker Research in Medicine, Graz, Austria; Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Lukas Kenner
- Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria; Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria; CBMed Core Lab2, Medical University of Vienna, Vienna, Austria
| | - Johannes Haybaeck
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria
| | - Richard Moriggl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; Medical University of Vienna, Vienna, Austria.
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Kimura H, Matsunaga N, Kakimoto K, Watanabe M, Tsuruta A, Kusunose N, Shiromizu S, Koyanagi S, Ohdo S. Epithelial cell adhesion molecule expression in hepatic stem/progenitor cells is controlled by the molecular clock system. Biochem Biophys Res Commun 2018; 503:1063-1069. [PMID: 29958886 DOI: 10.1016/j.bbrc.2018.06.117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 06/20/2018] [Indexed: 01/02/2023]
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Chen H, Zhang Y, Li S, Li N, Chen Y, Zhang B, Qu C, Ding H, Huang J, Dai M. Direct comparison of five serum biomarkers in early diagnosis of hepatocellular carcinoma. Cancer Manag Res 2018; 10:1947-1958. [PMID: 30022853 PMCID: PMC6044429 DOI: 10.2147/cmar.s167036] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although a number of serum biomarkers for detection of hepatocellular carcinoma (HCC) have been explored, their exact diagnostic value remains unclear. We aimed to conduct a direct comparison of five representative serum biomarkers for detecting HCC and to derive multi-marker prediction algorithms. PATIENTS AND METHODS In total, 846 patients were recruited from three hospitals in China, including 202 HCC patients, 226 liver cirrhosis patients, 215 chronic hepatitis B virus-infected patients, and 203 healthy volunteers. Serum levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), squamous cell carcinoma antigen, and centromere protein F autoantibody were measured by ELISA. The diagnostic performances of individual biomarkers and multi-marker combinations were evaluated by receiver operating characteristics analysis. The bootstrapping method was adopted to adjust for potential overfitting of all diagnostic indicators. RESULTS DCP exhibited the best diagnostic performance, with areas under the curve (AUC) for detecting HCC of 0.82 (95% CI 0.64-0.80) and sensitivity of 65.2% (95% CI 63.3-82.1%) at 90% specificity. Of note, DCP showed similar diagnostic efficacy for detecting AFP-positive and AFP-negative HCC. After a comprehensive search for multi-marker combinations, a two-marker prediction algorithm including AFP and DCP was constructed and yielded an AUC of 0.87 (95% CI 0.68-0.84) for detecting HCC. In addition, the combination showed good ability in discriminating early-stage HCC and decompensated liver cirrhosis, with an AUC of 0.81 (95% CI 0.75-0.86). CONCLUSION DCP could be a complementary biomarker in the early diagnosis of HCC. The constructed multi-marker prediction algorithms could contribute toward distinguishing HCC from non-malignant chronic liver diseases.
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Affiliation(s)
- Hongda Chen
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
| | - Yue Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
- Office of Scientific Research, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Siwen Li
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China,
| | - Ni Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
| | - Yuhan Chen
- Department of Gastrointestinal and Hepatology, Beijing You' An Hospital Affiliated to Capital Medical University, Beijing, China
| | - Bei Zhang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China,
| | - Chunfeng Qu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
| | - Huiguo Ding
- Department of Gastrointestinal and Hepatology, Beijing You' An Hospital Affiliated to Capital Medical University, Beijing, China
| | - Jian Huang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China,
- National Clinical Research Center of Digestive Diseases, Beijing, China,
| | - Min Dai
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,
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Kim E, Kim D, Lee JS, Yoe J, Park J, Kim CJ, Jeong D, Kim S, Lee Y. Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4-MMP1 axis. Hepatology 2018; 67:2287-2301. [PMID: 29251790 DOI: 10.1002/hep.29738] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 12/24/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signaling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor, Capicua (CIC), as a suppressor of HCC progression and a potential therapeutic target. Expression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. Levels of polyoma enhancer activator 3 (PEA3) group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETS translocation variant 4 (ETV4) is the most significantly up-regulated in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, it induces expression of matrix metalloproteinase 1 (MMP1), the MMP gene highly relevant to HCC progression, in HCC cells; and knockdown of MMP1 completely blocks the CIC deficiency-induced HCC cell proliferation and invasion. CONCLUSION Our study demonstrates that the CIC-ETV4-MMP1 axis is a regulatory module controlling HCC progression. (Hepatology 2018;67:2287-2301).
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Affiliation(s)
- Eunjeong Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Donghyo Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jeon-Soo Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jeehyun Yoe
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Jongmin Park
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Chang-Jin Kim
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea
| | - Dongjun Jeong
- Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea.,Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Cheonan, Chungnam, Republic of Korea
| | - Sanguk Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.,Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
| | - Yoontae Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea.,Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, Republic of Korea
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Freitas N, Lukash T, Gunewardena S, Chappell B, Slagle BL, Gudima SO. Relative Abundance of Integrant-Derived Viral RNAs in Infected Tissues Harvested from Chronic Hepatitis B Virus Carriers. J Virol 2018; 92:e02221-17. [PMID: 29491161 PMCID: PMC5923063 DOI: 10.1128/jvi.02221-17] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 02/17/2018] [Indexed: 02/07/2023] Open
Abstract
Five matching sets of nonmalignant liver tissues and hepatocellular carcinoma (HCC) samples from individuals chronically infected with hepatitis B virus (HBV) were examined. The HBV genomic sequences were determined by using overlapping PCR amplicons covering the entire viral genome. Four pairs of tissues were infected with HBV genotype C, while one pair was infected with HBV genotype B. HBV replication markers were found in all tissues. In the majority of HCC samples, the levels of pregenomic/precore RNA (pgRNA) and covalently closed circular DNA (cccDNA) were lower than those in liver tissue counterparts. Regardless of the presence of HBV replication markers, (i) integrant-derived HBV RNAs (id-RNAs) were found in all tissues by reverse transcription-PCR (RT-PCR) analysis and were considerably abundant or predominant in 6/10 tissue samples (2 liver and 4 HCC samples), (ii) RNAs that were polyadenylated using the cryptic HBV polyadenylation signal and therefore could be produced by HBV replication or derived from integrated HBV DNA were found in 5/10 samples (3 liver and 2 HCC samples) and were considerably abundant species in 3/10 tissues (2 livers and 1 HCC), and (iii) cccDNA-transcribed RNAs polyadenylated near position 1931 were not abundant in 7/10 tissues (2 liver and 5 HCC samples) and were predominant in only two liver samples. Subsequent RNA sequencing analysis of selected liver/HCC samples also showed relative abundance of id-RNAs in most of the examined tissues. Our findings suggesting that id-RNAs could represent a significant source of HBV envelope proteins, which is independent of viral replication, are discussed in the context of the possible contribution of id-RNAs to the HBV life cycle.IMPORTANCE The relative abundance of integrant-derived HBV RNAs (id-RNAs) in chronically infected tissues suggest that id-RNAs coding for the envelope proteins may facilitate the production of a considerable fraction of surface antigens (HBsAg) in infected cells bearing HBV integrants. If the same cells support HBV replication, then a significant fraction of assembled HBV virions could bear id-RNA-derived HBsAg as a major component of their envelopes. Therefore, the infectivity of these HBV virions and their ability to facilitate virus cell-to-cell spread could be determined mainly by the properties of id-RNA-derived envelope proteins and not by the properties of replication-derived HBsAg. These interpretations suggest that id-RNAs may play a role in the maintenance of chronic HBV infection and therefore contribute to the HBV life cycle. Furthermore, the production of HBsAg from id-RNAs independently of viral replication may explain at least in part why treatment with interferon or nucleos(t)ides in most cases fails to achieve a loss of serum HBsAg.
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Affiliation(s)
- Natalia Freitas
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Tetyana Lukash
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Sumedha Gunewardena
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Benjamin Chappell
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Betty L Slagle
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
| | - Severin O Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
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Hu J, Hu J, Jiao H, Li Q. Anesthetic effects of isoflurane and the molecular mechanism underlying isoflurane‑inhibited aggressiveness of hepatic carcinoma. Mol Med Rep 2018; 18:184-192. [PMID: 29749446 PMCID: PMC6059668 DOI: 10.3892/mmr.2018.8945] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 11/02/2017] [Indexed: 02/06/2023] Open
Abstract
Anesthesia is produced by drugs or other methods, and refers to the attenuation of pain via reversible suppression of neuronal transmission in the central and peripheral nervous systems, during surgery. Clinical investigations have indicated that the anesthetic action of isoflurane is efficient to alleviate pain during tumor resection clinical trials. In addition, it has been reported that isoflurane can induce caspase-3 activation and is associated with apoptosis of tumor cells. The present study investigated the anesthetic effects and molecular mechanisms underlying isoflurane-induced apoptosis in patients with hepatic carcinoma. Furthermore, the pain of patients with hepatic carcinoma was evaluated during the perioperative period according to the pain index. The apoptotic rate of hepatic carcinoma cells was analyzed in tumor tissues using TUNEL assay. The expression levels of apoptosis-associated proteins were detected in liver cancer cells following anesthesia in patients. Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and nuclear factor (NF)-κB signaling pathways were also analyzed in liver cancer cells following treatment with isoflurane. The results demonstrated that isoflurane inhibited growth and decreased viability of liver cancer cells in vitro and in vivo. In addition, the apoptotic rate was increased in cells obtained from isoflurane-treated patients. The results also demonstrated that isoflurane upregulated the expression levels of proapoptotic genes and downregulated anti-apoptotic mRNA expression. In addition, a molecular mechanism analysis indicated that isoflurane inhibited PI3K and AKT expression in liver cancer cells. Isoflurane also induced caspase-3 activation in liver cancer cells. Furthermore, isoflurane treatment attenuated NF-κB activity and inhibited migration and invasion of liver cancer cells. In conclusion, these findings indicated that isoflurane treatment efficiently attenuated surgical pain and inhibited tumor aggressiveness via regulation of NF-κB activity and the PI3K/AKT signaling pathway, thus suggesting that isoflurane is an efficient anesthetic drug that induces pain remission and promotes apoptosis of liver cancer cells.
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Affiliation(s)
- Jing Hu
- Department of Anesthesiology, Linyi Cancer Hospital, Linyi, Shandong 276001, P.R. China
| | - Jingli Hu
- Department of Anesthesiology, Linyi Cancer Hospital, Linyi, Shandong 276001, P.R. China
| | - Hongmei Jiao
- Department of Anesthesiology, Linyi Cancer Hospital, Linyi, Shandong 276001, P.R. China
| | - Qingguo Li
- Department of Anesthesiology, Linyi Cancer Hospital, Linyi, Shandong 276001, P.R. China
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Singer AW, Reddy KR, Telep LE, Osinusi AO, Brainard DM, Buti M, Chokkalingam AP. Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. Aliment Pharmacol Ther 2018. [PMID: 29516535 DOI: 10.1111/apt.14593] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment. AIMS The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data. METHODS From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods. RESULTS Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon-based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81). CONCLUSIONS In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent.
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Affiliation(s)
- A W Singer
- Gilead Sciences Inc., Foster City, CA, USA
| | - K R Reddy
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - L E Telep
- Gilead Sciences Inc., Foster City, CA, USA
| | | | | | - M Buti
- Hospital General Universitari Vall d'Hebron, Barcelona, Spain
| | - A P Chokkalingam
- Gilead Sciences Inc., Foster City, CA, USA.,School of Public Health, University of California, Berkeley, CA, USA
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Djokic M, Cemazar M, Popovic P, Kos B, Dezman R, Bosnjak M, Zakelj MN, Miklavcic D, Potrc S, Stabuc B, Tomazic A, Sersa G, Trotovsek B. Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2018; 44:651-657. [PMID: 29402556 DOI: 10.1016/j.ejso.2018.01.090] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 12/21/2017] [Accepted: 01/16/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy. PATIENTS AND METHODS Electrochemotherapy with bleomycin was performed on 17 hepatocellular carcinomas in 10 patients using a previously established protocol. The procedure was performed during open surgery and the patients were followed for median 20.5 months. RESULTS Electrochemotherapy was feasible for all 17 lesions, and no treatment-related adverse events or major post-operative complications were observed. The median size of the treated lesions was 24 mm (range 8-41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally. The complete response rate at 3-6 months was 80% per patient and 88% per treated lesion. CONCLUSIONS Electrochemotherapy of hepatocellular carcinoma proved to be a feasible and safe treatment in all 10 patients included in this study. To evaluate the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment are encouraging, in 15 out of 17 lesions complete response was obtained. Electrochemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/perioperative risk for high morbidity and mortality.
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Affiliation(s)
- Mihajlo Djokic
- University Medical Centre Ljubljana, Department of Abdominal Surgery, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Maja Cemazar
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia; University of Primorska, Faculty of Health Sciences, Polje 42, SI-6310 Izola, Slovenia
| | - Peter Popovic
- University Medical Centre Ljubljana, Institute of Radiology, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Bor Kos
- University of Ljubljana, Faculty of Electrical Engineering, Trzaska 25, Ljubljana SI-1000, Slovenia
| | - Rok Dezman
- University Medical Centre Ljubljana, Institute of Radiology, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Masa Bosnjak
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia
| | - Martina Niksic Zakelj
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia
| | - Damijan Miklavcic
- University of Ljubljana, Faculty of Electrical Engineering, Trzaska 25, Ljubljana SI-1000, Slovenia
| | - Stojan Potrc
- University Clinical Centre Maribor, Department of Abdominal Surgery, Ljubljanska ulica 5, SI-2000 Maribor, Slovenia
| | - Borut Stabuc
- University Medical Centre Ljubljana, Department of Gastroenterology, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Ales Tomazic
- University Medical Centre Ljubljana, Department of Abdominal Surgery, Zaloska 7, SI-1000 Ljubljana, Slovenia
| | - Gregor Sersa
- Institute of Oncology Ljubljana, Department of Experimental Oncology, Zaloska 2, SI-1000 Ljubljana, Slovenia; University of Ljubljana, Faculty of Health Sciences, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia.
| | - Blaz Trotovsek
- University Medical Centre Ljubljana, Department of Abdominal Surgery, Zaloska 7, SI-1000 Ljubljana, Slovenia.
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Gu L, Wen W, Wu Z, Bai K, Liu W, Lai G, Li D. Abnormal platelet count correlates with poor survival in hepatocellular carcinoma. INFECTION INTERNATIONAL 2018. [DOI: 10.1515/ii-2017-0160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractBackgroundNormal platelet (PLT) plays a vital role in thrombosis, the inflammatory response, and liver regeneration. The effect of abnormal PLT counts has been seldom explored in hepatocellular carcinoma (HCC); hence, this investigation was conducted to evaluate the prognostic importance of preoperative abnormal PLT count in HCC patients after liver resection retrospectively.MethodologyThe PLT counts were determined using Sysmex XT-1800i automated hematology analyzer and its matching reagents. Patients were divided into two groups: a normal PLT group and an abnormal PLT group. Chi-square test, Kaplan–Meier method, and Cox univariable and multivariable regressions were utilized to analyze the data.ResultsA total of 391 HCC patients who underwent liver resection were included in this study. The overall survival (OS) rates were 59% and 31%, and the median survival time was 69 months and 31 months in the normal and abnormal PLT groups, respectively. The PLT level was associated with OS in univariate and multivariate analyses (hazard ratio [HR], 1.991 [95% confidence interval {CI}, 1.412–2.808] and HR, 2.217 [95% CI, 1.556–3.159], respectively).ConclusionsPatients with normal PLT had a better outcome in terms of OS. The results suggested that abnormal PLT count is an independent prognostic factor for HCC patients after liver resection.
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Wang L, Chen C, Feng S, Tian J. TIPE‑2 suppresses growth and aggressiveness of hepatocellular carcinoma cells through downregulation of the phosphoinositide 3‑kinase/AKT signaling pathway. Mol Med Rep 2018; 17:7017-7026. [PMID: 29568863 PMCID: PMC5928656 DOI: 10.3892/mmr.2018.8789] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 12/14/2017] [Indexed: 12/13/2022] Open
Abstract
Rapid proliferation and migration are the main features of hepatocellular carcinoma (HCC) cells, which serve an essential role in carcinogenesis and are a hallmark of cancer therapy resistance. Previous studies have reported that tumor necrosis factor-α-induced protein-8 like-2 (TIPE-2) is involved in cancer initiation and the progression of HCC. The present study aimed to clarify the role of TIPE-2 in HCC carcinogenesis, growth and aggressiveness. The effects of TIPE-2 on HCC were determined using colony forming and cell cycle analyses. Cell apoptosis, and growth and aggressiveness of HCC cells, were investigated following TIPE-2 treatment. Treatment with TIPE-2 markedly suppressed HCC cell proliferation and increased the number of cells in S phase of the cell cycle. The results demonstrated that TIPE-2 significantly inhibited growth, migration and invasion of HCC cells via the downregulation of tumor metastasis-associated genes. Flow cytometric analysis indicated that TIPE-2 promoted apoptosis of HCC cells via regulation of apoptosis-associated gene transcription. In addition, TIPE-2 administration downregulated the expression of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. In addition, TIPE-2 selectively decreased neuroblastoma Ras viral oncogene and p27 expression in HCC cells. In vivo assays revealed that TIPE-2 significantly inhibited tumor growth and prolonged animal survival by promoting apoptosis of tumor cells. The results of the present study indicated that TIPE-2 acts as an inhibitor of HCC cell growth and aggressiveness, and promotes apoptosis, thus suggesting that TIPE-2 may inhibit the metastasis-associated PI3K/AKT signaling cascade and may arrest the tumor cell cycle. These findings provide a potential molecular mechanism by which TIPE-2 promotes apoptosis of HCC cells.
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Affiliation(s)
- Lin Wang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China
| | - Chen Chen
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China
| | - Shuzhi Feng
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China
| | - Jianli Tian
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin 300052, P.R. China
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