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1
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Wan DD, Li XJ, Wang XR, Liu TX. Metachronous multifocal carcinoma: A case report. World J Gastrointest Oncol 2024; 16:3350-3356. [PMID: 39072183 PMCID: PMC11271799 DOI: 10.4251/wjgo.v16.i7.3350] [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: 03/31/2024] [Revised: 05/06/2024] [Accepted: 05/21/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND The incidence of multiple primary carcinomas (MPC) varies greatly, ranging from 0.73% to 11.70% in foreign countries, with duo-duplex carcinoma being the most common, trio-duplex carcinoma and above being rare, and simultaneous multigenic carcinoma being even rarer, accounting for 18.4% to 25.3% of the incidence of MPC. However, there is no report regarding patients presenting with simultaneous dual-origin carcinoma of the liver and colon and heterochronous pancreatic cancer. CASE SUMMARY We report a special case of multifocal carcinoma, in which one patient had a medical condition of primary liver and colon cancer and pancreatic cystadenocarcinoma 2 years after surgery. Through aggressive advanced fluorescent laparoscopic techniques, standardized immunotherapy, targeting, and chemotherapy, a better prognosis and a desirable survival period were achieved for the patient. CONCLUSION There is a need to clarify the nature of MPC through advanced surgical means to ensure better diagnosis and treatment.
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Affiliation(s)
- Dan-Dan Wan
- School of Clinical Medicine, Qujing Medical College, Qujing 655000, Yunnan Province, China
| | - Xiao-Ju Li
- Department of Hepatobiliary Surgery, Qujing Second People’s of Yunnan Province, Qujing 655000, Yunnan Province, China
| | - Xing-Ru Wang
- Institute of Hepatobiliary Surgery, The First Affiliated Hospital, Army Medical University, Chongqing 400038, China
| | - Tian-Xi Liu
- Department of Hepatobiliary Surgery, Qujing Central Hospital of Yunnan Regional Medical Center, Qujing 655000, Yunnan Province, China
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2
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Adugna A. Histomolecular characterisation of hepatitis B virus induced liver cancer. Rev Med Virol 2023; 33:e2485. [PMID: 37902197 DOI: 10.1002/rmv.2485] [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: 05/28/2023] [Revised: 08/06/2023] [Accepted: 09/26/2023] [Indexed: 10/31/2023]
Abstract
Hepatitis B virus (HBV)-associated liver cancer is the third most prevalent cancer-related cause of death worldwide. Different studies have been done on the histomolecular analysis of HBV induced-liver cancer including epigenetics which are dynamic molecular mechanisms to control gene expression without altering the host deoxyribonucleic acid, genomics characterise the integration of the viral genome with host genome, proteomics characterise how gene modifies and results overexpression of proteins, glycoproteomics discover different glyco-biomarker candidates and show glycosylation in malignant hepatocytes, metabolomics characterise how HBV impairs a variety of metabolic functions during hepatocyte immortalisation, exosomes characterise immortalised liver cells in terms of their differentiation and proliferation, and autophagy plays a role in the development of hepatocarcinogenesis linked to HBV infection.
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Affiliation(s)
- Adane Adugna
- Medical Microbiology, Medical Laboratory Sciences, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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3
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Arriola-Montenegro J, Beas R, Cerna-Viacava R, Chaponan-Lavalle A, Hernandez Randich K, Chambergo-Michilot D, Flores Sanga H, Mutirangura P. Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease. World J Cardiol 2023; 15:328-341. [PMID: 37576545 PMCID: PMC10415861 DOI: 10.4330/wjc.v15.i7.328] [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: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.
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Affiliation(s)
- Jose Arriola-Montenegro
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
| | - Renato Beas
- Department of Medicine, Indiana University School of Medicine, Indiana, IN 46202, United States
| | | | | | | | | | - Herson Flores Sanga
- Department of Telemedicine, Cardiology, Hospital Nacional Carlos Alberto Seguin Escobedo, Arequipa 8610, Peru
| | - Pornthira Mutirangura
- Department of Medicine, University of Minnesota, Minneapolis, MN 55415, United States
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Sukumaran S, Tan M, Ben-Uliel SF, Zhang H, De Zotti M, Chua MS, So SK, Qvit N. Rational design, synthesis and structural characterization of peptides and peptidomimetics to target Hsp90/Cdc37 interaction for treating hepatocellular carcinoma. Comput Struct Biotechnol J 2023; 21:3159-3172. [PMID: 37304004 PMCID: PMC10250827 DOI: 10.1016/j.csbj.2023.05.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/23/2023] [Accepted: 05/23/2023] [Indexed: 06/13/2023] Open
Abstract
Heat shock protein 90 (Hsp90) and cell division cycle 37 (Cdc37) work together as a molecular chaperone complex to regulate the activity of a multitude of client protein kinases. These kinases belong to a wide array of intracellular signaling networks that mediate multiple cellular processes including proliferation. As a result, Hsp90 and Cdc37 represent innovative therapeutic targets in various cancers (such as leukemia, multiple myeloma, and hepatocellular carcinoma (HCC)) in which their expression levels are elevated. Conventional small molecule Hsp90 inhibitors act by blocking the conserved adenosine triphosphate (ATP) binding site. However, by targeting less conserved sites in a more specific manner, peptides and peptidomimetics (modified peptides) hold potential as more efficacious and less toxic alternatives to the conventional small molecule inhibitors. Using a rational approach, we herein developed bioactive peptides targeting Hsp90/Cdc37 interaction. A six amino acid linear peptide derived from Cdc37, KTGDEK, was designed to target Hsp90. We used in silico computational docking to first define its mode of interaction, and binding orientation, and then conjugated the peptide with a cell penetrating peptide, TAT, and a fluorescent dye to confirm its ability to colocalize with Hsp90 in HCC cells. Based on the parent linear sequence, we developed a peptidomimetics library of pre-cyclic and cyclic derivatives. These peptidomimetics were evaluated for their binding affinity to Hsp90, and bioactivity in HCC cell lines. Among them, a pre-cyclic peptidomimetic demonstrates high binding affinity and bioactivity in HCC cells, causing reduced cell proliferation that is associated with induction of cell apoptosis, and down-regulation of phosphorylated MEK1/2. Overall, this generalized approach of rational design, structural optimization, and cellular validation of 'drug-like' peptidomimetics against Hsp90/Cdc37 offers a feasible and promising way to design novel therapeutic agents for malignancies and other diseases that are dependent on this molecular chaperone complex.
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Affiliation(s)
- Surya Sukumaran
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel
| | - Mingdian Tan
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Palo Alto, CA 94305, USA
| | - Shulamit Fluss Ben-Uliel
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel
| | - Hui Zhang
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Palo Alto, CA 94305, USA
| | - Marta De Zotti
- Department of Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy
| | - Mei-Sze Chua
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Palo Alto, CA 94305, USA
| | - Samuel K. So
- Asian Liver Center, Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, Palo Alto, CA 94305, USA
| | - Nir Qvit
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Henrietta Szold St. 8, Safed 1311502, Israel
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5
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Shi K, Bi Y, Zeng X, Wang X. Effects of adjuvant huaier granule therapy on survival rate of patients with hepatocellular carcinoma. Front Pharmacol 2023; 14:1163304. [PMID: 37251326 PMCID: PMC10213905 DOI: 10.3389/fphar.2023.1163304] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
Objective: Clinical trials have reported that Huaier granule inhibits the recurrence of hepatocellular carcinoma (HCC) after resection. However, its efficacy in patients at different clinical stages of HCC remains unknown. We investigated the effects of Huaier granule on the 3-year overall survival (OS) rate of patients at different clinical stages. Design: This cohort study included 826 patients with HCC, screened between January 2015 and December 2019. The patients were divided into Huaier (n = 174) and control groups (n = 652), and the 3-year OS rates were compared between the two groups. To eliminate bias caused by confounding factors, propensity score matching (PSM) was performed. We used the Kaplan-Meier method to estimate OS rate and tested the difference using the log-rank test. Results: Multivariable regression analysis revealed that Huaier therapy was an independent protective factor for 3-year survival rate. After PSM (1:2), the Huaier and control groups comprised 170 and 340 patients, respectively. The 3-year OS rate was remarkably higher in the Huaier group than in the control group (adjusted hazard ratio [aHR]: 0.36; 95% confidence interval: 0.26-0.49; p < 0.001). The aHR for Huaier use for 3-12, 12-24, and >24 months was 0.48, 0.23, and 0.16, respectively, indicating a dose-response pattern. For the 3-12-, 12-24-, and >24-month groups, the 3-year OS rate was 54.1%, 68.6%, and 90.4%, respectively. Multivariate stratified analysis confirmed that the mortality risk in Huaier users was lower than that in non-Huaier users in most subgroups. Conclusion: Adjuvant Huaier therapy improved the OS rate in patients with HCC. However, these findings require further verification through prospective clinical studies.
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Verma S, Sahu BD, Mugale MN. Role of lncRNAs in hepatocellular carcinoma. Life Sci 2023; 325:121751. [PMID: 37169145 DOI: 10.1016/j.lfs.2023.121751] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/21/2023] [Accepted: 04/29/2023] [Indexed: 05/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies.
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Affiliation(s)
- Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bidhya Dhar Sahu
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, 781101, Assam, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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7
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Shi K, Hou J, Zhang Q, Bi Y, Zeng X, Wang X. Neutrophil-to-high-density-lipoprotein-cholesterol ratio and mortality among patients with hepatocellular carcinoma. Front Nutr 2023; 10:1127913. [PMID: 37215223 PMCID: PMC10198653 DOI: 10.3389/fnut.2023.1127913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/29/2023] [Indexed: 05/24/2023] Open
Abstract
Background Inflammatory responses and lipid metabolism disorders contribute to the development and prognosis of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of lipid-related inflammatory parameters in patients with HCC. Methods From January 2010 to June 2017, we enrolled 1,639 patients with HCC at Beijing Ditan Hospital. Multivariate Cox regression analysis and area under the receiver operating characteristic (AUC) analysis were used to evaluate and compare the predictability and reliability of high-density lipoprotein cholesterol (HDL-C), neutrophil-to-HDL-C ratio (NHR), monocyte-to-HDL-C ratio (MHR), and lymphocyte-to-HDL-C ratio (LHR) values. A restricted cubic spline was used to explore the association between the NHR and 3-year mortality in patients with HCC. Differences in survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. The results were validated in an internal cohort between July 2017 and October 2019 (n = 373). Results After adjusting for confounding variables, NHR was independently associated with 3-year mortality, both as a continuous and categorical variable (both p < 0.05). The correlation between the mortality and the MHR and LHR was not statistically significant. The NHR showed a suitable prognostic value (AUC at 3 years: 0.740), similar to that of the Model for End-stage Liver Disease (MELD) (AUC at 3 years: 0.761). In the validation cohort, the AUC of the NHR was 0.734 at 3 years. The optimal cut-off values of NHR and MELD were 3.5 and 9, respectively. The 3-year survival rates in the low- (NHR < 3.5 and MELD <9) and high-risk (NHR ≥ 3.5 and MELD ≥9) groups were 81.8 and 19.4%, respectively, in the training cohort, and 84.6 and 27.5%, respectively, in the validation cohort. Conclusion Baseline NHR is a promising prognostic parameter for mortality in patients with HCC and patients with NHR ≥ 3.5 and MELD ≥9 have a high mortality rate.
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Affiliation(s)
- Ke Shi
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jie Hou
- Department of Spleen and Stomach Diseases, Hengshui Hospital of Traditional Chinese Medicine, Hebei, China
| | - Qun Zhang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yufei Bi
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xuanwei Zeng
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Ince V, Sahin TT, Akbulut S, Yilmaz S. Liver transplantation for hepatocellular carcinoma: Historical evolution of transplantation criteria. World J Clin Cases 2022; 10:10413-10427. [PMID: 36312504 PMCID: PMC9602233 DOI: 10.12998/wjcc.v10.i29.10413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/27/2022] [Accepted: 08/25/2022] [Indexed: 02/05/2023] Open
Abstract
Liver transplantation (LT) for hepatocellular carcinoma is still a hot topic, and the main factor that is associated with the success of treatment is to determine the patients who will benefit from LT. Milan criteria have been defined 25 years ago and still is being used for patient selection for LT. However, in living donor LT, the Milan criteria is being extended. Current criteria for patient selection do not only consider morphologic characteristics such as tumor size and number of tumor nodules but also biologic markers that show tumor aggressiveness is also being considered. In the present review article, we have summarized all the criteria and scoring systems regarding LT for hepatocellular carcinoma. All criteria have 5-year overall survival rates that were comparable to the Milan Criteria and ranged between 60%-85%. On the other hand, it was seen that the recurrence rates had increased as the Milan criteria were exceeded; the 5-year recurrence rates ranged between 4.9% to 39.9%. Treatment of hepatocellular carcinoma needs a multidisciplinary approach. Ideal selection criteria are yet to be discovered. The same is true for treatment modalities. The goal will be achieved by a harmonic interplay between basic science researchers and clinicians.
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Affiliation(s)
- Volkan Ince
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Tevfik Tolga Sahin
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sami Akbulut
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
- Biostatistics and Medical Informatics, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Sezai Yilmaz
- Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya 44280, Turkey
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Lei B, Song H, Xu F, Wei Q, Wang F, Tan G, Ma H. When does hepatitis B virus meet long-stranded noncoding RNAs? Front Microbiol 2022; 13:962186. [PMID: 36118202 PMCID: PMC9479684 DOI: 10.3389/fmicb.2022.962186] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/22/2022] [Indexed: 01/16/2023] Open
Abstract
Hepatitis B virus (HBV) infection in humans and its associated diseases are long-standing problems. HBV can produce a large number of non-self-molecules during its life cycle, which acts as targets for innate immune recognition and initiation. Among these, interferon and its large number of downstream interferon-stimulated gene molecules are important early antiviral factors. However, the development of an effective antiviral immune response is not simple and depends not only on the delicate regulation of the immune response but also on the various mechanisms of virus-related immune escape and immune tolerance. Therefore, despite there being a relatively well-established consensus on the major pathways of the antiviral response and their component molecules, the complete clearance of HBV remains a challenge in both basic and clinical research. Long-noncoding RNAs (lncRNAs) are generally >200 bp in length and perform different functions in the RNA strand encoding the protein. As an important part of the IFN-inducible genes, interferon-stimulated lncRNAs are involved in the regulation of several HBV infection-related pathways. This review traces the basic elements of such pathways and characterizes the various recent targets of lncRNAs, which not only complement the regulatory mechanisms of pathways related to chronic HBV infection, fibrosis, and cancer promotion but also present with new potential therapeutic targets for controlling HBV infection and the malignant transformation of hepatocytes.
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Affiliation(s)
- Bingxin Lei
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongxiao Song
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengchao Xu
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Qi Wei
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fei Wang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Guangyun Tan
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Department of Immunology, Center for Pathogen Biology and Infectious Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
- *Correspondence: Guangyun Tan,
| | - Haichun Ma
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, Jilin, China
- Haichun Ma,
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An advanced network pharmacology study to explore the novel molecular mechanism of Compound Kushen Injection for treating hepatocellular carcinoma by bioinformatics and experimental verification. BMC Complement Med Ther 2022; 22:54. [PMID: 35236335 PMCID: PMC8892752 DOI: 10.1186/s12906-022-03530-3] [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: 10/19/2021] [Accepted: 02/07/2022] [Indexed: 12/13/2022] Open
Abstract
Background Compound Kushen Injection (CKI) is a Chinese patent drug that exerts curative effects in the clinical treatment of hepatocellular carcinoma (HCC). This study aimed to explore the targets and potential pharmacological mechanisms of CKI in the treatment of HCC. Methods In this study, network pharmacology was used in combination with molecular biology experiments to predict and verify the molecular mechanism of CKI in the treatment of HCC. The constituents of CKI were identified by UHPLC-MS/MS and literature search. The targets corresponding to these compounds and the targets related to HCC were collected based on public databases. To screen out the potential hub targets of CKI in the treatment of HCC, a compound-HCC target network was constructed. The underlying pharmacological mechanism was explored through the subsequent enrichment analysis. Interactive Gene Expression Profiling Analysis and Kaplan-Meier plotter were used to examine the expression and prognostic value of hub genes. Furthermore, the effects of CKI on HCC were verified through molecular docking simulations and cell experiments in vitro. Results Network analysis revealed that BCHE, SRD5A2, EPHX2, ADH1C, ADH1A and CDK1 were the key targets of CKI in the treatment of HCC. Among them, only CDK1 was highly expressed in HCC tissues, while the other 5 targets were lowly expressed. Furthermore, the six hub genes were all closely related to the prognosis of HCC patients in survival analysis. Molecular docking revealed that there was an efficient binding potential between the constituents of CKI and BCHE. Experiments in vitro proved that CKI inhibited the proliferation of HepG2 cells and up-regulated SRD5A2 and ADH1A, while down-regulated CDK1 and EPHX2. Conclusions This study revealed and verified the targets of CKI on HCC based on network pharmacology and experiments and provided a scientific reference for further mechanism research. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03530-3.
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Qian X, Yang Z, Gao L, Liu Y, Yan J. The role of complement in the clinical course of hepatocellular carcinoma. Immun Inflamm Dis 2022; 10:e569. [PMID: 34813686 PMCID: PMC8926509 DOI: 10.1002/iid3.569] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/06/2021] [Accepted: 11/10/2021] [Indexed: 01/10/2023] Open
Abstract
Background The complement system, an innate immune system, may either play an antitumor role, or promote tumorigenesis and cancer progression in different kinds of cancer. The function of complement in hepatocellular carcinoma (HCC) is unclear. Methods The gene expressions of the complement system were based on data obtained from TCGA and GEO. We explored gene expressions, mutation, enrichment analysis, clinicopathology, patients' outcome, and immune infiltration via Gepia2, cBioPortal, Metascape, UALCAN, Kaplan–Meier Plotter, and TIMER 2. Results Five complement genes, including C1R, C6, C7, CFP, and CFHR3, were not only found to be significantly downregulated in HCC samples compared with normal liver samples, but also found to be significantly associated with overall survival, disease‐free survival, and progress‐free survival in HCC patients. In addition, lower mRNA expression of C1R, C6, C7, and CFHR3 were found correlated with advanced cancer stages and higher tumor grades in HCC patients. Also, the expression levels of CFP were correlated with many sets of immune markers of tumor immune cells, such as those of CD8+ T cells, CD4+ T cells, B cells, M2 macrophages, neutrophils, DCs, Th1 cells, Th2 cells, and T cell exhaustion in HCC. Based on that, we developed a prognostic model for HCC patients—Riskscore = (−0.0053)*C6+(−0.0498)*C7+(−0.1045)*CFHR3. Conclusion C1R, C6, C7, CFP, and CFHR3 could be prognostic biomarkers for patients with HCC.
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Affiliation(s)
- Xinye Qian
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Zhoujing Yang
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Lu Gao
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yipiao Liu
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jun Yan
- Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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Valente M, Covre A, Giacomo AMD, Maio M. Personalized Medicine for Patients with Liver, Biliary Tract, and Pancreatic Cancer. HEPATO-PANCREATO-BILIARY MALIGNANCIES 2022:761-776. [DOI: 10.1007/978-3-030-41683-6_50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Cai X, Zhou J, Deng J, Chen Z. Prognostic biomarker SMARCC1 and its association with immune infiltrates in hepatocellular carcinoma. Cancer Cell Int 2021; 21:701. [PMID: 34937564 PMCID: PMC8697473 DOI: 10.1186/s12935-021-02413-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 12/15/2021] [Indexed: 12/15/2022] Open
Abstract
Background Epigenetic alterations contribute greatly to metastasis and dissemination in hepatocellular carcinoma (HCC). SMARCC1, as a SWI/SNF chromatin remodeling factor, has been reported to play important roles in many cancers. For the first time, with the bioinformatics analysis and wet-bench experiments, we explored the biological significance of SMARCC1 and its potential as putative therapeutic target in HCC. Methods The mRNA expression profiles and prognostic value of SMARCC1 were analyzed in the Oncomine, UALCAN and Kaplan–Meier Plotter databases. The expression of SMARCC1 and associated clinicopathological factors were further evaluated using a tissue microarray. Differentially expressed genes associated with SMARCC1 in HCC were obtained and analyzed via the LinkedOmics and GEPIA databases and Cytoscape software. To verify the important role of SMARCC1 in HCC, we knocked down and overexpressed SMARCC1 in different hepatic cell lines and conducted several functional experiments. Then, we evaluated the mutation profiles and transcriptional regulators of SMARCC1 using the cBioPortal, COSMIC, CistromeDB and TCGA databases. Finally, we addressed the relationship of SMARCC1 expression with immune cell infiltration via TIMER database analysis. Results Through data mining and tissue microarray verification, we found that the protein and mRNA levels of SMARCC1 are high in tumor tissues, which has remarkable diagnostic value in HCC patients. SMARCC1 and its hub genes showed prognostic value in HCC. Furthermore, we confirmed that SMARCC1 influenced the proliferation, migration, and invasion of HCC cells. Moreover, correlation analyses revealed that SMARCC1 expression was positively correlated with ZBTB40 transcription factors and negatively correlated with the DNA methylation level. Overall, we found that SMARCC1 affects immune infiltration and plays a tumor-promoting role in HCC. Conclusions SMARCC1 is overexpressed and is a putative prognostic predictor in HCC. Due to the tumor-promoting role of SMARCC1, treatments inhibiting DNA methyltransferases and transcription factors or weakening the role of SMARCC1 in immune infiltration might improve the survival of HCC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02413-w.
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Identification of an m6A-Related Signature as Biomarker for Hepatocellular Carcinoma Prognosis and Correlates with Sorafenib and Anti-PD-1 Immunotherapy Treatment Response. DISEASE MARKERS 2021; 2021:5576683. [PMID: 34221187 PMCID: PMC8213471 DOI: 10.1155/2021/5576683] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022]
Abstract
Background N6-methyladenosine (m6A) modification plays an essential role in diverse key biological processes and may take part in the development and progression of hepatocellular carcinoma (HCC). Here, we systematically analyzed the expression profiles and prognostic values of 13 widely reported m6A modification-related genes in HCC. Methods The mRNA expression of 13 m6A modification-related genes and clinical parameters of HCC patients were downloaded from TCGA, ICGC, GSE109211, and GSE78220. Univariate and LASSO analyses were used to develop risk signature. Time-dependent ROC was performed to assess the predictive accuracy and sensitivity of risk signature. Results FTO, YTHDC1, YTHDC2, ALKBH5, KIAA1429, HNRNPC, METTL3, RBM15, YTHDF2, YTHDF1, and WTAP were significantly overexpressed in HCC patients. YTHDF1, HNRNPC, RBM15, METTL3, and YTHDF2 were independent prognostic factors for OS and DFS in HCC patients. Next, a risk signature was also developed and validated with five m6A modification-related genes in TCGA and ICGC HCC cohort. It could effectively stratify HCC patients into high-risk patients with shorter OS and DFS and low-risk patients with longer OS and DFS and showed good predictive efficiency in predicting OS and DFS. Moreover, significantly higher proportions of macrophages M0 cells, neutrophils, and Tregs were found to be enriched in HCC patients with high risk scores, while significantly higher proportions of memory CD4 T cells, gamma delta T cells, and naive B cells were found to be enriched in HCC patients with low scores. Finally, significantly lower risk scores were found at sorafenib treatment responders and anti-PD-1 immunotherapy responders compared to that in nonresponders, and anti-PD-1 immunotherapy-treated patients with lower risk scores had better OS than patients with higher risk scores. Conclusion A risk signature developed with the expression of 5 m6A-related genes could improve the prediction of prognosis of HCC and correlated with sorafenib treatment and anti-PD-1 immunotherapy response.
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Sartorius K, An P, Winkler C, Chuturgoon A, Li X, Makarova J, Kramvis A. The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation. Front Immunol 2021; 12:661204. [PMID: 33995383 PMCID: PMC8117219 DOI: 10.3389/fimmu.2021.661204] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.,Department of Surgery, University of KwaZulu-Natal Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Ping An
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Cheryl Winkler
- Basic Research Laboratory, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Xiaodong Li
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Julia Makarova
- Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Moscow, Russia.,Higher School of Economics University, Moscow, Russia
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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Ferreira GD, Fernandes GMDM, Penteado C, Cória VR, Galbiatti-Dias ALDS, Russo A, Castanhole-Nunes MMU, Silva RFD, Silva RDCMAD, Pavarino ÉC, Torreglosa Ruiz Cintra M, Goloni-Bertollo EM. Polymorphisms in xenobiotic metabolism-related genes in patients with hepatocellular carcinoma: a case-control study. Xenobiotica 2021; 51:737-744. [PMID: 33896378 DOI: 10.1080/00498254.2021.1893408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This study was performed to investigate the relationship between polymorphisms in microsomal epoxide hydrolase (mEH; Tyr113His and His139Arg substitution) and glutathione S-transferase (GST; GSTM1 deletion, GSTT1 deletion, and GSTP1.Ala114Val substitution) and their correlation with clinico-histopathological features in hepatocellular carcinoma (HCC).We evaluated environmental risk factors and genetic alterations in 556 individuals (86 cases and 470 controls). PCR multiplex for GSTM1 and GSTT1, polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) for GSTP1, and real-time PCR for mEH were performed. Statistical analyses were performed using multiple logistic regression tests.Age over 48 years (p < 0.001) and alcohol consumption (p = 0.021) were the predictors of increased risk of developing HCC. GSTP1.Ala114Val for all regression models (p < 0.05), except the recessive model, and the GSTT1 null genotype (odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.21-0.87, p = 0.019) were predictors of an increased risk of developing HCC. Polymorphic GSTT1, GSTM1, GSTP1.Ala114Val, and mEH.His139Arg and wild-type mEH.Tyr113His (OR = 5.04; 95% CI = 1.59-16.04; p = 0.006) were associated with HCC.Age over 48 years, alcohol consumption, and the presence of polymorphic variants of GSTP1 and GSTT1 were associated with the risk of developing HCC.
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Affiliation(s)
- Gislaine Dionísio Ferreira
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil
| | - Glaucia Maria de Mendonça Fernandes
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil
| | - Camila Penteado
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil
| | - Vivian Romanholi Cória
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil
| | - Ana Lívia da Silva Galbiatti-Dias
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
| | - Anelise Russo
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil
| | - Márcia Maria Urbanin Castanhole-Nunes
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
| | - Renato Ferreira da Silva
- Study Group of Liver Tumors - GETF, Surgery Department, São José do Rio Preto Medical School Fundation - FAMERP/FUNFARME, São José do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
| | - Rita de Cássia Martins Alves da Silva
- Study Group of Liver Tumors - GETF, Surgery Department, São José do Rio Preto Medical School Fundation - FAMERP/FUNFARME, São José do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
| | - Érika Cristina Pavarino
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
| | | | - Eny Maria Goloni-Bertollo
- Molecular Biology Department, Genetics and Molecular Biology Research Unit - UPGEM, São José do Rio Preto Medical School - FAMERP, São Jose do Rio Preto, Brazil.,São José do Rio Preto Regional Medical School Foundation - FUNFARME, São José do Rio Preto, Brazil
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Identification of miRNAs as diagnostic and prognostic markers in hepatocellular carcinoma. Aging (Albany NY) 2021; 13:6115-6133. [PMID: 33617479 PMCID: PMC7950227 DOI: 10.18632/aging.202606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 10/27/2020] [Indexed: 12/24/2022]
Abstract
The development of high-throughput technologies has yielded a large amount of data from molecular and epigenetic analysis that could be useful for identifying novel biomarkers of cancers. We analyzed Gene Expression Omnibus (GEO) DataSet micro–ribonucleic acid (miRNA) profiling datasets to identify miRNAs that could have value as diagnostic and prognostic biomarkers in hepatocellular carcinoma (HCC). We adopted several computing methods to identify the functional roles of these miRNAs. Ultimately, via integrated analysis of three GEO DataSets, three differential miRNAs were identified as valuable markers in HCC. Combining the results of receiver operating characteristic (ROC) analyses and Kaplan–Meier Plotter (KM) survival analyses, we identified hsa-let-7e as a novel potential biomarker for HCC diagnosis and prognosis. Then, we found via quantitative reverse-transcription polymerase chain reaction (RT-qPCR) that let-7e was upregulated in HCC tissues and that such upregulation was significantly associated with poor prognosis in HCC. The results of functional analysis indicated that upregulated let-7e promoted tumor cell growth and proliferation. Additionally, via mechanistic analysis, we found that let-7e could regulate mitochondrial apoptosis and autophagy to adjust and control cancer cell proliferation. Therefore, the integrated results of our bioinformatics analyses of both clinical and experimental data showed that let-7e was a novel biomarker for HCC diagnosis and prognosis and might be a new treatment target.
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Hepigenetics: A Review of Epigenetic Modulators and Potential Therapies in Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9593254. [PMID: 33299889 PMCID: PMC7707949 DOI: 10.1155/2020/9593254] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/13/2020] [Accepted: 11/05/2020] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma is the fifth most common cancer worldwide and the second most lethal, following lung cancer. Currently applied therapeutic practices rely on surgical resection, chemotherapy and radiotherapy, or a combination thereof. These treatment options are associated with extreme adversities, and risk/benefit ratios do not always work in patients' favor. Anomalies of the epigenome lie at the epicenter of aberrant molecular mechanisms by which the disease develops and progresses. Modulation of these anomalous events poses a promising prospect for alternative treatment options, with an abundance of felicitous results reported in recent years. Herein, the most recent epigenetic modulators in hepatocellular carcinoma are recapitulated on.
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Buocikova V, Rios-Mondragon I, Pilalis E, Chatziioannou A, Miklikova S, Mego M, Pajuste K, Rucins M, Yamani NE, Longhin EM, Sobolev A, Freixanet M, Puntes V, Plotniece A, Dusinska M, Cimpan MR, Gabelova A, Smolkova B. Epigenetics in Breast Cancer Therapy-New Strategies and Future Nanomedicine Perspectives. Cancers (Basel) 2020; 12:E3622. [PMID: 33287297 PMCID: PMC7761669 DOI: 10.3390/cancers12123622] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/30/2020] [Accepted: 11/30/2020] [Indexed: 12/12/2022] Open
Abstract
Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics.
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Affiliation(s)
- Verona Buocikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Ivan Rios-Mondragon
- Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway; (I.R.-M.); (M.R.C.)
| | - Eleftherios Pilalis
- e-NIOS Applications Private Company, Alexandrou Pantou 25, 17671 Kallithea, Greece; (E.P.); (A.C.)
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Aristotelis Chatziioannou
- e-NIOS Applications Private Company, Alexandrou Pantou 25, 17671 Kallithea, Greece; (E.P.); (A.C.)
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Svetlana Miklikova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia;
| | - Karlis Pajuste
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Martins Rucins
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Naouale El Yamani
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Eleonora Marta Longhin
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Arkadij Sobolev
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Muriel Freixanet
- Vall d Hebron, Institut de Recerca (VHIR), 08035 Barcelona, Spain; (M.F.); (V.P.)
| | - Victor Puntes
- Vall d Hebron, Institut de Recerca (VHIR), 08035 Barcelona, Spain; (M.F.); (V.P.)
- Institut Català de Nanosciència i Nanotecnologia (ICN2), Bellaterra, 08193 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
| | - Aiva Plotniece
- Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; (K.P.); (M.R.); (A.S.); (A.P.)
| | - Maria Dusinska
- Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; (N.E.Y.); (E.M.L.); (M.D.)
| | - Mihaela Roxana Cimpan
- Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway; (I.R.-M.); (M.R.C.)
| | - Alena Gabelova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
| | - Bozena Smolkova
- Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; (V.B.); (S.M.); (A.G.)
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BRD4/8/9 are prognostic biomarkers and associated with immune infiltrates in hepatocellular carcinoma. Aging (Albany NY) 2020; 12:17541-17567. [PMID: 32927435 PMCID: PMC7521508 DOI: 10.18632/aging.103768] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 06/29/2020] [Indexed: 01/24/2023]
Abstract
Bromodomain (BRD)-containing proteins are a class of epigenetic readers with unique recognition for N-acetyl-lysine in histones and functions of gene transcription and chromatin modification, known to be critical in various cancers. However, little is known about the roles of distinct BRD-containing protein genes in hepatocellular carcinoma (HCC). Most recently, we investigated the transcriptional and survival data of BRD1, BRD2, BRD3, BRD4, BRD7, BRD8, BRD9 in HCC patients through ONCOMINE, UALCAN, Human Protein Atlas, GEPIA, cBioPortal, STRING, TIMER databases. BRD1/2/3/4/7/8/9 were over-expressed in HCC and were significantly associated with clinical cancer stages and pathological tumor grades. High mRNA expressions of BRD4/8/9 were promising candidate biomarkers in HCC patients. The rate of sequence alternations in BRD1/2/3/4/7/8/9 was relatively high (52%) in HCC patients, and the genetic alternations were correlated with shorter overall survival and disease-free survival in HCC patients. Additionally, the mRNA expression levels of individual BRD genes were significantly positively associated with the immune infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. And the associations between BRD1/2/3/4/7/8/9 and diverse immune marker sets showed a significance. Overall, these results indicated that BRD4/8/9 could be potential prognostic markers and druggable epigenetic targets in HCC patients.
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Mungamuri SK, Mavuduru VA. Role of epigenetic alterations in aflatoxin‐induced hepatocellular carcinoma. ACTA ACUST UNITED AC 2020. [DOI: 10.1002/lci2.20] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Sathish Kumar Mungamuri
- Division of Food Safety Indian Council of Medical Research (ICMR) ‐ National Institute of Nutrition (NIN) Hyderabad Telangana India
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Makary MS, Khandpur U, Cloyd JM, Mumtaz K, Dowell JD. Locoregional Therapy Approaches for Hepatocellular Carcinoma: Recent Advances and Management Strategies. Cancers (Basel) 2020; 12:1914. [PMID: 32679897 PMCID: PMC7409274 DOI: 10.3390/cancers12071914] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/12/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and third leading cause of cancer-related mortality worldwide. While surgical resection and transplantation are the standard first-line treatments for early-stage HCC, most patients do not fulfill criteria for surgery. Fortunately, catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable HCC. Improved outcomes have been achieved with novel techniques which can be employed for diverse applications ranging from curative-intent for small localized tumors, to downstaging or bridging to resection and transplantation for early and intermediate disease, and locoregional control and palliation for advanced disease. This review explores recent advances in liver-directed techniques for HCC including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies, with a focus on patient selection, procedural technique, periprocedural management, and outcomes.
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Affiliation(s)
- Mina S. Makary
- Division of Vascular and Interventional Radiology, Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Umang Khandpur
- Division of Vascular and Interventional Radiology, Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Jordan M. Cloyd
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
| | - Khalid Mumtaz
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA;
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Wang A, Meng J, Liu H, Li C, Zhou Z. Long non-coding RNA BCAR4 promotes liver cancer progression by regulating proliferation, migration and invasion. Oncol Lett 2020; 20:2779-2787. [PMID: 32782595 PMCID: PMC7400972 DOI: 10.3892/ol.2020.11826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023] Open
Abstract
Liver cancer (LC) is one of the primary contributors of cancer-associated death worldwide. Long non-coding RNAs (lncRNAs) have been shown to participate in almost every aspect of cell biology and serve fundamental roles in carcinogenesis and cancer progression, including in LC. However, the clinical significance and functional role of the lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) in LC have not yet been identified. The present study measured the expression levels of BCAR4 in LC cells and tissues, and discovered that BCAR4 was upregulated in LC tissues compared with adjacent normal tissues. Furthermore, high BCAR4 expression was associated with the presence of multiple tumors and advanced Tumor-Node-Metastasis stages (III/IV). Survival analysis found that high BCAR4 expression indicated poor overall survival (OS) and progression-free survival (PFS). By analyzing the risk factors of poor OS and PFS using univariate analysis and multivariate analysis, high BCAR4 expression was revealed to be an independent risk factor of poor prognosis. In addition, the role of BCAR4 was further investigated in vitro, which revealed overexpression of BCAR4 to markedly promote the proliferation, migration and invasion of LC cells. Conversely, the loss of BCAR4 expression repressed the proliferation, migration and invasion of LC cells. In conclusion, BCAR4 is overexpressed in LC and is associated with LC progression. Therefore, BCAR4 may be used as a potential prognostic marker in LC.
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Affiliation(s)
- Aiyao Wang
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jun Meng
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Hui Liu
- Department of Gastroenterology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Chen Li
- Department of Orthopedics, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiyong Zhou
- Department of Oncology, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Liu Y, Feng Y, Li Y, Hu Y, Zhang Q, Huang Y, Shi K, Ran C, Hou J, Zhou G, Wang X. Chlorogenic Acid Decreases Malignant Characteristics of Hepatocellular Carcinoma Cells by Inhibiting DNMT1 Expression. Front Pharmacol 2020; 11:867. [PMID: 32655395 PMCID: PMC7325898 DOI: 10.3389/fphar.2020.00867] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 05/26/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common malignant tumor of the adult liver, exhibiting rapid progression and poor prognosis. Chlorogenic acid (CGA), a polyphenol, has several biological activities, including the suppression of liver cancer cell invasion and metastasis. Increased levels or alterations in the function of DNMT1 are associated with the inactivation of tumor suppressor genes. However, the CGA-affected DNMT1 expression mediated mechanism is still unclear. Methods The human hepatocellular carcinoma (HCC) HepG2 cells were treated with a positive control drug (5-AZA) or varying doses of CGA. DNA methyltransferase 1 (DNMT1) protein levels and other relevant proteins were evaluated using Western blotting and immunocytochemistry. Cell-cycle analysis was performed by flow cytometry-based PI staining, and cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The transwell invasion and wound healing assays were used to evaluate cell migration and invasion. In vivo proliferation of the HCC cells was detected. We investigated the expression of DNMT1, p53, p21, p-ERK, MMP-2, and MMP-9 in tumors using immunohistochemical analysis. Results Our results showed that CGA inhibited the proliferation, colony formation, invasion, and metastasis of HepG2 cells both in vitro and in vivo by down-regulating DNMT1 protein expression, which enhanced p53 and p21 activity, and resulting in a significant reduction in cell proliferation and metastasis. Moreover, CGA inactivated ERK1/2 and reduced MMP-2 and MMP-9 expression in HepG2 cells. Conclusions CGA can suppress liver cancer cell proliferation, invasion, and metastasis through several pathways. CGA could serve as a candidate chemopreventive agent for HCC.
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Affiliation(s)
- Yao Liu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ying Feng
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuxin Li
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ying Hu
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Qun Zhang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yunyi Huang
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ke Shi
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Chongping Ran
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Jie Hou
- Department of Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guiqin Zhou
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xianbo Wang
- Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China
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Wu J, Niu Q, Yuan J, Xu X, Cao L. lncRNA-CD160 decreases the immunity of CD8 + T cells through epigenetic mechanisms in hepatitis B virus infection. Oncol Lett 2020; 20:235-247. [PMID: 32565950 PMCID: PMC7286002 DOI: 10.3892/ol.2020.11534] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/07/2020] [Indexed: 02/06/2023] Open
Abstract
The transfer and development of chronic hepatitis B virus (HBV) infection is associated with the T cell immune response, therefore investigating the key regulators of cell immune response is needed to improve chronic HBV treatment. Blood samples from patients with chronic HBV infection were used to confirm the correlation between HBV infection stage and CD160 receptor expression levels in CD8+ T cells, the CD8+ T cells are used to research the mechanism of T cell immune response modulation, moreover, C3H/HeN mice with reduced CD160 expression levels were used to investigate the association between long non-coding (lnc)RNA-CD160 and HBV infection. Long non-coding (lnc)RNA-CD160 and histone-modification enzyme gene histone deacetylase 11 (HDAC11) expression levels were negatively associated with CD160 expression. lncRNA-CD160 can inhibit the secretion of IFN-γ and TNF-α through HDAC11 recruitment and bind to HDAC11 to form a complex on the promoters of IFN-γ and TNF-α. The HDAC11, IFN-γ and TNF-α form a complex and enhance the methylation of H3K9Me1, chromatin changes into the heterochromatin and the transcription of IFN-γ and TNF-α is blocked; moreover, the HDAC11/IFN-γ/TNF-α complex can also inhibit the secretion of IFN-γ and TNF-α in CD160− CD8+ T cells and suppresses the function of CD8+ T cells. Furthermore, small interfering RNA targeting lncRNA-CD160 can block HBV infection progression. lncRNA-CD160 acts as an immune suppressive factor and is expressed at a high level in peripheral blood CD8+ T cells of HBV infected patients. Furthermore, high expression levels of lncRNA-CD160 can contribute to the inhibition of IFN-γ and TNF-α secretion in CD8+ T cells and decrease the immune response of CD8+ T cells. Therefore, lncRNA-CD160 may become a new target for immunotherapy of chronic HBV infection in the future and may provide a new therapeutic strategy for the treatment of HBV infection.
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Affiliation(s)
- Jiansong Wu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Qiang Niu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Jie Yuan
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Xiaodan Xu
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
| | - Liuxia Cao
- Department of Infectious Diseases, General Hospital of the Peoples' Liberation Army Rocket Force, Beijing 100088, P.R. China
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Binh MT, Hoan NX, Giang DP, Tong HV, Bock CT, Wedemeyer H, Toan NL, Bang MH, Kremsner PG, Meyer CG, Song LH, Velavan TP. Upregulation of SMYD3 and SMYD3 VNTR 3/3 polymorphism increase the risk of hepatocellular carcinoma. Sci Rep 2020; 10:2797. [PMID: 32071406 PMCID: PMC7029004 DOI: 10.1038/s41598-020-59667-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 02/03/2020] [Indexed: 12/24/2022] Open
Abstract
SMYD3 (SET and MYND domain-containing protein 3) is involved in histone modification, which initiates oncogenesis by activating transcription of multiple downstream genes. To investigate associations of variable numbers of tandem repeats (VNTR) variants in the SMYD3 gene promoter, SMYD3 serum levels and SMYD3 mRNA expression in hepatitis B virus (HBV) infection and clinical progression of related liver disease. SMYD3 VNTRs were genotyped in 756 HBV patients and 297 healthy controls. SMYD3 serum levels were measured in 293 patients and SMYD3 mRNA expression was quantified in 48 pairs of hepatocellular tumor and adjacent non-tumor liver tissues. Genotype SYMD3 VNTR 3/3 was more frequent among HCC patients than in controls (Padjusted = 0.037). SMYD3 serum levels increased according to clinical progression of liver diseases (P = 0.01); HCC patients had higher levels than non-HCC patients (P = 0.04). Among patients with SMYD3 VNTR 3/3, HCC patients had higher SMYD3 levels than others (P < 0.05). SMYD3 mRNA expression was up-regulated in HCC tumor tissues compared to other tissues (P = 0.008). In conclusion, upregulation of SMYD3 correlates with the occurrence of HCC and SMYD3 VNTR 3/3 appears to increase the risk of HCC through increasing SMYD3 levels. SMYD3 may be an indicator for HCC development in HBV patients.
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Affiliation(s)
- Mai Thanh Binh
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,108 Military Central Hospital, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,108 Military Central Hospital, Hanoi, Vietnam
| | - Dao Phuong Giang
- Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,108 Military Central Hospital, Hanoi, Vietnam
| | - Hoang Van Tong
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,Vietnam Military Medical University, Hanoi, Vietnam
| | - C-Thomas Bock
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Nguyen Linh Toan
- Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,Vietnam Military Medical University, Hanoi, Vietnam
| | | | - Peter G Kremsner
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Christian G Meyer
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,Duy Tan University, Da Nang, Vietnam
| | - Le Huu Song
- Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam.,108 Military Central Hospital, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany. .,Vietnamese-German Center for Medical Research (VGCARE), Hanoi, Vietnam. .,Duy Tan University, Da Nang, Vietnam.
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27
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dos Santos PWDS, Machado ART, De Grandis RA, Ribeiro DL, Tuttis K, Morselli M, Aissa AF, Pellegrini M, Antunes LMG. Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol 2020; 136:111047. [DOI: 10.1016/j.fct.2019.111047] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/30/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
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Jiang HY, Ning G, Wang YS, Lv WB. 14-CpG-Based Signature Improves the Prognosis Prediction of Hepatocellular Carcinoma Patients. BIOMED RESEARCH INTERNATIONAL 2020; 2020:9762067. [PMID: 31998802 PMCID: PMC6970499 DOI: 10.1155/2020/9762067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epigenetic dysregulation via alteration of DNA methylation often occurs during the development and progression of cancer, including hepatocellular carcinoma (HCC). In the past, many patterns of single-gene DNA methylation have been extensively explored in the context of HCC prognosis prediction. However, the combined model of a mixture of CpGs has rarely been evaluated. In the present study, we aimed to develop and validate a CpG-based signature model for HCC patient prognosis. METHODS Data from methylation profiling of GSE73003, GSE37988, and GSE57958 from the Gene Expression Omnibus (GEO) database and 371 HCC patients from the Cancer Genome Atlas (TCGA) were downloaded. The 371 HCC patients were randomly divided into a development cohort (N = 263) and a validation cohort (N = 263) and a validation cohort (. RESULTS Fourteen differential CpGs associated with OS were identified in HCC patients. The MSH, based on these 14 differential CpGs, could effectively divide HCC patients into two distinct subgroups with high risk or low risk of death (P < 0.0001) in the development cohort (26.35 vs 83.18 months, HR = 3.83, 95% CI: 2.56-5.90, P < 0.0001) in the development cohort (26.35 vs 83.18 months, HR = 3.83, 95% CI: 2.56-5.90, P < 0.0001) in the development cohort (26.35 vs 83.18 months, HR = 3.83, 95% CI: 2.56-5.90. CONCLUSION The 14-CpG-based signature is significantly associated with OS and may be used as a novel prognostic biomarker for HCC patients.
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Affiliation(s)
- Hong-ye Jiang
- Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (the First People's Hospital of Shunde), Foshan 528300, Guangdong Province, China
| | - Gang Ning
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Yen-sheng Wang
- Department of Environmental Health Science, Yale School of Public Health, New Haven, Connecticut, USA
| | - Wei-biao Lv
- Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (the First People's Hospital of Shunde), Foshan 528300, Guangdong Province, China
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Heidor R, Affonso JM, Ong TP, Moreno FS. Nutrition and Liver Cancer Prevention. NUTRITION AND CANCER PREVENTION 2019:339-367. [DOI: 10.1039/9781788016506-00339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Liver cancer represents a major public health problem. Hepatocarcinogenesis is a complex process that comprises several stages and is caused by multiple factors. Both progressive genetic and epigenetic alterations are described in liver cancer development. The most effective strategy to reduce the impact of this disease is through prevention. In addition to vaccination against HBV and treatment of HCV infection, other preventive measures include avoiding ingesting aflatoxin-contaminated foods and drinking alcoholic beverages, as well as maintaining healthy body weight and practicing physical exercise. Bioactive compounds from fruits and vegetables present great potential for liver cancer chemoprevention. Among them, tea catechins, carotenoids, retinoids, β-ionone, geranylgeraniol and folic acid can be highlighted. In addition, butyric acid, tributyrin and structured lipids based on butyric acid and other fatty acids represent additional promising chemopreventive agents. These bioactive food compounds have been shown to modulate key cellular and molecular processes that are deregulated in hepatocarcinogenesis. Furthermore, combinations of different classes of bioactive food compounds or of bioactive food compounds with synthetic drugs could lead to synergistic liver cancer chemopreventive effects.
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Affiliation(s)
- R. Heidor
- University of São Paulo, Faculty of Pharmaceutical Sciences, Department of Food and Experimental Nutrition, Food Research Center (FoRC) São Paulo 05508-000 Brazil
| | - J. M. Affonso
- University of São Paulo, Faculty of Pharmaceutical Sciences, Department of Food and Experimental Nutrition, Food Research Center (FoRC) São Paulo 05508-000 Brazil
| | - T. P. Ong
- University of São Paulo, Faculty of Pharmaceutical Sciences, Department of Food and Experimental Nutrition, Food Research Center (FoRC) São Paulo 05508-000 Brazil
| | - F. S. Moreno
- University of São Paulo, Faculty of Pharmaceutical Sciences, Department of Food and Experimental Nutrition, Food Research Center (FoRC) São Paulo 05508-000 Brazil
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Lin T, Gu J, Qu K, Zhang X, Ma X, Miao R, Xiang X, Fu Y, Niu W, She J, Liu C. A new risk score based on twelve hepatocellular carcinoma-specific gene expression can predict the patients' prognosis. Aging (Albany NY) 2019; 10:2480-2497. [PMID: 30243023 PMCID: PMC6188480 DOI: 10.18632/aging.101563] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 09/14/2018] [Indexed: 12/31/2022]
Abstract
A large panel of molecular biomarkers have been identified to predict the prognosis of hepatocellular carcinoma (HCC), yet with limited clinical application due to difficult extrapolation. We here generated a genetic risk score system comprised of 12 HCC-specific genes to better predict the prognosis of HCC patients. Four genomics profiling datasets (GSE5851, GSE28691, GSE15765 and GSE14323) were searched to seek HCC-specific genes by comparisons between cancer samples and normal liver tissues and between different subtypes of hepatic neoplasms. Univariate survival analysis screened HCC-specific genes associated with overall survival (OS) in the training dataset for next-step risk model construction. The prognostic value of the constructed HCC risk score system was then validated in the TCGA dataset. Stratified analysis indicated this scoring system showed better performance in elderly male patients with HBV infection and preoperative lower levels of creatinine, alpha-fetoprotein and platelet and higher level of albumin. Functional annotation of this risk model in high-risk patients revealed that pathways associated with cell cycle, cell migration and inflammation were significantly enriched. In summary, our constructed HCC-specific gene risk model demonstrated robustness and potentiality in predicting the prognosis of HCC patients, especially among elderly male patients with HBV infection and relatively better general conditions.
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Affiliation(s)
- Ting Lin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Jingxian Gu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Kai Qu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Xing Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Xiaohua Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Runchen Miao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Xiaohong Xiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Yunong Fu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Wenquan Niu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Junjun She
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
| | - Chang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'a, Shaanxi 710061, China
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31
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Cozma A, Fodor A, Vulturar R, Sitar-Tăut AV, Orăşan OH, Mureşan F, Login C, Suharoschi R. DNA Methylation and Micro-RNAs: The Most Recent and Relevant Biomarkers in the Early Diagnosis of Hepatocellular Carcinoma. ACTA ACUST UNITED AC 2019; 55:medicina55090607. [PMID: 31546948 PMCID: PMC6780418 DOI: 10.3390/medicina55090607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 09/08/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a frequently encountered cancer type, and its alarming incidence is explained by genetic and epigenetic alterations. Epigenetic changes may represent diagnostic and prognostic biomarkers of HCC. In this review we discussed deoxyribonucleic acid (DNA) hypomethylation, DNA hypermethylation, and aberrant expression of small non-coding ribonucleic acid (RNA), which could be useful new biomarkers in the early diagnosis of HCC. We selected the articles on human subjects published in English over the past two years involving diagnostic markers detected in body fluids, cancer diagnosis made on histopathological exam, and a control group of those with benign liver disease or without liver disease. These biomarkers need further investigation in clinical trials to develop clinical applications for early diagnosis and management of HCC.
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Affiliation(s)
- Angela Cozma
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Adriana Fodor
- Department of Diabetes and Metabolic Diseases, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Romana Vulturar
- Department of Cell Biology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Adela-Viviana Sitar-Tăut
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Olga Hilda Orăşan
- Internal Medicine Department, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Flaviu Mureşan
- Department of Surgery, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Cezar Login
- Department of Physiology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania.
| | - Ramona Suharoschi
- Faculty of Food Science and Technology, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania.
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Shi Z, Luo Y, Zhu M, Zhou Y, Zheng B, Wu D, Wang S, Xie X, Lin H, Yu X. Expression Analysis of Long Non-Coding RNA HAR1A and HAR1B in HBV-Induced Hepatocullular Carcinoma in Chinese Patients. Lab Med 2019; 50:150-157. [PMID: 30304523 DOI: 10.1093/labmed/lmy055] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To determine the clinical relevance of long noncoding RNA (lncRNA) HAR1A and HAR1B expression in hepatocellular carcinoma (HCC). METHODS In this study, we enrolled 50 cases of chronic hepatitis B (CHB) without cirrhosis, 50 cases of CHB and liver cirrhosis (LC), and 100 cases of HBV and HCC. The expression profiles of lncRNA HAR1A and HAR1B were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS The expression levels of HAR1A and HAR1B were significantly lower in the HCC group, compared with the CHB and LC groups (P <.01). HAR1A and HAR1B were negatively associated with histologic grade and TNM (tumor/nodes/metastasis) stage (all P <.05). Univariable multivariable analysis showed that decreased HAR1A (HR = 0.753, P = .02) and HAR1B (HR = 0.551, P = .01) levels were independent predictors for shorter overall survival (OS) in HCC. CONCLUSION Decreased HAR1A and HAR1B expression in HCC indicates poor prognosis.
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Affiliation(s)
- Zhenjing Shi
- Department of Intervention, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Ya Luo
- Department of Intervention, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Minghui Zhu
- Department of Hepatobiliary Surgery, Wenzhou People's Hospital, China
| | - Yu Zhou
- Department of Infectious Diseases, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Bingru Zheng
- Department of Intervention, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Daoyi Wu
- Department of Gastrointestinal Surgery, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Shuting Wang
- Department of Imaging and Intervention, Zhejiang Chinese Medicine Hospital, Hangzhou, China
| | - Xiangbang Xie
- Department of Intervention, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Heping Lin
- Department of Respiratory Diseases, Third Affiliated Hospital of Wenzhou Medical University, Ruian, China
| | - Xixiang Yu
- Department of Vasointerventional Surgery, Wenzhou People's Hospital, China
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LncRNAs with miRNAs in regulation of gastric, liver, and colorectal cancers: updates in recent years. Appl Microbiol Biotechnol 2019; 103:4649-4677. [PMID: 31062053 DOI: 10.1007/s00253-019-09837-5] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Long noncoding RNA (lncRNA) is a kind of RNAi molecule composed of hundreds to thousands of nucleotides. There are several major types of functional lncRNAs which participate in some important cellular pathways. LncRNA-RNA interaction controls mRNA translation and degradation or serves as a microRNA (miRNA) sponge for silencing. LncRNA-protein interaction regulates protein activity in transcriptional activation and silencing. LncRNA guide, decoy, and scaffold regulate transcription regulators of enhancer or repressor region of the coding genes for alteration of expression. LncRNA plays a role in cellular responses including the following activities: regulation of chromatin structural modification and gene expression for epigenetic and cell function control, promotion of hematopoiesis and maturation of immunity, cell programming in stem cell and somatic cell development, modulation of pathogen infection, switching glycolysis and lipid metabolism, and initiation of autoimmune diseases. LncRNA, together with miRNA, are considered the critical elements in cancer development. It has been demonstrated that tumorigenesis could be driven by homeostatic imbalance of lncRNA/miRNA/cancer regulatory factors resulting in biochemical and physiological alterations inside the cells. Cancer-driven lncRNAs with other cellular RNAs, epigenetic modulators, or protein effectors may change gene expression level and affect the viability, immortality, and motility of the cells that facilitate cancer cell cycle rearrangement, angiogenesis, proliferation, and metastasis. Molecular medicine will be the future trend for development. LncRNA/miRNA could be one of the potential candidates in this category. Continuous studies in lncRNA functional discrepancy between cancer cells and normal cells and regional and rational genetic differences of lncRNA profiles are critical for clinical research which is beneficial for clinical practice.
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Zhao J, Gray SG, Greene CM, Lawless MW. Unmasking the pathological and therapeutic potential of histone deacetylases for liver cancer. Expert Rev Gastroenterol Hepatol 2019; 13:247-256. [PMID: 30791763 DOI: 10.1080/17474124.2019.1568870] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, currently ranking as one of the highest neoplastic-related mortalities in the world. Due to the difficulty in early diagnosis and lack of effective treatment options, the 5-year survival rate of HCC remains extremely low. Histone deacetylation is one of the most important epigenetic mechanisms, regulating cellular events such as differentiation, proliferation and cell cycle. Histone deacetylases (HDACs), the chief mediators of this epigenetic mechanism, are often aberrantly expressed in various tumours including HCC. Areas covered: This review focuses on the most up-to-date findings of HDACs and their associated molecular mechanisms in HCC onset and progression. In addition, a potential network between HDACs and non-coding RNAs including microRNAs and long noncoding RNAs underlying hepatocarcinogenesis is considered. Expert opinion: Unmasking the role of HDACs and their association with HCC pathogenesis could have implications for future personalized therapeutic and diagnostic targeting.
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Affiliation(s)
- Jun Zhao
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
| | - Steven G Gray
- b Department of Clinical Medicine , Trinity Centre for Health Sciences, Trinity Translational Medicine Institute, St. James's Hospital & Trinity College , Dublin , Ireland
| | - Catherine M Greene
- c Clinical Microbiology , Royal College of Surgeons in Ireland, Beaumont Hospital , Dublin , Ireland
| | - Matthew W Lawless
- a Experimental Medicine, UCD School of Medicine and Medical Science , Mater Misericordiae University Hospital , Dublin , Ireland
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35
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Ferreira RG, Cardoso MV, de Souza Furtado KM, Espíndola KMM, Amorim RP, Monteiro MC. Epigenetic alterations caused by aflatoxin b1: a public health risk in the induction of hepatocellular carcinoma. Transl Res 2019; 204:51-71. [PMID: 30304666 DOI: 10.1016/j.trsl.2018.09.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/27/2018] [Accepted: 09/02/2018] [Indexed: 02/07/2023]
Abstract
Aflatoxin B1 (AFB1) is currently the most commonly studied mycotoxin due to its great toxicity, its distribution in a wide variety of foods such as grains and cereals and its involvement in the development of + (hepatocellular carcinoma; HCC). HCC is one of the main types of liver cancer, and has become a serious public health problem, due to its high incidence mainly in Southeast Asia and Africa. Studies show that AFB1 acts in synergy with other risk factors such as hepatitis B and C virus leading to the development of HCC through genetic and epigenetic modifications. The genetic modifications begin in the liver through the biomorphic AFB1, the AFB1-exo-8.9-Epoxy active, which interacts with DNA to form adducts of AFB1-DNA. These adducts induce mutation in codon 249, mediated by a transversion of G-T in the p53 tumor suppressor gene, causing HCC. Thus, this review provides an overview of the evidence for AFB1-induced epigenetic alterations and the potential mechanisms involved in the development of HCC, focusing on a critical analysis of the importance of severe legislation in the detection of aflatoxins.
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Affiliation(s)
- Roseane Guimarães Ferreira
- Neurosciences and Cell Biology Post-Graduation Program, Biological Sciences Institute, Federal University of Pará/UFPA, Belém, Pará, Brazil.
| | - Magda Vieira Cardoso
- Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPA, Belém, Pará, Brazil.
| | | | | | | | - Marta Chagas Monteiro
- Neurosciences and Cell Biology Post-Graduation Program, Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPA, Belém, Pará, Brazil.
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Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int 2019; 13:125-137. [PMID: 30600478 DOI: 10.1007/s12072-018-9919-1] [Citation(s) in RCA: 366] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/04/2018] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and its incidence continues to rise. While cirrhosis underlies most cases of HCC, many molecular pathways are implicated in HCC carcinogenesis, including the TERT promoter mutation, Wnt/β-catenin, P53, Akt/mTOR, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor (EGFR)/RAS/MAPK pathways. While the most widely used staging and treatment algorithm for HCC-the Barcelona Clinic Liver Cancer (BCLC) system-does not recommend systemic molecular therapy for early HCC, a variety of treatment options are available depending upon the stage of HCC at diagnosis. Determining the best treatment options must take into account not only the burden and extent of HCC, but also the patient's performance status, underlying liver function, extra-hepatic disease and co-morbidities. Radiofrequency or microwave ablation, liver resection, or liver transplantation, all potential curative therapies for HCC, should be the first-line treatments when possible. For patients who are not candidates of curative treatments, locoregional therapies such as transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiation (SBRT) can improve survival and quality of life. Sorafenib, a multi-kinase VEGF inhibitor, is the most widely used systemic chemotherapy approved as a first-line agent for unresectable or advanced HCC. Clinical trials are underway directed towards molecular therapies that target different aspects of the hepatocellular carcinogenesis cascade. Ideally, the goal of future therapy should be to target multiple pathways in the HCC cascade with combination treatments to achieve personalized care aimed at improving overall survival.
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Affiliation(s)
- Thomas Couri
- Department of Internal Medicine, University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Anjana Pillai
- Division of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA.
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Ning G, Huang YL, Zhen LM, Xu WX, Jiao Q, Yang FJ, Wu LN, Zheng YY, Song J, Wang YS, Xie C, Peng L. Transcriptional expressions of Chromobox 1/2/3/6/8 as independent indicators for survivals in hepatocellular carcinoma patients. Aging (Albany NY) 2018; 10:3450-3473. [PMID: 30481161 PMCID: PMC6286817 DOI: 10.18632/aging.101658] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Accepted: 11/15/2018] [Indexed: 12/27/2022]
Abstract
Chromobox (CBX) proteins are important components of epigenetic regulation complexes known to play key roles in hepatocellular carcinoma (HCC). Little is known about the function of distinct CBXs in HCC. To address this issue, the study investigated the roles of CBXs in the prognosis of HCC using ONCOMINE, UALCAN, Human Protein Atlas, Kaplan-Meier Plotter, c-BioPortal databases. Over expressions of 8 CBXs members were found to be significantly associated with clinical cancer stages and pathological tumor grades in HCC patients. Besides, higher mRNA expressions of CBX1/2/3/6/8 were found to be significantly associated with shorter overall survival (OS) in HCC patients, while higher mRNA expression of CBX7 was associated with favorable OS. Multivariate analysis also showed that high mRNA expressions of CBX1/2/3/6/8 were independent prognostic factors for shorter OS of HCC patients. Moreover, high mutation rate of CBXs (51%) was also observed in HCC patients, and genetic alteration in CBXs was associated with shorter OS and disease-free survival (DFS) in HCC patients. Taken together, these results indicated that CBX1/2/3/6/8 could be prognostic biomarkers for survivals of HCC patients.
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Affiliation(s)
- Gang Ning
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Equal contribution
| | - Yan-Lin Huang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research,the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Equal contribution
| | - Li-Min Zhen
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Equal contribution
| | - Wen-Xiong Xu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Qian Jiao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Fang-Ji Yang
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Li-Na Wu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yong-Yuan Zheng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jie Song
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Yen-Sheng Wang
- Department of Environmental Health Science, Yale School of Public Health, New Haven, Connecticut 06520, USA
| | - Chan Xie
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Liang Peng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Li BH, Wang Y, Wang CY, Zhao MJ, Deng T, Ren XQ. Up-Regulation of Phosphatase in Regenerating Liver-3 (PRL-3) Contributes to Malignant Progression of Hepatocellular Carcinoma by Activating Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)/Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway. Med Sci Monit 2018; 24:8105-8114. [PMID: 30418964 PMCID: PMC6243833 DOI: 10.12659/msm.913307] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 10/23/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The purpose of the study was to investigate the functional roles of phosphatase in regenerating liver-3 (PRL-3) in hepatocellular carcinoma (HCC), as well as the related molecular mechanisms. MATERIAL AND METHODS HCC tissues and adjacent normal tissues were collected from 124 HCC patients. The mRNA and protein levels of PRL-3 were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assays, respectively. The relationship between PRL-3 expression and clinical characteristics of HCC patients was evaluated by chi-square test. MTT and Transwell assays were performed to estimate cell proliferation and motility, respectively. RESULTS The expression of PRL-3 was significantly increased in HCC tissues and cells at both protein and mRNA levels (P<0.01 for all). Furthermore, the up-regulation of PRL-3 was positively correlated with hepatic vascular invasion (P=0.019), lymph node metastasis (P=0.012), and TNM stage (P=0.001). The knockdown of PRL-3 suppressed HCC cell proliferation, migration, and invasion, and PR3K/AKT pathway activity was also obviously inhibited in HCC cells with PRL-3 deficiency. The levels of PTEN were negatively associated with PRL-3 expression. PRL-3 might inhibit the protein level of PTEN through enhancing its phosphorylation level. The transfection of si-PTEN can reverse the anti-tumor action caused by PRL-3 knockdown in HCC cells. CONCLUSIONS Up-regulation of PRL-3 may activate the PI3K/AKT signaling pathway and enhance malignant progression of HCC through targeting PTEN.
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Affiliation(s)
- Bing-Hui Li
- Department of General Surgery, Center for Evidence-Based Medicine and Clinical Research, Huaihe Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Yang Wang
- Department of General Surgery, Center for Evidence-Based Medicine and Clinical Research, Huaihe Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Chao-Yang Wang
- Department of General Surgery, Center for Evidence-Based Medicine and Clinical Research, Huaihe Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Ming-Juan Zhao
- Department of Cardiology, The First Affiliated Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Tong Deng
- Department of General Surgery, Center for Evidence-Based Medicine and Clinical Research, Huaihe Hospital of Henan University, Kaifeng, Henan, P.R. China
| | - Xue-Qun Ren
- Department of General Surgery, Center for Evidence-Based Medicine and Clinical Research, Huaihe Hospital of Henan University, Kaifeng, Henan, P.R. China
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Lin Z, Jia H, Hong L, Zheng Y, Shao W, Ren X, Zhu W, Lu L, Lu M, Zhang J, Chen J. Prognostic impact of SET domain-containing protein 8 and protein arginine methyltransferase 5 in patients with hepatocellular carcinoma following curative resection. Oncol Lett 2018; 16:3665-3673. [PMID: 30127976 PMCID: PMC6096198 DOI: 10.3892/ol.2018.9083] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Accepted: 04/04/2018] [Indexed: 12/12/2022] Open
Abstract
Histone methyltransferases are important determinants of the initiation and progression of hepatocellular carcinoma (HCC) and represent promising therapeutic targets. However, whether the expression profile of multiple histone methyltransferases represents a poorer prognosis is entirely unknown. The aim of the present study was to investigate the association between histone methylation and HCC phenotype, and the prognostic value of combining expression levels of SET domain-containing protein 8 (SET8) with protein arginine methyltransferase 5 (PRMT5) in patients with HCC following curative resection. The retrospective study included 195 consecutive patients who had undergone hepatectomy for HCC. Immunohistochemical staining for SET8 and PRMT5 was performed on paraffin-embedded tumor tissue microarrays. Expression was analyzed for correlations with clinicopathological features, marker co-expression and patients' survival by univariate and multivariate analyses. Positive SET8 expression was noted in 104 patients (53.3%), and was associated with PRMT5 expression (n=106, 54.4%, P<0.05). Immunohistochemical analysis demonstrated that high expression of SET8 and PRMT5 was significantly associated with poor overall survival (OS, P<0.001) and time to recurrence (TTR, P<0.001). Multivariate Cox analysis revealed that SET8 and PRMT5, along with vascular invasion, tumor size and tumor number, were independent prognostic factors for OS and TTR. The combination of SET8 and PRMT5 demonstrated an improved capacity to predict patient mortality and disease recurrence (P=0.002 and P=0.004, respectively), particularly for the prediction of early recurrence (P<0.001). In conclusion, high expression of SET8 combined with PRMT5 was associated with a high rate of recurrence and poor survival in patients with HCC. The independent pattern of histone methylation represents a novel insight into tumor progression and therapeutic targets for HCC.
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Affiliation(s)
- Zhifei Lin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Huliang Jia
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Liang Hong
- Department of Infectious Diseases, Ruian People's Hospital, Wenzhou, Zhejiang 325200, P.R. China
| | - Yahui Zheng
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Weiqin Shao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Xudong Ren
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Wenwei Zhu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Lu Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Ming Lu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jubo Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
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The therapeutic properties of resminostat for hepatocellular carcinoma. Oncoscience 2018; 5:196-208. [PMID: 30035186 PMCID: PMC6049311 DOI: 10.18632/oncoscience.420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 03/03/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with increases in new cases being reported annually. Histopathologists have identified hepatic steatosis as a characteristic of a broad range of chronic liver diseases that are associated with the onset and development of HCC. In this context, epigenetic modifications may serve as precancerous factors predisposing normal cells to the initiation of carcinogenesis. This study demonstrated that hepatic tumorigenesis and differentiated adipocytes may modulate both global histone deacetylase (HDAC) expression and specific class I HDAC genes in the tumour microenvironment. The novel class I HDAC inhibitor Resminostat was shown to reduce the proliferation of HCC cells along with its specificity in targeting class I HDACs and oncogenes. The combined effect of Resminostat with several pharmaceutical agents such as Sorafenib, Cisplatin and Doxorubicin was also demonstrated. The inhibition of heat shock protein 90 (HSP90) has been demonstrated as a potential therapeutic option for HCC. In line with this, the specific HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was selected and it was found that the combination of Resminostat and 17-AAG may provide a “smart” clinical strategy for HCC patients by targeting cellular communication within the tumour microenvironment. This study provides an insight into the use of Resminostat as an epigenetic based therapeutic for HCC along with other pharmaceutical options, in particular by targeting the cell-to-cell communication that occurs between hepatoma and adipocytes.
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Amicone L, Marchetti A. Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma. Transl Gastroenterol Hepatol 2018; 3:24. [PMID: 29971255 DOI: 10.21037/tgh.2018.04.05] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 04/11/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), is one of the most frequent human cancer and is characterized by a high mortality rate. The aggressiveness appears strictly related to the liver pathological background on which cancer develops. Inflammation and the consequent fibro/cirrhosis, derived from chronic injuries of several origins (viral, toxic and metabolic) and observable in almost all oncological patients, represents the most powerful risk factor for HCC and, at the same time, an important obstacle to the efficacy of systemic therapy. Multiple microenvironmental cues, indeed, play a pivotal role in the pathogenesis, evolution and recurrence of HCC as well as in the resistance to standard therapies observed in most of patients. The identification of altered pathways in cancer cells and of microenvironmental changes, strictly connected in pathogenic feedback loop, may permit to plan new therapeutic approaches targeting tumor cells and their permissive microenvironment, simultaneously.
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Affiliation(s)
- Laura Amicone
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
| | - Alessandra Marchetti
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy
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Daher S, Massarwa M, Benson AA, Khoury T. Current and Future Treatment of Hepatocellular Carcinoma: An Updated Comprehensive Review. J Clin Transl Hepatol 2018; 6:69-78. [PMID: 29607307 PMCID: PMC5863001 DOI: 10.14218/jcth.2017.00031] [Citation(s) in RCA: 197] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 10/07/2017] [Accepted: 10/23/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality. The principal treatment is surgical resection or liver transplantation, depending on whether the patient is a suitable transplant candidate. However, in most patients with HCC the diagnosis is often late, thereby excluding the patients from definitive surgical resection. Medical treatment includes sorafenib, which is the most commonly used systemic therapy; although, it has been shown to only minimally impact patient survival by several months. Chemotherapy and radiotherapy are generally ineffective. Due to the poor prognosis of patients with HCC, newer treatments are needed with several being in development, either in pre-clinical or clinical studies. In this review article, we provide an update on the current and future medical and surgical management of HCC.
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Affiliation(s)
- Saleh Daher
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Muhammad Massarwa
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel A. Benson
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- *Correspondence to: Tawfik Khoury, Institute of Gastroenterology and Liver diseases, Hebrew University-Hadassah Medical Center, P.O.B. 12000, Jerusalem IL-91120, Israel. Tel: +972-509870611, E-mail:
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Sanna L, Marchesi I, Melone MAB, Bagella L. The role of enhancer of zeste homolog 2: From viral epigenetics to the carcinogenesis of hepatocellular carcinoma. J Cell Physiol 2018; 233:6508-6517. [PMID: 29574790 DOI: 10.1002/jcp.26545] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 02/16/2018] [Indexed: 12/17/2022]
Abstract
Nowadays, epigenetics covers a crucial role in different fields of science. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), is a big proponent of how epigenetic changes can affect the initiation and progression of several diseases. Through its catalytic activity, responsible for the tri-methylation of lysine 27 of the histone H3 (H3K27me3), EZH2 is a good target for both diagnosis and therapy of different pathologies. A large number of studies have demonstrated its crucial role in cancer initiation and progression. Nevertheless, only recently its function in virus diseases has been uncovered; therefore, EZH2 can be an important promoter of viral carcinogenesis. This review explores the role of EZH2 in viral epigenetics based on recent progress that demonstrated the role of this protein in virus environment. In particular, the review focuses on EZH2 behavior in Hepatitis B Virus, analyzing its role in the rise of Hepatocellular Carcinoma.
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Affiliation(s)
- Luca Sanna
- Department of Biomedical Science, and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy
| | - Irene Marchesi
- Department of Biomedical Science, and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy
| | - Mariarosa A B Melone
- Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, Second Division of Neurology, Center for Rare Neurological e Neuromuscular Diseases and Interuniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania
| | - Luigi Bagella
- Department of Biomedical Science, and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania
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Nrf2-p62 autophagy pathway and its response to oxidative stress in hepatocellular carcinoma. Transl Res 2018; 193:54-71. [PMID: 29274776 DOI: 10.1016/j.trsl.2017.11.007] [Citation(s) in RCA: 167] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 11/06/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
Abstract
Deregulation of autophagy is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the third leading cause of cancer death. Autophagy is an evolutionarily conserved catabolic process activated to degrade and recycle cell's components. Under stress conditions, such as oxidative stress and nutrient deprivation, autophagy is an essential survival pathway that operates in harmony with other stress response pathways. These include the redox-sensitive transcription complex Nrf2-Keap1 that controls groups of genes with roles in detoxification and antioxidant processes, intermediary metabolism, and cell cycle regulation. Recently, a functional association between a dysfunctional autophagy and Nrf2 pathway activation has been identified in HCC. This appears to occur through the physical interaction of the autophagy adaptor p62 with the Nrf2 inhibitor Keap1, thus leading to increased stabilization and transcriptional activity of Nrf2, a key event in reprogramming metabolic and stress response pathways of proliferating hepatocarcinoma cells. These emerging molecular mechanisms and the therapeutic perspective of targeting Nrf2-p62 interaction in HCC are discussed in this paper along with the prognostic value of autophagy in this type of cancer.
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Yang C, Hou A, Yu C, Dai L, Wang W, Zhang K, Shao H, Ma J, Xu W. Kanglaite reverses multidrug resistance of HCC by inducing apoptosis and cell cycle arrest via PI3K/AKT pathway. Onco Targets Ther 2018; 11:983-996. [PMID: 29520149 PMCID: PMC5833758 DOI: 10.2147/ott.s153814] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Multidrug resistance (MDR) frequently contributes to the failure of chemotherapeutic treatments in patients diagnosed with hepatocellular carcinoma (HCC). Revealing the molecular mechanism of MDR is indispensable for the development of effective chemotherapeutic drugs. PURPOSE Due to the low-toxicity modulators to inhibit MDR, we considered that Kanglaite (KLT) is a potential agent for reversing MDR in HCC. MATERIALS AND METHODS BEL-7402/5-fluorouracil (5-FU) and HepG2/adriamycin (ADM) were analyzed for cell viability, colony formation assay, cell scratch assay, and cell cycle analysis and apoptosis assay by flow cytometry. The expression of PARP, caspase-3, Bax, Bcl-2, CDC25C, Cyclin B1 and phosphorylation of PTEN, PI3K, and AKT in HepG2/ADM cells were detected by western blotting. RESULTS The proliferation of drug-resistant cell lines BEL-7402/5-FU and HepG2/ADM pretreated with KLT was significantly inhibited when compared with drug alone. KLT could increase the accumulation of ADM in HepG2/ADM cells. In this study, we found that KLT treatment notably reduced cell viability, induced apoptosis and cell cycle arrest in human HepG2/ADM and BEL-7402/5-FU cells, and effectively reversed the MDR by p-glycoprotein (P-gp) inhibition. Moreover, KLT decreased the phosphorylation of AKT and PI3K in KLT-treated HepG2/ADM cells. These data together implied that KLT might reverse drug resistance in HCC by blocking the PI3K/AKT signaling. CONCLUSION We demonstrated that KLT reversed MDR of human HCC by inducing apoptosis and cell cycle arrest via the PI3K/AKT signaling pathway.
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Affiliation(s)
| | - Aihua Hou
- Yantai Hospital of Traditional Chinese Medicine
- Binzhou Medical University, Yantai, China
| | - Chunfeng Yu
- Yantai Hospital of Traditional Chinese Medicine
| | | | - Wen Wang
- Yantai Hospital of Traditional Chinese Medicine
| | | | | | - Jinghua Ma
- Yantai Hospital of Traditional Chinese Medicine
| | - Wenjuan Xu
- Binzhou Medical University, Yantai, China
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El Khodiry A, Afify M, El Tayebi HM. Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis. World J Gastroenterol 2018; 24:549-572. [PMID: 29434445 PMCID: PMC5799857 DOI: 10.3748/wjg.v24.i5.549] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 01/17/2018] [Accepted: 01/23/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide. HCC is the fifth common malignancy in the world and the second leading cause of cancer death in Asia. Long non-coding RNAs (lncRNAs) are RNAs with a length greater than 200 nucleotides that do not encode proteins. lncRNAs can regulate gene expression and protein synthesis in several ways by interacting with DNA, RNA and proteins in a sequence specific manner. They could regulate cellular and developmental processes through either gene inhibition or gene activation. Many studies have shown that dysregulation of lncRNAs is related to many human diseases such as cardiovascular diseases, genetic disorders, neurological diseases, immune mediated disorders and cancers. However, the study of lncRNAs is challenging as they are poorly conserved between species, their expression levels aren't as high as that of mRNAs and have great interpatient variations. The study of lncRNAs expression in cancers have been a breakthrough as it unveils potential biomarkers and drug targets for cancer therapy and helps understand the mechanism of pathogenesis. This review discusses many long non-coding RNAs and their contribution in HCC, their role in development, metastasis, and prognosis of HCC and how to regulate and target these lncRNAs as a therapeutic tool in HCC treatment in the future.
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Affiliation(s)
- Aya El Khodiry
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Menna Afify
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
| | - Hend M El Tayebi
- Genetic Pharmacology Research Group, Clinical Pharmacy Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt
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Bhat V, Srinathan S, Pasini E, Angeli M, Chen E, Baciu C, Bhat M. Epigenetic basis of hepatocellular carcinoma: A network-based integrative meta-analysis. World J Hepatol 2018; 10:155-165. [PMID: 29399289 PMCID: PMC5787679 DOI: 10.4254/wjh.v10.i1.155] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Revised: 11/17/2017] [Accepted: 12/07/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify the key epigenetically modulated genes and pathways in HCC by performing an integrative meta-analysis of all major, well-annotated and publicly available methylation datasets using tools of network analysis.
METHODS PubMed and Gene Expression Omnibus were searched for genome-wide DNA methylation datasets. Patient clinical and demographic characteristics were obtained. DNA methylation data were integrated using the Ingenuity Pathway Analysis, a software package for visualizing and analyzing biological networks. Pathway enrichment analysis was performed using IPA, which also provides literature-driven and computationally-predicted annotations for significant association of genes to curated molecular pathways.
RESULTS From an initial 928 potential abstracts, we identified and analyzed 11 eligible high-throughput methylation datasets representing 354 patients. A significant proportion of studies did not provide concomitant clinical data. In the promoter region, HIST1H2AJ and SPDYA were the most commonly methylated, whereas HRNBP3 gene was the most commonly hypomethylated. ESR1 and ERK were central genes in the principal networks. The pathways most associated with the frequently methylated genes were G-protein coupled receptor and cAMP-mediated signalling.
CONCLUSION Using an integrative network-based analysis approach of genome-wide DNA methylation data of both the promoter and body of genes, we identified G-protein coupled receptor signalling as the most highly associated with HCC. This encompasses a diverse range of cancer pathways, such as the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways, and is therefore supportive of previous literature on gene expression in HCC. However, there are novel targetable genes such as HIST1H2AJ that are epigenetically modified, suggesting their potential as biomarkers and for therapeutic targeting of the HCC epigenome.
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Affiliation(s)
- Venkat Bhat
- Department of Psychiatry, University Health Network and University of Toronto, Toronto M5G2N2, Canada
| | - Sujitha Srinathan
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Elisa Pasini
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Marc Angeli
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Emily Chen
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Cristina Baciu
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
| | - Mamatha Bhat
- Multi Organ Transplant Program, University Health Network, Toronto M5G2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network and University of Toronto, Toronto M5G2N2, Canada
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Irshad M, Gupta P, Irshad K. Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection. World J Hepatol 2017; 9:1305-1314. [PMID: 29359013 PMCID: PMC5756719 DOI: 10.4254/wjh.v9.i36.1305] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Revised: 11/08/2017] [Accepted: 12/05/2017] [Indexed: 02/06/2023] Open
Abstract
Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.
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Affiliation(s)
- Mohammad Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Priyanka Gupta
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Khushboo Irshad
- Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
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Zamani P, Matbou Riahi M, Momtazi-Borojeni AA, Jamialahmadi K. Gankyrin: a novel promising therapeutic target for hepatocellular carcinoma. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:1301-1313. [PMID: 29025272 DOI: 10.1080/21691401.2017.1388250] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Hepatocellular carcinoma (HCC) is known as fifth common malignancies and third common cause of cancer-related death worldwide. The identification of various mechanisms which are involved in hepatocarcinogenesis contributes in finding a variety of cellular and molecular targets for HCC diagnosis, prevention and therapy. Among various identified targets in HCC pathogenesis, Gankyrin is a crucial oncoprotein that is up-regulated in HCC and plays a pivotal role in the initiation and progression of the HCC. Oncogenic role of Gankyrin has been found to stem from inhibition of two ubiquitous tumour suppressor proteins, retinoblastoma protein (pRb) and P53, and also modulation of several vital cellular signalling pathways including Wnt/β-Catenin, NF-κB, STAT3/Akt, IL-1β/IRAK-1 and RhoA/ROCK. As a result, Gankyrin can be considered as a potential candidate for diagnosis and treatment of HCC. In this review, we summarized the physiological function and the significant role of Gankyrin as an important therapeutic target in HCC.
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Affiliation(s)
- Parvin Zamani
- a Department of Medical Biotechnology , Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Maryam Matbou Riahi
- a Department of Medical Biotechnology , Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Amir Abbas Momtazi-Borojeni
- b Nanotechnology Research Center, Bu-Ali Research Institute , Mashhad University of Medical Sciences , Mashhad , Iran.,c Department of Medical Biotechnology , Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Khadijeh Jamialahmadi
- a Department of Medical Biotechnology , Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran.,d Biotechnology Research Center , Mashhad University of Medical Sciences , Mashhad , Iran
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Wang D, Yang C, Wang Z, Yang Y, Li D, Ding X, Xu W, Zheng Q. Norcantharidin combined with Coix seed oil synergistically induces apoptosis and inhibits hepatocellular carcinoma growth by downregulating regulatory T cells accumulation. Sci Rep 2017; 7:9373. [PMID: 28839202 PMCID: PMC5571147 DOI: 10.1038/s41598-017-09668-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/27/2017] [Indexed: 12/30/2022] Open
Abstract
The immune system plays a critical role in exerts effects in the growth and progression of hepatocellular carcinoma (HCC), which needs interacting approaches for effective therapy. In this study, we have found that the Norcantharidin (NCTD) + Coix lacryma-jobi seed oil (CLSO) combination exhibited more potent antitumor effects in an terms of cytotoxicity and apoptotic induction in human HepG2 and HepG2/ADM cells than NCTD or CLSO alone. In vivo, administration of NCTD+CLSO combinations significantly suppressed the formation of tumor in Hepal-1 hepatoma-bearing mice. Furthermore, we found that the in vitro co-cultures of HepG2 or HepG2/ADM cells with PBMCs from healthy donors led to an increase in the number of CD4 + CD25 + T cells. This increase was down-regulated by the combination effectively. Down-regulation of FoxP3 mRNA and protein expression occurred during the combination in the co-cultures. The amount of Tregs of Hepal-1 hepatoma-bearing mice was significantly decreased in the combination treated group. The combination down-regulated the expression of FoxP3, CTLA-4 and Tregs related cytokine (TGF-β and IL-10) in the serum of tumor bearing mice. Taken together, these results suggest that the most valuable aspect of the NCTD+CLSO combined use improves the anti-tumor activity and regulates tumor infiltrating Tregs.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Biomarkers
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Checkpoints/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Coix/chemistry
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Synergism
- Humans
- Immunophenotyping
- Liver Neoplasms/drug therapy
- Liver Neoplasms/immunology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Mice
- Plant Oils/pharmacology
- Seeds/chemistry
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Dan Wang
- Binzhou Medical University, Yantai, 264003, China
| | - Chendong Yang
- Yantai Hospital of Traditional Chinese Medicine, Yantai, 264003, China
| | - Zhuien Wang
- Binzhou Medical University, Yantai, 264003, China
| | - Yi Yang
- Binzhou Medical University, Yantai, 264003, China
| | - Defang Li
- Binzhou Medical University, Yantai, 264003, China
| | - Xiaojie Ding
- Binzhou Medical University, Yantai, 264003, China
| | - Wenjuan Xu
- Binzhou Medical University, Yantai, 264003, China.
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