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Ndirangu K, Paine A, Pilkington H, Trueman D. An Indirect Treatment Comparison of Lenvatinib for the First-Line Treatment of Patients with Unresectable Hepatocellular Carcinoma. Adv Ther 2025; 42:977-994. [PMID: 39680315 PMCID: PMC11787224 DOI: 10.1007/s12325-024-03068-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/08/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses. METHODS Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators. RESULTS Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W. CONCLUSIONS These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies.
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Affiliation(s)
- Kerigo Ndirangu
- Global Value & Access (GV&A), Eisai Inc., 200 Metro Blvd., Nutley, NJ, 07110, USA.
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Diwan R, Gaytan SL, Bhatt HN, Pena-Zacarias J, Nurunnabi M. Liver fibrosis pathologies and potentials of RNA based therapeutics modalities. Drug Deliv Transl Res 2024; 14:2743-2770. [PMID: 38446352 DOI: 10.1007/s13346-024-01551-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2024] [Indexed: 03/07/2024]
Abstract
Liver fibrosis (LF) occurs when the liver tissue responds to injury or inflammation by producing excessive amounts of scar tissue, known as the extracellular matrix. This buildup stiffens the liver tissue, hinders blood flow, and ultimately impairs liver function. Various factors can trigger this process, including bloodborne pathogens, genetic predisposition, alcohol abuse, non-steroidal anti-inflammatory drugs, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. While some existing small-molecule therapies offer limited benefits, there is a pressing need for more effective treatments that can truly cure LF. RNA therapeutics have emerged as a promising approach, as they can potentially downregulate cytokine levels in cells responsible for liver fibrosis. Researchers are actively exploring various RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides, to assess their efficacy in animal models. Furthermore, targeted drug delivery systems hold immense potential in this field. By utilizing lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles, researchers aim to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, increasing their effectiveness and reducing side effects. In conclusion, this review highlights the complex nature of liver fibrosis, its underlying causes, and the promising potential of RNA-based therapeutics and targeted delivery systems. Continued research in these areas could lead to the development of more effective and personalized treatment options for LF patients.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Samantha Lynn Gaytan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Himanshu Narendrakumar Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Jacqueline Pena-Zacarias
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biological Sciences, College of Science, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA.
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA.
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA.
- Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968, USA.
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Yang J, Chen J, Li Q, Xu RA, Chen X. Effects of three flavonoids on the metabolism of lenvatinib. Front Pharmacol 2024; 15:1438259. [PMID: 39228528 PMCID: PMC11368737 DOI: 10.3389/fphar.2024.1438259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 07/26/2024] [Indexed: 09/05/2024] Open
Abstract
Lenvatinib is a first-line therapy for the treatment of hepatocellular carcinoma (HCC), an active multi-target tyrosine kinase inhibitor (TKI). The interaction between Traditional Chinese Medicine (TCM) and chemicals has increasingly become a research hotspot. The objective of this study was to pinpoint the effects of three flavonoids on the metabolism of lenvatinib. Enzyme reaction system was established and optimized in vitro, and in vivo experiments were conducted in Sprague-Dawley (SD) rats, where the analytes were detected by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We found that among three flavonoids, luteolin and myricetin had strong inhibitory effects on lenvatinib metabolism, with half-maximal inhibitory concentration (IC50) values of 11.36 ± 0.46 µM and 11.21 ± 0.81 µM in rat liver microsomes (RLM), respectively, and 6.89 ± 0.43 µM and 12.32 ± 1.21 µM in human liver microsomes (HLM), respectively. In Sprague-Dawley rats, the combined administration of lenvatinib and luteolin obviously expanded the exposure to lenvatinib; however, co-administered with myricetin did not have any changes, which may be due to the poor bioavailability of myricetin in vivo. Furthermore, the inhibitory type of luteolin on lenvatinib showed an un-competitive in RLM and a mixed in HLM. Collectively, flavonoids with liver protection, especially luteolin, may inhibit lenvatinib metabolism in vitro and in vivo.
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Affiliation(s)
- Jinzhao Yang
- Wenzhou People’s Hospital, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Chen
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qingqing Li
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ren-ai Xu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiaohai Chen
- The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Moore LL, Qu D, Sureban S, Mitchell S, Pitts K, Cooper N, Fazili J, Harty R, Oseini A, Ding K, Bronze M, Houchen CW. From Inflammation to Oncogenesis: Tracing Serum DCLK1 and miRNA Signatures in Chronic Liver Diseases. Int J Mol Sci 2024; 25:6481. [PMID: 38928187 PMCID: PMC11203803 DOI: 10.3390/ijms25126481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/06/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024] Open
Abstract
Chronic liver diseases, fibrosis, cirrhosis, and HCC are often a consequence of persistent inflammation. However, the transition mechanisms from a normal liver to fibrosis, then cirrhosis, and further to HCC are not well understood. This study focused on the role of the tumor stem cell protein doublecortin-like kinase 1 (DCLK1) in the modulation of molecular factors in fibrosis, cirrhosis, or HCC. Serum samples from patients with hepatic fibrosis, cirrhosis, and HCC were analyzed via ELISA or NextGen sequencing and were compared with control samples. Differentially expressed (DE) microRNAs (miRNA) identified from these patient sera were correlated with DCLK1 expression. We observed elevated serum DCLK1 levels in fibrosis, cirrhosis, and HCC patients; however, TGF-β levels were only elevated in fibrosis and cirrhosis. While DE miRNAs were identified for all three disease states, miR-12136 was elevated in fibrosis but was significantly increased further in cirrhosis. Additionally, miR-1246 and miR-184 were upregulated when DCLK1 was high, while miR-206 was downregulated. This work distinguishes DCLK1 and miRNAs' potential role in different axes promoting inflammation to tumor progression and may serve to identify biomarkers for tracking the progression from pre-neoplastic states to HCC in chronic liver disease patients as well as provide targets for treatment.
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Affiliation(s)
- Landon L. Moore
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Dongfeng Qu
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Sripathi Sureban
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Stephanie Mitchell
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Kamille Pitts
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Nasya Cooper
- Department of Natural Sciences, Langston University, Langston, OK 73050, USA;
| | - Javid Fazili
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Richard Harty
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Abdul Oseini
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Kai Ding
- Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Michael Bronze
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
| | - Courtney W. Houchen
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (L.L.M.); (D.Q.); (S.S.); (S.M.); (K.P.); (J.F.); (R.H.); (A.O.); (M.B.)
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
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Hiltunen N, Kemi N, Väyrynen JP, Böhm J, Kauppila JH, Huhta H, Helminen O. Toll-like receptors 1-9 in small bowel neuroendocrine tumors-Clinical significance and prognosis. PLoS One 2024; 19:e0302813. [PMID: 38709790 PMCID: PMC11073674 DOI: 10.1371/journal.pone.0302813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 04/12/2024] [Indexed: 05/08/2024] Open
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors of the innate immunity. TLRs are known to mediate both antitumor effects and tumorigenesis. TLRs are abundant in many cancers, but their expression in small bowel neuroendocrine tumors (SB-NETs) is unknown. We aimed to characterize the expression of TLRs 1-9 in SB-NETs and lymph node metastases and evaluate their prognostic relevance. The present study included 125 patients with SB-NETs, of whom 95 had lymph node metastases, from two Finnish hospitals. Tissue samples were stained immunohistochemically for TLR expression, assessed based on cytoplasmic and nucleic staining intensity and percentage of positively stained cells. Statistical methods for survival analysis included Kaplan-Meier method and Cox regression adjusted for confounding factors. Disease-specific survival (DSS) was the primary outcome. TLRs 1-2 and 4-9 were expressed in SB-NETs and lymph node metastases. TLR3 showed no positive staining. In primary SB-NETs, TLRs 1-9 were not associated with survival. For lymph node metastases, high cytoplasmic TLR7 intensity associated with worse DSS compared to low cytoplasmic intensity (26.4% vs. 84.9%, p = 0.028). Adjusted mortality hazard (HR) was 3.90 (95% CI 1.07-14.3). The expression of TLRs 1-6 and 8-9 in lymph node metastases were not associated with survival. SB-NETs and their lymph node metastases express cytoplasmic TLR 1-2 and 4-9 and nucleic TLR5. High TLR7 expression in SB-NET lymph node metastases was associated with worse prognosis. The current research has future perspective, as it can help create base for clinical drug trials to target specific TLRs with agonists or antagonists to treat neuroendocrine tumors.
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Affiliation(s)
- Niko Hiltunen
- Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Niko Kemi
- Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Juha P. Väyrynen
- Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jan Böhm
- Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland
| | - Joonas H. Kauppila
- Surgery Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Upper Gastrointestinal Surgery, Stockholm, Sweden
| | - Heikki Huhta
- Surgery Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Olli Helminen
- Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
- Surgery Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital, Oulu, Finland
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Buttell A, Qiu W. The action and resistance mechanisms of Lenvatinib in liver cancer. Mol Carcinog 2023; 62:1918-1934. [PMID: 37671815 PMCID: PMC10840925 DOI: 10.1002/mc.23625] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 09/07/2023]
Abstract
Lenvatinib is a tyrosine kinase inhibitor that prevents the formation of new blood vessels namely by inhibiting tyrosine kinase enzymes as the name suggests. Specifically, Lenvatinib acts on vascular endothelial growth factor receptors 1-3 (VEGFR1-3), fibroblast growth factor receptors 1-4 (FGFR1-4), platelet-derived growth factor receptor-alpha (PDGFRα), tyrosine-kinase receptor (KIT), and rearranged during transfection receptor (RET). Inhibition of these receptors works to inhibit tumor proliferation. It is through these inhibition mechanisms that Lenvatinib was tested to be noninferior to Sorafenib. However, resistance to Lenvatinib is common, making the positive effects of Lenvatinib on a patient's survival null after resistance is acquired. Therefore, it is crucial to understand mechanisms related to Lenvatinib resistance. This review aims to piece together various mechanisms involved in Lenvatinib resistance and summarizes the research done so far investigating it.
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Affiliation(s)
- Anna Buttell
- Departments of Surgery, Loyola University Chicago Stritch School of Medicine, 2160 South 1 Avenue., Maywood, IL 60153, USA
- Departments of Cancer Biology, Loyola University Chicago Stritch School of Medicine, 2160 South 1 Avenue., Maywood, IL 60153, USA
| | - Wei Qiu
- Departments of Surgery, Loyola University Chicago Stritch School of Medicine, 2160 South 1 Avenue., Maywood, IL 60153, USA
- Departments of Cancer Biology, Loyola University Chicago Stritch School of Medicine, 2160 South 1 Avenue., Maywood, IL 60153, USA
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Tiyuri A, Baghermanesh SS, Davatgaran-Taghipour Y, Eslami SS, Shaygan N, Parsaie H, Barati M, Jafari D. Diagnostic accuracy of serum derived exosomes for hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Mol Diagn 2023; 23:971-983. [PMID: 37715364 DOI: 10.1080/14737159.2023.2260306] [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: 02/10/2023] [Revised: 08/26/2023] [Accepted: 09/01/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Early and non-invasive detection of hepatocellular carcinoma (HCC), which is usually asymptomatic, can improve overall survival outcomes. The objective of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of serum-derived exosomes for diagnosing HCC. METHODS PubMed, Web of Science, and Scopus databases were searched for relevant studies up to April 2023. The quality of included studies was assessed using the QUADAS-2 checklist, and data were extracted. Statistical analysis was performed on 18 studies from 3,993 records, and a diagnostic meta-analysis was conducted. Biomarkers were categorized into four groups based on their type (exosomal miRNAs, exosomal RNAs, alpha-fetoprotein (AFP), and exosomal RNAs+AFP panel), and a meta-analysis was conducted for each category separately. RESULTS The highest pooled sensitivity was 0.86 for exosomal miRNAs, and exosomal RNAs+AFP had the highest pooled specificity; (0.89). Furthermore, exosomal RNAs+AFP had the highest pooled positive likelihood ratio; (7.55), the highest pooled diagnostic odds ratio (35.96) and the highest pooled area under the curve (0.93). Exosomal miRNAs had the lowest pooled negative likelihood ratio; (0.17). CONCLUSIONS The diagnostic accuracy of exosomal biomarkers is superior to that of AFP, and combining the two in a panel yields the better results.
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Affiliation(s)
- Amir Tiyuri
- Department of Epidemiology and Biostatistics, School of Health, Birjand University of Medical Sciences, Birjand, Iran
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Shayeste Sadat Baghermanesh
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Yasamin Davatgaran-Taghipour
- Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Sadegh Eslami
- Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Nasibeh Shaygan
- Department of Plant Breeding and Biotechnology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Houman Parsaie
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahmood Barati
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Davod Jafari
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
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Aslani F, Afarin R, Dehghani Madiseh N, Beheshti Nasab H, Monjezi S, Igder S, Rashidi M. Potentiation of Apoptotic Effect of Combination of Etoposide and Quercetin on HepG2 Liver Cancer Cells. HEPATITIS MONTHLY 2023. [DOI: 10.5812/hepatmon-136194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The current remedies for cancer, including chemotherapy and radiation therapy, might damage patients’ organs, sometimes causing death. Etoposide (ETO), as a widely used chemo-drug, possesses the same problems. For years, combinational therapy has been considered a potential adjustor for common treatments, alleviating their side effects. Quercetin (Que), a phytochemical drug, has been used due to its potential against cancer. Objectives: This study explored whether synergy occurs between Que and ETO on the apoptosis of HepG2 HCC cells or not. Methods: The impacts of the drugs on cell growth were assessed through the MTT assay. The apoptotic death rates of treated cells were examined through Annexin/PI double staining and caspase-9 and caspase-3 activities. The relative expression of B-cell lymphoma 2 (Bcl-2) Associated X-protein (Bax), and Bcl-2 genes and proteins were analyzed using quantitative reverse transcription polymerase chain reaction and western blot analysis. Additionally, the levels of p53 protein were determined. Results: Both Que and ETO reduced the cell viability and increased apoptotic rates, caspases activities, Bax gene and protein expression, and the p53 protein levels of HepG2 cells. The combination of Que and ETO showed apparent synergy in terms of cell growth and cell apoptosis. Que significantly enhanced the effects of ETO on caspase activities, Bax and Bcl-2 genes’ expression, and p53 protein levels. Conclusions: The obtained results demonstrated that Que showed synergy when co-treated with ETO on HepG2 cells. Therefore, it is concluded that further studies on the aforementioned combination could lead to a potential anticancer compound against HCC.
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Abdi E, Latifi-Navid S. Long noncoding RNA polymorphisms and hepatocellular carcinoma and pancreatic cancer risk. Per Med 2023. [PMID: 36705078 DOI: 10.2217/pme-2021-0156] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) are among serious malignancies with no proper biomarker suffering from poor prognosis and late onset. Regulation of long noncoding RNAs (lncRNAs) is disturbed in tumors, making them appropriate diagnostic markers or therapeutic targets in systemic therapies. The expression and function of some significant lncRNAs are under the influence of SNPs, highlighting their key role in carcinogenesis. This review assesses the associations between SNPs in lncRNAs and HCC and PC risk. A panel of cancer-associated SNPs in lncRNA genes could help evaluate the clinical use of lncRNAs, including their role as diagnostic markers and therapeutic targets. Nonetheless, more large-scale surveys on various ethnic groups are required to validate results.
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Affiliation(s)
- Esmat Abdi
- Department of Biology, University of Mohaghegh Ardabili, Ardabil, 5619911367, Iran
| | - Saeid Latifi-Navid
- Department of Biology, University of Mohaghegh Ardabili, Ardabil, 5619911367, Iran
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Farooq U, Wang H, Hu J, Li G, Jehan S, Shi J, Li D, Sui G. Polydatin Inhibits Hepatocellular Carcinoma Cell Proliferation and Sensitizes Doxorubicin and Cisplatin through Targeting Cell Mitotic Machinery. Cells 2023; 12:cells12020222. [PMID: 36672157 PMCID: PMC9856937 DOI: 10.3390/cells12020222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/06/2023] Open
Abstract
Polydatin (PD) is a natural compound with anticancer activities, but the underlying mechanisms remain largely unclear. To understand how PD inhibited hepatocellular carcinoma (HCC), we studied PD treatments in HCC HepG2 and SK-HEP1 cells, and normal liver HL-7702 cells. PD selectively blocked the proliferation of HCC cells but showed low toxicity in normal cells, while the effects of doxorubicin (DOX) and cisplatin (DDP) on HCC and normal liver cells were opposite. In the cotreatment studies, PD synergistically improved the inhibitory activities of DOX and DDP in HCC cells but alleviated their toxicity in HL-7702 cells. Furthermore, RNA-seq studies of PD-treated HepG2 cells revealed multiple altered signaling pathways. We identified 1679 Differentially Expressed Genes (DEGs) with over a 2.0-fold change in response to PD treatment. Integrative analyses using the DEGs in PD-treated HepG2 cells and DEGs in a TCGA dataset of HCC patients revealed five PD-repressed DEGs regulating mitotic spindle midzone formation. The expression of these genes showed significantly positive correlation with poor clinical outcomes of HCC patients, suggesting that mitotic machinery was likely a primary target of PD. Our findings improve the understanding of PD's anticancer mechanisms and provide insights into developing effective clinical approaches in HCC therapies.
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Affiliation(s)
- Umar Farooq
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
| | - Hao Wang
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
| | - Jingru Hu
- Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education and State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China
| | - Guangyue Li
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
| | - Shah Jehan
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
| | - Jinming Shi
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
| | - Dangdang Li
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
- Correspondence: (D.L.); (G.S.)
| | - Guangchao Sui
- College of Life Sciences, Northeast Forestry University, 26 Hexing Road, Harbin 150040, China
- Correspondence: (D.L.); (G.S.)
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Berhane T, Holm A, Karstensen KT, Petri A, Ilieva MS, Krarup H, Vyberg M, Løvendorf MB, Kauppinen S. Knockdown of the long noncoding RNA PURPL induces apoptosis and sensitizes liver cancer cells to doxorubicin. Sci Rep 2022; 12:19502. [PMID: 36376362 PMCID: PMC9663437 DOI: 10.1038/s41598-022-23802-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/06/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with increasing incidence in western countries. Most HCC patients have advanced cancer at the time of diagnosis due to the asymptomatic nature of early-stage HCC and do not qualify for potentially curative surgical treatment, thus, highlighting the need for new therapeutic strategies. Long noncoding RNAs (lncRNAs) comprise a large and heterogeneous group of non-protein coding transcripts that play important regulatory roles in numerous biological processes in cancer. In this study, we performed RNA sequencing of liver biopsies from ten HCC, ten hepatitis C virus-associated HCC, and four normal livers to identify dysregulated lncRNAs in HCC. We show that the lncRNA p53-upregulated-regulator-of-p53-levels (PURPL) is upregulated in HCC biopsies and that its expression is p53-dependent in liver cancer cell lines. In addition, antisense oligonucleotide-mediated knockdown of PURPL inhibited cell proliferation, induced apoptosis, and sensitized HepG2 human HCC cells to treatment with the chemotherapeutic agent doxorubicin. In summary, our findings suggest that PURPL could serve as a new therapeutic target for reversing doxorubicin resistance in HCC.
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Affiliation(s)
- Tsinat Berhane
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark ,grid.5170.30000 0001 2181 8870Present Address: Department of Health Technology, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Anja Holm
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Kasper Thystrup Karstensen
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark ,grid.6203.70000 0004 0417 4147Present Address: Department of Bacteria, Parasites and Fungi, Statens Serum Institute, Copenhagen, Denmark
| | - Andreas Petri
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark ,grid.424580.f0000 0004 0476 7612Present Address: Department of Bioinformatics, Lundbeck, Valby, Denmark
| | - Mirolyuba Simeonova Ilieva
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Henrik Krarup
- grid.5117.20000 0001 0742 471XDepartment of Molecular Diagnostics and Department of Medical Gastroenterology, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Mogens Vyberg
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark ,grid.5117.20000 0001 0742 471XDepartment of Pathology, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Marianne Bengtson Løvendorf
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark ,grid.5254.60000 0001 0674 042XPresent Address: Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Sakari Kauppinen
- grid.5117.20000 0001 0742 471XCenter for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
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12
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A Review of Current and Emerging Therapies for Advanced Hepatocellular Carcinoma. Curr Oncol 2022; 29:6445-6462. [PMID: 36135076 PMCID: PMC9498097 DOI: 10.3390/curroncol29090507] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 11/18/2022] Open
Abstract
Hepatocellular carcinoma remains a leading cause of cancer-related deaths worldwide. Liver disease including cirrhosis and viral hepatitis remains among the leading causes of hepatocellular carcinoma and despite increased screening, many patients are diagnosed in the advanced stages precluding them from locoregional therapy. Therapeutic agents for advanced hepatocellular carcinoma were limited to Sorafenib for several years; however, with the emergence of molecular targeted therapies including tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors, in addition to immunotherapies, the way hepatocellular carcinoma is treated has changed significantly. In this review, we summarize the key clinical trials that lead to the approval of these agents for systemic treatment of hepatocellular carcinoma and discuss the preferred sequence of treatment options as well as prospective studies for management of hepatocellular carcinoma.
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13
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Culp WTN, Johnson EG, Giuffrida MA, Rebhun RB, Cawthra JK, Schwanz HA, Burton JH, Kent MS. Evaluation of the use of a novel bioabsorbable polymer drug-eluting microsphere for transarterial embolization of hepatocellular neoplasia in dogs. PLoS One 2022; 17:e0269941. [PMID: 35939428 PMCID: PMC9359553 DOI: 10.1371/journal.pone.0269941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 05/31/2022] [Indexed: 01/26/2023] Open
Abstract
In dogs with non-resectable hepatic neoplasia, treatment options are limited. The objectives of this study were to describe the use of a novel drug-eluting embolic microsphere containing paclitaxel for use during transarterial chemoembolization (TACE), to compare results of liver-specific owner questionnaires and tumor volume pre- and post-TACE, and to measure systemic paclitaxel concentration post-TACE. Client-owned dogs with non-resectable hepatic neoplasia were prospectively enrolled. All owners completed questionnaires validated for the assessment of subjective outcomes in dogs with cancer before the TACE procedure and approximately 4 weeks after the TACE procedure. A CT scan was performed before TACE and 1 month after TACE; results were compared. Blood samples were obtained at specified time points post-TACE to determine systemic paclitaxel concentrations. Seven dogs (median weight: 8.9 kg; range, 4.3-31 kg) were enrolled. TACE was successfully performed in all dogs, and no intra-procedural complications were encountered. Questionnaire scores improved significantly post-TACE. Among the 6 dogs for which full data were available, median pre-TACE tumor volume was 390 cc (range 152-1,484; interquartile range 231-1,139) and median post-TACE tumor volume was 203 cc (range 98-889; interquartile range 151-369), which was significantly (P = .028) lower. All 6 dogs had a reduction in volume at the post-TACE measurement. Mean percent change in tumor volume was -45.6% (95%CI -58.6 to -32.6%). The mean plasma paclitaxel concentration in canine blood peaked at 4 days post-TACE procedure and was 25.7 ng/mL (range = 3.09-110 ng/mL) Median survival time was 629 days (95%CI 18 to upper limit not reached). The use of a novel paclitaxel-eluting microsphere in this cohort of dogs successfully decreased tumor volume significantly after TACE and improved clinical signs. Future investigation into the use of TACE and other similar therapies is warranted due to the promising outcomes noted in this cohort.
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Affiliation(s)
- William T. N. Culp
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
- * E-mail:
| | - Eric G. Johnson
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
| | - Michelle A. Giuffrida
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
| | - Robert B. Rebhun
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
| | - James K. Cawthra
- Boston Scientific Corporation, Marlborough, Massachusetts, United States of America
| | - Heidi A. Schwanz
- Boston Scientific Corporation, Marlborough, Massachusetts, United States of America
| | - Jenna H. Burton
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
| | - Michael S. Kent
- Department of Veterinary Surgical and Radiological Sciences, University of California-Davis, School of Veterinary Medicine, Davis, California, United States of America
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14
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Xia C, Sun Y, Li Y, Ma J, Shi J. LncRNA CCAT1 enhances chemoresistance in hepatocellular carcinoma by targeting QKI-5. Sci Rep 2022; 12:7826. [PMID: 35552451 PMCID: PMC9098857 DOI: 10.1038/s41598-022-11644-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 04/20/2022] [Indexed: 12/24/2022] Open
Abstract
A major reason for treatment failure of cancer is acquisition of drug resistance. The specific mechanisms underlying hepatocellular carcinoma (HCC) chemoresistance need to be fully elucidated. lncRNAs involve in drug resistance in some cancers, however, the exact functions of lncRNA colon cancer-associated transcript 1 (CCAT1) in oxaliplatin resistance in HCC are still unknown. Our study indicated that CCAT1 promoted HCC proliferation and reduced the apoptosis induced by oxaliplatin. Knockout of CCAT1 could increased chemosensitivity in vitro and in vivo. Further study found that QKI-5 was an important mediator and blocking of QKI-5/p38 MAPK signaling pathway could enhance oxaliplatin sensitivity. In conclusions, CCAT1 promoted proliferation and oxaliplatin resistance via QKI-5/p38 MAPK signaling pathway in HCC. Targeting CCAT1 in combination with chemotherapeutics may be a promising alternative to reverse drug resistance in HCC treatment.
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Affiliation(s)
- Chongsheng Xia
- Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Yurui Sun
- Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Yang Li
- Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Junli Ma
- Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China
| | - Jing Shi
- Affiliated Hospital of Jining Medical University, Jining, 272029, Shandong, China.
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15
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Prolonged Inhalation Exposure to Coal Dust on Irradiated Rats and Consequences. ScientificWorldJournal 2022; 2022:8824275. [PMID: 35153629 PMCID: PMC8828334 DOI: 10.1155/2022/8824275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 12/17/2021] [Accepted: 12/23/2021] [Indexed: 11/21/2022] Open
Abstract
The purposes of this study were to research immune system changes and liver and lung tissues in irradiated rats after prolonged exposure to coal dust. A study was carried out on 30 male Wistar rats that were divided into 3 groups: group I, intact animals; group II, exposure to coal dust and 0.2 Gy γ-irradiation; and group III, combined exposure to 6 Gy γ-irradiation and coal dust. The combination of a low and sublethal dose of γ-irradiation with coal dust leads to a significant change in immunity at the remote period. Particularly, the increase in radioactivity at the combined effect causes weakening of phagocytosis, and reduction in T lymphocytes by a factor of 2, immunoglobulin imbalance, and cytokine dysfunction develop secondary immune failure. During prolonged inhalation with coal dust of irradiated animals with the dose of 0.2 Gy, fibrosis and perivascular sclerosis of the bronchial wall of the lungs are formed, and perivascular fibrosis is formed in the liver. The increase in exposure dose up to 6 Gy in combination with coal, in the distant period, caused pulmonary hypertension amid hypertrophy of light arterial vessels and fibrous changes in arteriole, and destructive changes and collection necrosis develop in liver parenchyma. In the case of dust radiation synergy, the increase in doses leads to a significant immune deficiency, which occurs according to the “dose effect” principle; increases damage to animal tissues; and leads to liver tissue necrosis, pulmonary fibrosis, and pulmonary hypertension.
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16
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Farshori NN. Hepatoprotective effect of Trigonella foenum graecum against ethanol-induced cell death in human liver cells (HepG2 and Huh7). Mol Biol Rep 2022; 49:2765-2776. [PMID: 35064405 DOI: 10.1007/s11033-021-07088-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 12/15/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND The plant Trigonella foenum graecum, also known as fenugreek, has been shown to have anticancer, antidiabetic, anti-inflammatory, and antioxidant properties. In this study, the hepatoprotective effect of fenugreek seed extract (FSE) against ethanol-induced cell death was investigated in human liver cells (HepG2 and Huh7). METHODS AND RESULTS The cytotoxic effect of FSE and ethanol on cells was evaluated by exposing the cells at different concentrations. Following that, the cells were pre-incubated with 5-25 μg/ml FSE, followed by a cytotoxic concentration (0.5 mM) of ethanol. MTT and neutral red uptake assays were performed in treated cells to assess the ability of FSE to protect cells from the cytotoxic effects of ethanol. When compared to controls, ethanol treatment significantly reduced the viability of HepG2 and Huh7 cells and altered the cell morphology, whereas treatment with FSE significantly increased cell viability and reversed ethanol-induced morphological changes. Furthermore, pretreatment with FSE dose-dependently reduced lactate dehydrogenate (LDH) leakage, lipid peroxidation (LPO) level, and catalase activities while increasing glutathione (GSH) level induced by ethanol. Pretreatment with FSE also reduced the generation of reactive oxygen species (ROS), caspase enzyme activities, and protein expression of caspase-3 and -9. In HepG2 cells, ethanol-induced apoptosis was observed, whereas FSE treatment reduced apoptosis by downregulating the expression of pro-apoptotic marker genes and upregulating the antiapoptotic gene. CONCLUSIONS In conclusion, this study reports on the mechanistic details of the hepatoprotective potential of FSE. The results also suggest that fenugreek seeds may be useful in preventing liver diseases caused by toxicants such as ethanol.
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Affiliation(s)
- Nida Nayyar Farshori
- Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh, 11495, Saudi Arabia.
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17
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Castro-Gil MP, Torres-Mena JE, Salgado RM, Muñoz-Montero SA, Martínez-Garcés JM, López-Torres CD, Mendoza-Vargas A, Gabiño-López NB, Villa-Treviño S, Del Pozo-Yauner L, Arellanes-Robledo J, Krötzsch E, Pérez-Carreón JI. The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism. Genomics 2021; 114:72-83. [PMID: 34861383 DOI: 10.1016/j.ygeno.2021.11.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/05/2021] [Accepted: 11/26/2021] [Indexed: 01/14/2023]
Abstract
Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.
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Affiliation(s)
| | | | - Rosa M Salgado
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
| | - Said A Muñoz-Montero
- Department of Computational Genomics, National Institute of Genomic Medicine, CDMX, Mexico
| | | | | | | | | | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, CDMX, Mexico
| | - Luis Del Pozo-Yauner
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology, CDMX, Mexico
| | - Edgar Krötzsch
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
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18
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Waqar W, Asghar S, Manzoor S. Platelets' RNA as biomarker trove for differentiation of early-stage hepatocellular carcinoma from underlying cirrhotic nodules. PLoS One 2021; 16:e0256739. [PMID: 34469466 PMCID: PMC8409664 DOI: 10.1371/journal.pone.0256739] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/15/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND & AIMS Among the multiplicity of factors involved in rising incidence of hepatocellular carcinoma (HCC)-the second deadliest cancer, late diagnosis of early-stage HCC nodules originating from late-stage cirrhotic nodules is the most crucial. In recent years, Tumor-educated platelets (TEPs) have emerged as a strong multimodal tool to be used in liquid-biopsy of cancers because of changes in their mRNA content. This study assessed the reliability of selected mRNA repertoire of platelets as biomarkers to differentiate early HCC from late-stage cirrhotic nodules. METHODS Quantitative real time PCR (qRT-PCR) was used to evaluate expression levels of selected platelets-specific mRNA between HCC patients compared to cirrhosis patients. ROC curve analysis assessed the sensitivity and specificity of the biomarkers. RESULTS RhoA, CTNNB1 and SPINK1 showed a significant 3.3-, 3.2- and 3.18-folds upregulation, respectively, in HCC patients compared to cirrhosis patients while IFITM3 and SERPIND1 presented a 2.24-fold change. Strikingly, CD41+ platelets also demonstrated a marked difference of expression in HCC and cirrhosis groups. CONCLUSIONS Our study reports liquid biopsy-based platelets mRNA signature for early diagnosis of HCC from underlying cirrhotic nodules. Moreover, differential expression of CD41+ platelets in two groups provides new insights into a probable link between CD41 expression on platelets with the progression of cirrhosis to HCC.
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MESH Headings
- Adult
- Aged
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/metabolism
- Blood Platelets/metabolism
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Case-Control Studies
- Diagnosis, Differential
- Female
- Gene Expression Regulation, Neoplastic
- Healthy Volunteers
- Humans
- Liquid Biopsy/methods
- Liver/pathology
- Liver Cirrhosis/blood
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/genetics
- Liver Cirrhosis/pathology
- Liver Neoplasms/blood
- Liver Neoplasms/diagnosis
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Middle Aged
- RNA, Messenger/analysis
- RNA, Messenger/metabolism
- Reproducibility of Results
- Trypsin Inhibitor, Kazal Pancreatic/genetics
- beta Catenin/genetics
- rhoA GTP-Binding Protein/genetics
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Affiliation(s)
- Walifa Waqar
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Sidra Asghar
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Sobia Manzoor
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
- * E-mail: ,
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19
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Mary YS, Mary YS, Rad AS, Yadav R, Celik I, Sarala S. Theoretical investigation on the reactive and interaction properties of sorafenib – DFT, AIM, spectroscopic and Hirshfeld analysis, docking and dynamics simulation. J Mol Liq 2021. [DOI: 10.1016/j.molliq.2021.115652] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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20
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Bai Y, Qi W, Liu L, Zhang J, Pang L, Gan T, Wang P, Wang C, Chen H. Identification of Seven-Gene Hypoxia Signature for Predicting Overall Survival of Hepatocellular Carcinoma. Front Genet 2021; 12:637418. [PMID: 33912215 PMCID: PMC8075060 DOI: 10.3389/fgene.2021.637418] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/15/2021] [Indexed: 01/01/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is ranked fifth among the most common cancer worldwide. Hypoxia can induce tumor growth, but the relationship with HCC prognosis remains unclear. Our study aims to construct a hypoxia-related multigene model to predict the prognosis of HCC. Methods RNA-seq expression data and related clinical information were download from TCGA database and ICGC database, respectively. Univariate/multivariate Cox regression analysis was used to construct prognostic models. KM curve analysis, and ROC curve were used to evaluate the prognostic models, which were further verified in the clinical traits and ICGC database. GSEA analyzed pathway enrichment in high-risk groups. Nomogram was constructed to predict the personalized treatment of patients. Finally, real-time fluorescence quantitative PCR (RT-qPCR) was used to detect the expressions of KDELR3 and SCARB1 in normal hepatocytes and 4 HCC cells. The expressions of SCARB1 in hepatocellular carcinoma tissue in 46 patients were detected by immunohistochemistry, and the correlation between its expressions and disease free survival of patient was calculated. Results Through a series of analyses, seven prognostic markers related to HCC survival were constructed. HCC patients were divided into the high and low risk group, and the results of KM curve showed that there was a significant difference between the two groups. Stratified analysis, found that there were significant differences in risk values of different ages, genders, stages and grades, which could be used as independent predictors. In addition, we assessed the risk value in the clinical traits analysis and found that it could accelerate the progression of cancer, while the results of GSEA enrichment analysis showed that the high-risk group patients were mainly distributed in the cell cycle and other pathways. Then, Nomogram was constructed to predict the overall survival of patients. Finally, RT-qPCR showed that KDELR3 and SCARB1 were highly expressed in HepG2 and L02, respectively. Results of IHC staining showed that SCARB1 was highly expressed in cancer tissues compared to adjacent normal liver tissues and its expression was related to hepatocellular carcinoma differentiation status. The Kaplan-Meier survival showed a poor percent survival in the SCARB1 high group compared to that in the SCARB1 low group. Conclusion This study provides a potential diagnostic indicator for HCC patients, and help clinicians to deepen the comprehension in HCC pathogenesis so as to make personalized medical decisions.
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Affiliation(s)
- Yuping Bai
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Wenbo Qi
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Le Liu
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
| | - Jing Zhang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
| | - Lan Pang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
| | - Tiejun Gan
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
| | - Pengfei Wang
- Department of MR, Lanzhou University Second Hospital, Lanzhou, China
| | - Chen Wang
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China.,The Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, China
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21
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1080] [Impact Index Per Article: 270.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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22
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Zhu Y, Ke KB, Xia ZK, Li HJ, Su R, Dong C, Zhou FM, Wang L, Chen R, Wu SG, Zhao H, Gu P, Leung KS, Wong MH, Lu G, Zhang JY, Jiang BH, Qiu JG, Shi XN, Lin MCM. Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma. Mol Med 2021; 27:15. [PMID: 33579185 PMCID: PMC7879659 DOI: 10.1186/s10020-021-00269-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023] Open
Abstract
Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.
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Affiliation(s)
- Ying Zhu
- Biomedical Engineering Research Center, Kunming Medical University, Kunming, 650500, Yunnan, China.,Department of Cadre Medical Branch, The 3rd Affiliated Hospital of Kunming Medical University, Kunming, 650118, Yunnan, China
| | - Kun-Bin Ke
- Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China
| | - Zhong-Kun Xia
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Hong-Jian Li
- CUHK-SDU Joint Laboratory On Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Rong Su
- Department of Geriatric Cardiology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China
| | - Chao Dong
- Department of the Second Medical Oncology, The 3rd Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, 650000, China
| | - Feng-Mei Zhou
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Lin Wang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Rong Chen
- Department of Physiology, Yunnan University of Chinese Medicine, Kunming, 650504, Yunnan, China
| | - Shi-Guo Wu
- Department of Teaching and Research of Formulas of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, 650000, Yunnan, China
| | - Hui Zhao
- Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China
| | - Peng Gu
- Department of Urology, The 1st Affiliated Hospital of Kunming Medical University, Kunming, 650000, China
| | - Kwong-Sak Leung
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Man-Hon Wong
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, 999077, China
| | - Gang Lu
- CUHK-SDU Joint Laboratory On Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jian-Ying Zhang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Bing-Hua Jiang
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Jian-Ge Qiu
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China
| | - Xi-Nan Shi
- Department of Pathology, Yunnan University of Chinese Medicine, Kunming, 650504, Yunnan, China. .,Department ofMedicine, Southwest Guizhou Vocational and Technical College for Nationalities, Xingyi, 562400, Guizhou, China.
| | - Marie Chia-Mi Lin
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, Henan, China.
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Sui P, Wang X, Sun L, Wang H. Diagnostic accuracy of ultrasound superb microvascular imaging for focal liver lesions: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e24411. [PMID: 33546085 PMCID: PMC7837924 DOI: 10.1097/md.0000000000024411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 01/04/2021] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Superb microvascular imaging (SMI) is a new ultrasound vascular imaging technology, which uses a new Doppler algorithm, it has the characteristics of high sensitivity and high resolution to detect low velocity blood flow; it is easier to detect microvessels with low-velocity flow compared with color Doppler flow imaging in theory; and it can image the microvessels of the lesion without angiography.[1] Previous studies showed that SMI can detect tumor neovascularization to differentiate benign from malignant focal liver lessions (FLLs). However, the results of these studies have been contradictory with low sample sizes. This meta-analysis tested the hypothesis that SMI is accurate in distinguishing benign and malignant FLLs. METHODS We will search PubMed, Web of Science, Cochrane Library, and Chinese biomedical databases from their inceptions to the November 30, 2020, without language restrictions. Two authors will independently carry out searching literature records, scanning titles and abstracts, full texts, collecting data, and assessing risk of bias. Review Manager 5.2 and Stata14.0 software will be used for data analysis. RESULTS This systematic review will determine the accuracy of SMI in the differential diagnosis between benign and malignant FLLs. CONCLUSION Its findings will provide helpful evidence for the accuracy of SMI in the differential diagnosis between benign and malignant FLLs. SYSTEMATIC REVIEW REGISTRATION INPLASY2020120081.
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Clinicopathological significance of miR-27b targeting Golgi protein 73 in patients with hepatocellular carcinoma. Anticancer Drugs 2020; 30:186-194. [PMID: 30418194 DOI: 10.1097/cad.0000000000000711] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Using five bioinformatics analysis software, we identified Golgi protein 73 (GP73) as a putative target of microRNA-27b (miR-27b), which is closely related to various biological processes or diseases such as bone metabolism disease, adipose cell and muscle cell development, pulmonary hypertension, cervical cancer, and breast cancer. However, the clinical significance of miR-27b in hepatocellular carcinoma (HCC) is still unclear. The differential expression of miR-27b in HCC and adjacent normal liver tissues was measured by quantitative reverse transcription PCR. Our results showed that the expression of miR-27b in tumor tissues is lower than that in adjacent nontumor tissues. The expression of miR-27b was significantly lower in HCC tissues with high expression of GP73, when compared with adjacent nontumor tissues. Moreover, down-regulated expression of miR-27b was closely correlated with serum GP73, tumor-node-metastasis stage, tumor size, and portal vein thrombosis. GP73 mRNA might be a target of miR-27b. The 5-year overall survival rate of the low miR-27b expression group was significantly lower than that of the high miR-27b expression group. Moreover, multivariate analysis of prognostic factors, with a Cox proportional hazards model, showed that low miR-27b expression was a significant and independent predictor of poor survival in HCC. Hence, the abnormal expression of miR-27b might be related to the occurrence and development of tumors. Similarly, a study in the Cancer Genome Atlas database demonstrated that the expression of miR-27b in 50 normal individuals was 1.6 times higher than that of 372 patients with liver cancer. The overall survival rate of the low GP73 expression group (275 liver cancer patients) was significantly longer than that of the high GP73 expression group (90 normal individuals). MiR-27b suppresses the expression of GP73 and is therefore a potential prognostic biomarker and therapy target in HCC.
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Abdelsameea E, Nada A, Omar N, Saleh SM, Naguib M, El-Ezawy HEDM, Bakry L, Elsabaawy M. Urine Neutrophil Gelatinase-Associated Lipocalin a Possible Diagnostic Marker for Egyptian Hepatocellular Carcinoma Patients. Asian Pac J Cancer Prev 2020; 21:2259-2264. [PMID: 32856853 PMCID: PMC7771944 DOI: 10.31557/apjcp.2020.21.8.2259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Most effective method for reducing mortality from hepatocellular carcinoma (HCC) is early diagnosis. Despite its lack of adequate sensitivity, ultrasound is considered fundamental for HCC screening. AIM to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) as non-invasive marker for HCC diagnosis in Egyptian patients. METHODS One hundred and twenty patients were divided into three groups (40 patients each): patients with chronic viral hepatitis (HCV or HBV), cirrhotic patients and HCC patients and 40 healthy age and gender matched subjects were enrolled as control group. After clinical assessments, urinary NGAL was measured by enzyme-linked immunosorbent assay. RESULTS Our results revealed that median level of urinary NGAL was 290, 834, 1090 and 1925 pg/ml in control, chronic hepatitis, cirrhotic and HCC groups respectively among studied groups (p<0.001). Receiver operating characteristics (ROC) analysis showed that urinary NGAL cutoff value of 1255 ng/ml could discriminate between HCC and cirrhosis. The area under curve (AUC) was 0.95 with 90% sensitivity, 87.5% specificity (p-value <0.001). In HCC group, urine NGAL level didn`t show significant correlation with Child Pugh score, MELD score or Barcelona Clinic Liver Cancer (BCLC) stage. CONCLUSION Urinary NGAL could be a simple, non-invasive test for diagnosis of HCC in chronic liver disease patients.
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Affiliation(s)
- Eman Abdelsameea
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Ali Nada
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Nabil Omar
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Saleh M Saleh
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Mary Naguib
- Department of Clinical Pathology, National Liver Institute, Menoufia University, Egypt.
| | - Hosam El-Din M El-Ezawy
- Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University, Egypt.
| | - Lamiaa Bakry
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
| | - Maha Elsabaawy
- Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Egypt.
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26
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Wang MX, Chen D, Zhao YY, Yang B, Jiang JP, Zeng FJ, Wei L, Chen ZS. Role of selected criteria and preventive chemotherapy in tumor recurrence after liver transplantation. Hepatobiliary Pancreat Dis Int 2020; 19:378-383. [PMID: 32622825 DOI: 10.1016/j.hbpd.2020.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 06/16/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Long-term survival after liver transplantation (LT) for hepatocellular carcinoma (HCC) patients remains poor because of tumor recurrence. To improve the prognosis of HCC patients after LT, we aimed to identify different transplantation criteria and risk factors related to tumor recurrence and evaluate the effect of preventive chemotherapy in a single center. METHODS In total, data on 20 variables and the survival of 199 patients with primary HCC who underwent LT between 2005 and 2015 were included for analysis. The patients were divided into the following three groups: Group 1, within the Milan and Hangzhou criteria (n = 51); Group 2, beyond the Milan but within the Hangzhou criteria (n = 36); and Group 3, beyond the Milan and Hangzhou criteria (n = 112). Survival probabilities for the three groups were calculated using multivariate Cox regression analysis. The association between preventive therapy and HCC-recurrence after LT was analyzed by multiple logistic regression analysis. RESULTS Child-Pugh stage C and hepatitis B virus (HBV) infection were independent risk factors for patients with tumor recurrence who did not meet the Milan criteria. The overall survival rates of the 199 patients showed statistically significant differences among the three groups (P < 0.001). Moreover, no significant difference was noted in the survival rate between Group 1 and Group 2 (P > 0.05). Multivariate logistic regression analysis showed that postoperative prophylactic chemotherapy reduced the risk of tumor recurrence in patients who did not meet the Hangzhou and Milan criteria (OR = 0.478; 95% CI: 0.308-0.741; P = 0.001). CONCLUSIONS Child-Pugh classification and HBV infection were the independent risk factors of tumor recurrence in HCC patients with LT. The Hangzhou criteria were effective and analogous compared with the Milan criteria. Preventive chemotherapy significantly reduced the risk of recurrence and prolonged the survival time for HCC patients beyond the Milan and Hangzhou criteria after LT.
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Affiliation(s)
- Mei-Xi Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Dong Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Yuan-Yuan Zhao
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Ji-Pin Jiang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Fan-Jun Zeng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
| | - Lai Wei
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China.
| | - Zhi-Shui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan 430030, China; NHC Key Laboratory of Organ Transplantation, Wuhan 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan 430030, China
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Kim SY, Hwangbo H, Lee H, Park C, Kim GY, Moon SK, Yun SJ, Kim WJ, Cheong J, Choi YH. Induction of Apoptosis by Coptisine in Hep3B Hepatocellular Carcinoma Cells through Activation of the ROS-Mediated JNK Signaling Pathway. Int J Mol Sci 2020; 21:E5502. [PMID: 32752099 PMCID: PMC7432186 DOI: 10.3390/ijms21155502] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a high mortality rate worldwide, and treatment is very limited due to its high recurrence and low diagnosis rate, and therefore there is an increasing need to develop more effective drugs to treat HCC. Coptisine is one of the isoquinoline alkaloids, and it has various pharmacological effects. However, the evidence for the molecular mechanism of the anticancer efficacy is still insufficient. Therefore, this study investigated the antiproliferative effect of coptisine on human HCC Hep3B cells and identified the action mechanism. Our results showed that coptisine markedly increased DNA damage and apoptotic cell death, which was associated with induction of death receptor proteins. Coptisine also significantly upregulated expression of proapoptotic Bax protein, downregulated expression of anti-apoptotic Bcl-2 protein, and activated caspase-3, -8, and -9. In addition, coptisine remarkably increased the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and release of cytochrome c into the cytoplasm. However, N-acetylcysteine (NAC), a ROS scavenger, significantly attenuated the apoptosis-inducing effect of coptisine. It is worth noting that coptisine significantly upregulated phosphorylation of ROS-dependent c-Jun N-terminal kinase (JNK), whereas treatment with JNK inhibitor could suppress an apoptosis-related series event. Taken together, our results suggest that coptisine has an anticancer effect in Hep3B cells through ROS-mediated activation of the JNK signaling pathway.
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Affiliation(s)
- So Young Kim
- Anti-Aging Research Center, Dong-Eui University, Busan 47340, Korea; (S.Y.K.); (H.H.); (H.L.)
- Department of Molecular Biology, Pusan National University, Busan 46241, Korea
| | - Hyun Hwangbo
- Anti-Aging Research Center, Dong-Eui University, Busan 47340, Korea; (S.Y.K.); (H.H.); (H.L.)
- Department of Molecular Biology, Pusan National University, Busan 46241, Korea
| | - Hyesook Lee
- Anti-Aging Research Center, Dong-Eui University, Busan 47340, Korea; (S.Y.K.); (H.H.); (H.L.)
- Department of Biochemistry, Dong-Eui University College of Korean Medicine, Busan 47227, Korea
| | - Cheol Park
- Division of Basic Sciences, College of Liberal Studies, Dong-Eui University, Busan 47340, Korea;
| | - Gi-Young Kim
- Department of Marine Life Sciences, School of Marine Biomedical Sciences, Jeju National University, Jeju 63243, Korea;
| | - Sung-Kwon Moon
- Department of Food and Nutrition, Chung-Ang University, Anseong 17546, Korea;
| | - Seok Joong Yun
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju 28644, Korea; (S.J.Y.); (W.-J.K.)
| | - Wun-Jae Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju 28644, Korea; (S.J.Y.); (W.-J.K.)
| | - Jaehun Cheong
- Department of Molecular Biology, Pusan National University, Busan 46241, Korea
| | - Yung Hyun Choi
- Anti-Aging Research Center, Dong-Eui University, Busan 47340, Korea; (S.Y.K.); (H.H.); (H.L.)
- Department of Biochemistry, Dong-Eui University College of Korean Medicine, Busan 47227, Korea
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Nair B, Anto RJ, M S, Nath LR. Kaempferol-Mediated Sensitization Enhances Chemotherapeutic Efficacy of Sorafenib Against Hepatocellular Carcinoma: An In Silico and In Vitro Approach. Adv Pharm Bull 2020; 10:472-476. [PMID: 32665908 PMCID: PMC7335979 DOI: 10.34172/apb.2020.058] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 02/02/2020] [Accepted: 02/03/2020] [Indexed: 02/05/2023] Open
Abstract
Purpose: Sorafenib is the sole FDA approved drug conventionally used for the treatment of advanced hepatocellular carcinoma (HCC). Despite of the beneficial use of sorafenib in the treatment of HCC, multidrug resistance still remains a challenge. HCC is inherently known as chemotherapy resistant tumor due to P-glycoprotein (P-gp)-mediated multidrug resistance. Methods: We studied the interaction energy of kaempferol with human multidrug resistance protein-1 (RCSB PDB ID: 2CBZ) using in silico method with the help of BIOVIA Discovery Studio. HepG2 and N1S1 liver cancer cell lines were treated in suitable cell culture media to evaluate the efficacy of kaempferol in chemo-sensitizing liver cancer cells towards the effect of sorafenib. Cell viability study was performed by MTT assay. Results: In silico analysis of kaempferol showed best docking score of 23.14 with Human Multi Drug Resistant Protein-1 (RCSB PDB ID: 2CBZ) compared with positive control verapamil. Inin-vitro condition, combination of sub-toxic concentrations of both kaempferol and sorafenib produced 50% cytotoxicity with concentration of 2.5 µM each which indicates that kaempferol has the ability to reverse the MDR by decreasing the over-expression of P-gp. Conclusion: Kaempferol is able to sensitize the HepG2 and N1S1 against the sub-toxic concentration of sorafenib. Hence, we consider that the efficacy of sorafenib chemotherapy can be enhanced by the significant approach of combining the sub-toxic concentrations of sorafenib with kaempferol. Thus, kaempferol can be used as a better candidate molecule along with sorafenib for enhancing its efficacy, if validated through preclinical studies.
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Affiliation(s)
- Bhagyalakshmi Nair
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Ruby John Anto
- Division of Cancer Research, Rajiv Gandhi Center for Biotechnology, Thycaud, Thiruvananthapuram, Kerala- 695014, India. Introduction
| | - Sabitha M
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Lekshmi R. Nath
- Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
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Thylur RP, Roy SK, Shrivastava A, LaVeist TA, Shankar S, Srivastava RK. Assessment of risk factors, and racial and ethnic differences in hepatocellular carcinoma. JGH OPEN 2020; 4:351-359. [PMID: 32514436 PMCID: PMC7273694 DOI: 10.1002/jgh3.12336] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/05/2020] [Accepted: 03/24/2020] [Indexed: 12/24/2022]
Abstract
Despite improved screening and surveillance guidelines, significant race/ethnicity‐specific disparities in hepatocellular carcinoma (HCC) continue to exist and disproportionately affect minority and disadvantaged populations. This trend indicates that social determinants, genetic, and environmental factors are driving the epidemic at the population level. Race and geography had independent associations with risk of mortality among patients with HCC. The present review discusses the risk factors and issues related to disparities in HCC. The underlying etiologies for these disparities are complex and multifactorial. Some of the risk factors for developing HCC include hepatitis B (HBV) and hepatitis C (HCV) viral infection, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, smoking and alcohol consumption. In addition, population genetics; socioeconomic and health care access; treatment and prevention differences; and genetic, behavioral, and biological influences can contribute to HCC. Acculturation of ethnic minorities, insurance status, and access to health care may further contribute to the observed disparities in HCC. By increasing awareness, better modalities for screening and surveillance, improving access to health care, and adapting targeted preventive and therapeutic interventions, disparities in HCC outcomes can be reduced or eliminated.
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Affiliation(s)
- Ramesh P Thylur
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA
| | - Sanjit K Roy
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA
| | | | - Thomas A LaVeist
- Department of Health Policy and Management Tulane University School of Public Health and Tropical Medicine New Orleans Louisiana USA
| | - Sharmila Shankar
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA.,Department of Genetics Louisiana State University Health Sciences Center-New Orleans New Orleans Louisiana USA
| | - Rakesh K Srivastava
- Stanley S. Scott Cancer Center Louisiana State University Health-New Orleans School of Medicine New Orleans Louisiana USA.,Department of Genetics Louisiana State University Health Sciences Center-New Orleans New Orleans Louisiana USA
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Tao Y, Wang J, Xu X. Emerging and Innovative Theranostic Approaches for Mesoporous Silica Nanoparticles in Hepatocellular Carcinoma: Current Status and Advances. Front Bioeng Biotechnol 2020; 8:184. [PMID: 32211399 PMCID: PMC7075945 DOI: 10.3389/fbioe.2020.00184] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/25/2020] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal solid cancers globally. To improve diagnosis sensitivities and treatment efficacies, the development of new theranostic nanoplatforms for efficient HCC management is urgently needed. In the past decade, mesoporous silica nanoparticles (MSNs) with tailored structure, large surface area, high agents loading volume, abundant chemistry functionality, acceptable biocompatibility have received more and more attention in HCC theranostic. This review outlines the recent advances in MSNs-based systems for HCC therapy and diagnosis. The multifunctional hybrid nanostructures that have both of therapy and diagnosis abilities are highlighted. And the precision delivery strategies of MSNs in HCC are also discussed. Final, we conclude with our personal perspectives on the future development and challenges of MSNs.
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Affiliation(s)
- Yaoye Tao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Chinese Academy of Medical Sciences (CAMS), Hangzhou, China
- Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Jianguo Wang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Chinese Academy of Medical Sciences (CAMS), Hangzhou, China
- Key Laboratory of Organ Transplantation, Hangzhou, China
| | - Xiao Xu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- National Health Commission (NHC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
- Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Chinese Academy of Medical Sciences (CAMS), Hangzhou, China
- Key Laboratory of Organ Transplantation, Hangzhou, China
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Zahran AM, Abdel-Rahim MH, Refaat A, Sayed M, Othman MM, Khalak LMR, Hetta HF. Circulating hematopoietic stem cells, endothelial progenitor cells and cancer stem cells in hepatocellular carcinoma patients: contribution to diagnosis and prognosis. Acta Oncol 2020; 59:33-39. [PMID: 31478425 DOI: 10.1080/0284186x.2019.1657940] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background and aim: Circulating hematopoietic stem cells (HSCs), circulating endothelial progenitor cells (EPCs) and cancer stem cells (CSCs) contribute to tumor development and progression and can predict patient outcome. The aim of this study was to investigate the frequency of circulating HSCs, EPCs and CSCs in the peripheral blood of patients with hepatocellular carcinoma (HCC) and to explore their potential prognostic significance for HCC patients.Methods: The study included 30 HCC patients and 20 healthy controls. The HSCs and EPCs were enumerated with CD45, CD34, CD133, CD144 markers, while CSCs were enumerated with CD45, CD44, CD133 markers using flow cytometry.Results: The mean percentages of circulating HSCs were significantly lower in HCC patients than the controls (p = .001), whereas the mean percentages of EPCs within the HSCs subpopulation were significantly higher in the HCC patients than the controls (p = .002). The absolute count of CSCs within 100,000 peripheral blood mononuclear cells was 23.5 ± 3.4 in the HCC patients. Also, the mean percentages of circulating HSCs, EPCs and the number of CSCs were significantly increased in patients with multiple hepatic focal lesions than in patients with a single hepatic focal lesion. Both circulating HSCs and EPCs showed significant positive correlation with the level of AFP and with the numbers of CSCs. In the meantime, the numbers of CSCs revealed significant direct correlation with ALT, AST and AFP levels. The one-year overall survival (OS) of the patients was 77.5%. High levels of CSCs, HSCs and EPCs at diagnosis were all associated with worse outcome for the HCC patients.Conclusions: Significant changes in the levels of the circulating HSCs, EPCs and CSCs occur in HCC. These changes help the diagnosis and the prediction of HCC outcome, as higher levels of these cells are associated with worse OS.
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Affiliation(s)
- Asmaa M. Zahran
- Department of Clinical Pathology, South Egypt Cancer Institute, Assiut, Egypt
| | - Mona H. Abdel-Rahim
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Refaat
- Medical Oncology, South Egypt Cancer Institute, Assiut, Egypt
| | - Mona Sayed
- Radiotherapy Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Mostafa M. Othman
- Radiodiagnosis Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Lamiaa M. R. Khalak
- Radiodiagnosis Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Helal F. Hetta
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Xu Y, Wang H, Gao W. MiRNA-610 acts as a tumour suppressor to depress the cisplatin resistance in hepatocellular carcinoma through targeted silencing of hepatoma-derived growth factor. Arch Med Sci 2020; 16:1394-1401. [PMID: 33224339 PMCID: PMC7667417 DOI: 10.5114/aoms.2019.87938] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/22/2017] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Hepatic malignancy is one of the most common malignant neoplasms around the globe, and hepatocellular carcinoma (HCC) is the most common type. In this study, the roles and mechanisms of MiRNA-610 in the chemo resistance of HCC will be discussed. MATERIAL AND METHODS The expression of MiRNA-610 and hepatoma-derived growth factor (HDGF) in HCC tissues and cell line was detected by quantitative real-time PCR. The proliferation and chemo resistance were analysed by MTT assay. Flow cytometry was used to examine the apoptosis rate. Luciferase reporter assay was used to verify the correlation between MiRNA-610 and HDGF. HDGF protein expression was detected by Western blot. RESULTS Our study confirmed the low-expression of MiRNA-610 in HCC tissues and cell line. Its low expression was related to high T stages and poor differentiation of HCC, and was a prognostic factor for HCC. MiRNA-610 upregulation inhibited cell proliferation and induced apoptosis of HepG2 cells. MiRNA-610 enhancement decreased the half maximal inhibitory concentration for cisplatin (DDP) and depressed the DDP resistance in HepG2 cells. The specific correlation between MiRNA-610 and HDGF was tested by luciferase reporter assay and western blot. The transfection with HDGF expression vector up-regulated the expression of HDGF protein silenced by MiRNA-610 enhancement. HDGF overexpression was found to reverse partly the regulatory roles of MiRNA-610 on malignancy and DDP resistance. CONCLUSIONS MiRNA-610 not only played a tumour suppressor role in HCC but also affected chemo resistance to DDP. This role is mainly mediated through targeted silencing of the HDGF gene, which may offer a new potential therapeutic target and improve the clinical therapeutic effect for HCC.
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Affiliation(s)
- Yongqing Xu
- Department of The Twelfth General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Helin Wang
- Department of The Twelfth General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Weike Gao
- Department of The Twelfth General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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Taskaeva I, Bgatova N, Gogaeva I. Lithium effects on vesicular trafficking in hepatocellular carcinoma cells. Ultrastruct Pathol 2019; 43:301-311. [PMID: 31826700 DOI: 10.1080/01913123.2019.1701167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most commonly malignant tumors worldwide, characterized by the presence of many heterogeneous molecular cell events that contribute to tumor growth and progression. Endocytic processes are intimately involved in various pathological conditions, including cancer, since they interface with various cellular signaling programs. The ability of lithium to induce cell death and autophagy and affect cell proliferation and intracellular signaling has been shown in various experimental tumor models. The aim of this study was to evaluate the effects of lithium on vesicular transport in hepatocellular carcinoma cells. Using transmission electron microscopy we have characterized the endocytic apparatus in hepatocellular carcinoma-29 (HCC-29) cells in vivo and detailed changes in endocytotic vesicles after 20 mM lithium carbonate administration. Immunofluorescent analysis was used to quantify cells positive for EEA1-positive early endosomes, Rab11-positive recycling endosomes and Rab7-positive late endosomes. Lithium treatment caused an increase in EEA1- and Rab11-positive structures and a decrease in Rab7-positive vesicles. Thus, lithium affects diverse endocytic pathways in HCC-29 cells which may modulate growth and development of hepatocellular carcinoma.
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Affiliation(s)
- Iuliia Taskaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.,Laboratory of Boron-Neutron Capture Therapy, Department of Physics, Novosibirsk State University, Novosibirsk, Russia
| | - Nataliya Bgatova
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Izabella Gogaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology - Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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The Pivotal Role of Long Noncoding RNA RAB5IF in the Proliferation of Hepatocellular Carcinoma Via LGR5 Mediated β-Catenin and c-Myc Signaling. Biomolecules 2019; 9:biom9110718. [PMID: 31717443 PMCID: PMC6920882 DOI: 10.3390/biom9110718] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/30/2019] [Accepted: 10/30/2019] [Indexed: 02/07/2023] Open
Abstract
In the current study, the function of long noncoding RNA (LncRNA) RAB5IF was elucidated in hepatocellular carcinoma (HCCs) in association with LGR5 related signaling. Here TCGA analysis revealed that LncRNA RAB5IF was overexpressed in HCC, and its overexpression level was significantly (p < 0.05) correlated with poor prognosis in patients with HCC. Furthermore, LncRNA RAB5IF depletion suppressed cell proliferation and colony formation, increased sub G1 population, cleavage of poly ADP-ribose polymerase (PARP) and cysteine aspartyl-specific protease (caspase 3) and attenuated the expression of procaspase 3, pro-PARP and B-cell lymphoma 2 (Bcl-2) in HepG2 and Hep3B cells. Furthermore, LncRNA RAB5IF depletion reduced the expression of LGR5 and its downstreams such as β-catenin and c-Myc in HepG2 and Hep3B cells. Notably, LGR5 depletion also attenuated the expression of pro-PARP, pro-caspase3, β-catenin and c-Myc in HepG2 and Hep3B cells. Conversely, LGR5 overexpression upregulated β-catenin and c-Myc in Alpha Mouse Liver 12 (AML-12) normal hepatocytes. Overall, these findings provide novel evidence that LncRNA RAB5IF promotes the growth of hepatocellular carcinoma cells via LGR5 mediated β-catenin and c-Myc signaling as a potent oncogenic target.
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Danilenko NG, Siniauskaya MG, Lukashyk SP, Karpov IA, Davydenko OG. “Double Punch”: Hepatitis C in Patients with Genetic Defects of Iron Metabolism. CYTOL GENET+ 2019. [DOI: 10.3103/s0095452719050062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Helmy SA, El-Mesery M, El-Karef A, Eissa LA, El Gayar AM. Thymoquinone upregulates TRAIL/TRAILR2 expression and attenuates hepatocellular carcinoma in vivo model. Life Sci 2019; 233:116673. [DOI: 10.1016/j.lfs.2019.116673] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 02/07/2023]
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Livingstone MC, Johnson NM, Roebuck BD, Kensler TW, Groopman JD. Serum miR-182 is a predictive biomarker for dichotomization of risk of hepatocellular carcinoma in rats. Mol Carcinog 2019; 58:2017-2025. [PMID: 31373075 DOI: 10.1002/mc.23093] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/13/2019] [Accepted: 07/23/2019] [Indexed: 12/11/2022]
Abstract
Exploration of animal models leads to discoveries that can reveal candidate biomarkers for translation to human populations. Herein, a model of hepatocarcinogenesis and protection was used in which rats treated with aflatoxin (AFB1 ) daily for 28 days (200 µg/kg BW) developed tumors compared with rats completely protected from tumors by concurrent administration of the chemoprotective agent, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im). Differential expression of miRNAs in tumors (AFB1 ) and nontumor (AFB1 + CDDO-Im) bearing livers and their levels in sera over the life-course of the animals was determined. miRNA transcriptome analysis identified 17 miRNAs significantly upregulated at greater than five-fold in the tumors. The ten most dysregulated miRNAs judged by fold-change and biological significance were selected for further study, including liver-specific miR-122-5p. Validation of sequencing results by real-time PCR confirmed the upregulation of the majority of these miRNAs in tumors, including miR-182, as well as miR-224-5p as the most dysregulated of these miRNAs (over 400-fold). The longitudinal analysis of levels of miR-182 in sera demonstrated significant and persistent increases (5.13-fold; 95% CI: 4.59-5.70). The increase in miR-182 was detected months before any clinical symptoms were present in the animals. By the terminal time point of the study, in addition to elevated levels of serum miR-182, serum miR-122-5p was also found to be increased (>1.5-fold) in animals that developed hepatocarcinomas. Thus, using the data from an unbiased discovery approach of the tissue findings, serum miR-182 was found to track across the complex, multistage process of hepatocarcinogenesis opening an opportunity for translation to human populations.
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Affiliation(s)
- Merricka C Livingstone
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Natalie M Johnson
- Department of Environmental and Occupational Health, Texas A&M School of Public Health, College Station, Texas
| | - Bill D Roebuck
- Department of Pharmacology and Toxicology, Giesel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Thomas W Kensler
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - John D Groopman
- Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Chatterjee S, Patra D, Chakraborti U, Sengupta D, Ghosh P, Basu A, Sadhukhan GC, Chowdhury KD. Association of p38MAPK-p53-Fas aggregation in S-allyl cysteine mediated regulation of hepatocarcinoma. ENVIRONMENTAL TOXICOLOGY 2019; 34:928-940. [PMID: 31067004 DOI: 10.1002/tox.22764] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 04/18/2019] [Accepted: 04/24/2019] [Indexed: 06/09/2023]
Abstract
Bioactive components of dietary phytochemicals have been reported to possess antitumor activities. Evidences suggested key role of stress responsive p38MAPK in the induction of nutraceuticals mediated apoptosis in hepatocellular carcinoma (HCC). Current study demonstrated detailed molecular bagatelle associated with p38 MAPK mediated effective suppression of cell growth both in HepG2 and chemically induced liver carcinoma after S-allyl cysteine (SAC) treatment. SAC promoted p38MAPK activity responsible for p53 phosphorylation, its stabilization followed by nuclear translocation leading to induction in expression and oligomerization of Fas protein. Distinctive p38MAPK-p53 axis dependent Fas-FasL-FADD mediated caspase activities along with perturbed cell cycling became normalized with continuation of SAC treatment for another month to diethylnitrosamine induced liver carcinoma. Co-treatment with SB203580, the p38MAPK inhibitor, prevented pro-apoptotic effect of SAC by altering p53 phosphorylation and death inducing signaling complex conformation in HepG2 and induced HCC. Collectively study suggested significant contribution of p38MAPK-p53-DISC-Caspase pathway in the regulation of anti-neoplastic activity of SAC against HCC.
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Affiliation(s)
- Sujan Chatterjee
- Molecular Biology and Tissue Culture Laboratory, Department of Zoology, Vidyasagar College, Kolkata, West Bengal, India
| | - Debajyoti Patra
- Molecular Biology and Tissue Culture Laboratory, Department of Zoology, Vidyasagar College, Kolkata, West Bengal, India
| | - Udipta Chakraborti
- Department of Zoology, University of Kalyani, Kalyani, West Bengal, India
| | - Dipanwita Sengupta
- Department of Comprehensive Cancer Center, Ohio State University College of Medicine, Columbus, Ohio
| | - Pujita Ghosh
- Cyto-genetics Laboratory, Department of Zoology, Rammohon College, Kolkata, West Bengal, India
| | - Anupam Basu
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Bardhaman, West Bengal, India
| | | | - Kaustav Dutta Chowdhury
- Cyto-genetics Laboratory, Department of Zoology, Rammohon College, Kolkata, West Bengal, India
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Xu D, Sheng JQ, Hu PJH, Huang TS, Lee WC. Predicting hepatocellular carcinoma recurrences: A data-driven multiclass classification method incorporating latent variables. J Biomed Inform 2019; 96:103237. [PMID: 31238108 DOI: 10.1016/j.jbi.2019.103237] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 03/30/2019] [Accepted: 06/18/2019] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC), a malignant form of cancer, is frequently treated with surgical resections, which have relatively high recurrence rates. Effective recurrence predictions enable physicians' timely detections and adequate therapeutic measures that can greatly improve patient care and outcomes. Toward that end, predictions of early versus late HCC recurrences should be considered separately to reflect their distinct onset time horizons, clinical causes, underlying clinical etiology, and pathogenesis. We propose a novel Bayesian network-based method to predict different HCC recurrence outcomes by considering the respective recurrence evolution paths. Typical patient information obtained in early stages is insufficiently informative to predict recurrence outcomes accurately, due to the lack of subsequent patient progression information. Our method alleviates such information deficiency constraints by incorporating an independent latent variable, dominant recurrence type, to regulate recurrence outcome predictions (early, late, or no recurrence). We use a real-world HCC data set to evaluate the proposed method, relative to three prevalent benchmark techniques. Overall, the results show that our method consistently and significantly outperforms all the benchmark techniques in terms of accuracy, precision, recall, and F-measures. For increased robustness, we use another data set to perform an out-of-sample evaluation and obtain similar results. This study thus contributes to HCC recurrence research and offers several implications for clinical practice.
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Affiliation(s)
- Da Xu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Jessica Qiuhua Sheng
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Paul Jen-Hwa Hu
- Department of Operations and Information Systems, David Eccles School of Business, University of Utah, USA.
| | - Ting Shuo Huang
- Department of General Surgery, Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC; Department of Chinese Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC.
| | - Wei-Chen Lee
- Department of Liver and Transplantation Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan, ROC; Department of Medicine, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan,Taiwan, ROC.
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Saleem S, Kazmi I, Ahmad A, Abuzinadah MF, Samkari A, Alkrathy HM, Khan R. Thiamin Regresses the Anticancer Efficacy of Methotrexate in the Amelioration of Diethyl Nitrosamine-Induced Hepatocellular Carcinoma in Wistar Strain Rats. Nutr Cancer 2019; 72:170-181. [PMID: 31088230 DOI: 10.1080/01635581.2019.1614199] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and occurs frequently in patients with liver cirrhosis. HCC is the leading cause of cancer-related mortality around the globe.Aim: This study assessed the effects of thiamin in the anticancer activity of methotrexate (MTX) in diethyl nitrosamine (DEN) induced hepatocellular Carcinoma in Wistar strain male rats.Method: Fifty rats were randomly segregated in five groups with 10 rats in each group. HCC was induced by single intraperitoneal (i.p) dose of DEN (200 mg/kg) and HCC promoter phenobarbital was used in the basal diet (0.05%) for 5 days per week until the termination of the study in all the rats except for the normal control (NC) group. Disease control (DC) was given no treatment, while DM (DEN + MTX) and DT (DEN + thiamin) groups were given MTX (5 mg/kg, i.p per week for 16 weeks) and thiamin (25 mg/kg, orally, daily for 16 weeks), respectively. DMT (DEN + MTX + thiamin) group was given the combined dose of MTX and thiamin. Histopathological study was carried out to confirm the liver function tests such as α-feto protein (AFP), alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TB), and total protein (TP) along with antioxidants vascular endothelial growth factor (VEGF), lipid per-oxidation (LPO), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT).Results: Results showed that liver biomarkers and antioxidants parameters were still abnormal in the DC group while DM group showed significant restoration, but DT group showed less significant normalization. DMT showed mild recovery of these parameters.Conclusion: The mechanism of action of MTX and thiamin is antiparallel to each other and hence their concomitant administration may lead to inefficient anticancer activity of MTX.
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Affiliation(s)
- Shakir Saleem
- Department of Pharmacology, School of Medical and Allied Sciences, KR Mangalam University, Gurugram, Haryana, India
| | - Imran Kazmi
- College of Pharmacy, Shine Abdur Razzaq Institute of Health Education and Research Centre Irba, Ranchi, Jharkhand, India
| | - Aftab Ahmad
- Health Information Technology Department, Jeddah Community College, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed F Abuzinadah
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ali Samkari
- Department of General Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Huda M Alkrathy
- Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ruqaiyah Khan
- Department of Pharmacology, Siddhartha Institute of Pharmacy, Dehradun, India
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Abstract
OBJECTIVE The purpose of this article is to review the most commonly used tumor markers in abdominal and pelvic tumors, describe their limitations and explain how to use them in the context of known cancer in order to optimize multidisciplinary care of oncologic patients. CONCLUSION Tumor markers are important for the diagnosis, staging, monitoring of treatment and detection of recurrence in many cancers. This knowledge is crucial in the daily interpretation of images of oncologic and non-oncologic patients. However, radiologists should also be aware of the limitations of the most commonly used tumor markers and they should not be used solely, but interpreted in conjunction with diagnostic imaging, clinical history and physical examination that will help optimize the multidisciplinary care and management of oncologic patients.
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E C, Li C, Li H, Yang J. Silencing of a novel lncRNA LOC105369748 suppresses the progression of hepatocellular carcinoma by sponging miR-5095 from MBD2. J Cell Physiol 2019; 234:18504-18512. [PMID: 30912130 DOI: 10.1002/jcp.28486] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/14/2019] [Accepted: 02/19/2019] [Indexed: 12/22/2022]
Abstract
A growing number of studies have suggested that long noncoding RNAs (lncRNAs) play critical roles in human malignant cancers, including hepatocellular carcinoma (HCC). However, the functions of most lncRNAs have not been elucidated in HCC. In the present study, we explored the potential functions of a novel lncRNA LOC105369748 in the HCC progression. We identified that LOC105369748 expression was significantly elevated in HCC tissues compared with normal tissues based on bioinformatics analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and in situ hybridization (ISH) examination. Moreover, we found that the LOC105369748 overexpression was associated with poor prognosis in patients with HCC. Then we measured the effects of LOC105369748 on HCC cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT). And our results demonstrated that LOC105369748 exerted oncogenic roles. In terms of mechanism, LOC105369748 was shown to promote MBD2 expression through competitively binding to microRNA(miR)-5095 in HCC. In conclusion, our findings elucidate that the LOC105369748/miR-5095/MBD2 signaling axis regulates the HCC progression and may be a novel therapeutic avenue.
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Affiliation(s)
- Changyong E
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Chunsheng Li
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Hang Li
- Department of Cerebral Surgery, Jilin Cancer Hospital, Changchun, China
| | - Jinghui Yang
- Department of Hepatobiliary and Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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Computational study of necrotic areas in rat liver tissue treated with photodynamic therapy. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2019; 192:40-48. [DOI: 10.1016/j.jphotobiol.2019.01.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 01/07/2019] [Accepted: 01/15/2019] [Indexed: 12/27/2022]
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Zhang XR, Ouyang J, Huang JY. Quantitative evaluation of blood perfusion in hepatocellular carcinoma after transcatheter arterial chemoembolization by contrast-enhanced ultrasound. Shijie Huaren Xiaohua Zazhi 2019; 27:276-281. [DOI: 10.11569/wcjd.v27.i4.276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the blood perfusion status of residual hepatocellular carcinoma (HCC) tumors after transcatheter arterial chemoembolization (TACE) by contrast-enhanced ultrasound (CEUS) as well as the application value of CEUS.
METHODS A total of 45 HCC patients with a total of 57 tumors who underwent TACE at our hospital were selected. CEUS was performed one day before treatment and one month after treatment. The blood perfusion parameters of residual tumors before and after TACE were compared.
RESULTS The sensitivity, accuracy, and specificity of CEUS in the diagnosis of residual HCC lesions were 95.45%, 94.74%, and 92.31%, respectively. The enhanced intensity (56.87% ± 4.15%) of residual HCC tumors after TACE decreased significantly compared with that (75.09% ± 6.42%) before TACE (P < 0.05). The peak time (25.26 s ± 3.83 s) of HCC residual tumors after TACE was significantly longer than that (21.02 s ± 3.70 s) before TACE (P < 0.05). The area under the curve (581.29 ± 86.43) for residual HCC tumors decreased significantly compared with that (1017.83 ± 111.76) before TACE (P < 0.05).
CONCLUSION CEUS can directly reflect the residual state of HCC after TACE and quantitatively evaluate the blood perfusion change of residual tumors, which can provide hemodynamic information for further clinical treatment.
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Affiliation(s)
- Xin-Rong Zhang
- Department of Ultrasonography, Deqing People's Hospital, Huzhou 313200, Zhejiang Province, China
| | - Jun Ouyang
- Department of Ultrasonography, Deqing People's Hospital, Huzhou 313200, Zhejiang Province, China
| | - Jing-Yuan Huang
- Department of Ultrasonography, Shulan (Hangzhou) Hospital, Hangzhou 310022, Zhejiang Province, China
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Yi PS, Li Y, Yan S, Wu B, Lan C, Li JS. Surgery combined with post-operative trancatheter arterial chemoembolization improves survival of intermediate hepatocellular carcinoma. Scand J Gastroenterol 2019; 54:240-245. [PMID: 30880503 DOI: 10.1080/00365521.2019.1577487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM To investigate the efficacy of surgery combined with post-operative trancatheter arterial chemoembolization (TACE) for intermediate hepatocellular carcinoma (HCC). METHODS A total of 102 patients were divided into two groups: Radical liver resection only (LR group, 52 patients) and radical liver resection combined with post-operative TACE (combined group, 50 patients). Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analysis were performed using Cox proportional analysis to detect prognostic factors of survival outcomes. RESULTS The 1-, 3- and 5-year survival rate in the LR group were significantly lower compared with those in combined group (p = .019). The 1-, 3- and 5-year progression-free survival rate in the LR group were also lower than those in the combined group (p = .048). Multivariate analysis detected that tumor number (multiple vs single), tumor distribution (both lobes vs semi-liver), treatment strategy (surgery + TACE vs surgery) were independent factors for OS (HR values were 2.307, 3.155 and 0.526, respectively) and PFS (HR values were 1.938, 3.425 and 0.633, respectively; p < .05). CONCLUSION In conclusion, surgery combined with post-operative TACE may improve survival outcomes for patients with intermediate HCC. Tumor number, tumor distribution and treatment strategy (surgery + TACE) were significantly associated with the prognosis of patients with intermediate HCC.
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Affiliation(s)
- Peng Sheng Yi
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
| | - Yong Li
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
| | - Shu Yan
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
| | - Bin Wu
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
| | - Chuan Lan
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
| | - Jian Shui Li
- a Department of hepato-biliary-pancreatic , Institute of General surgery, Affiliated Hospital of North Sichuan Medical College , Nanchong , P.R. China
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Waly AA, El-Ekiaby N, Assal RA, Abdelrahman MM, Hosny KA, El Tayebi HM, Esmat G, Breuhahn K, Abdelaziz AI. Methylation in MIRLET7A3 Gene Induces the Expression of IGF-II and Its mRNA Binding Proteins IGF2BP-2 and 3 in Hepatocellular Carcinoma. Front Physiol 2019; 9:1918. [PMID: 30733684 PMCID: PMC6353855 DOI: 10.3389/fphys.2018.01918] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/20/2018] [Indexed: 01/08/2023] Open
Abstract
miR-let-7a is a tumor suppressor miRNA with reduced expression in most cancers. Methylation of MIRLET7A3 gene was reported to be the cause of this suppression in several cancers; however, it was not explicitly investigated in hepatocellular carcinoma (HCC). We aimed at investigating miR-let-7a expression and molecular mode in HCC, identifying drug-targetable networks, which might be affected by its abundance. Our results illustrated a significant repression of miR-let-7a, which correlated with hypermethylation of its gene of origin MIRLRT7A3. This was further supported by the induction of miR-let-7a expression upon treatment of HCC cells with a DNA-methyltransferase inhibitor. Using a computational approach, insulin-like growth factor (IGF)-II and IGF-2 mRNA binding proteins (IGF2BP)-2/-3 were identified as potential targets for miR-let-7a that was further confirmed experimentally. Indeed, miR-let-7a mimics diminished IGF-II as well as IGF2BP-2/-3 expression. Direct binding of miR-let-7a to each respective transcript was confirmed using a luciferase reporter assay. In conclusion, this study suggests that DNA hypermethylation leads to epigenetic repression of miR-let-7a in HCC cells, which induces the oncogenic IGF-signaling pathway.
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Affiliation(s)
- Amr A. Waly
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Reem A. Assal
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Karim A. Hosny
- Department of General Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend M. El Tayebi
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatology, Cairo University, Cairo, Egypt
| | - Kai Breuhahn
- Molecular Hepatopathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ahmed I. Abdelaziz
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
- School of Medicine, Newgiza University, Cairo, Egypt
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47
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Okrah K, Tarighat S, Liu B, Koeppen H, Wagle MC, Cheng G, Sun C, Dey A, Chang MT, Sumiyoshi T, Mounir Z, Cummings C, Hampton G, Amler L, Fridlyand J, Hegde PS, Turley SJ, Lackner MR, Huang SM. Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of disease progression and tumor immune biology. NPJ Precis Oncol 2018; 2:25. [PMID: 30456308 PMCID: PMC6237857 DOI: 10.1038/s41698-018-0068-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) develops in the context of chronic inflammatory liver disease and has an extremely poor prognosis. An immunosuppressive tumor microenvironment may contribute to therapeutic failure in metastatic HCC. Here, we identified unique molecular signatures pertaining to HCC disease progression and tumor immunity by analyzing genome-wide RNA-Seq data derived from HCC patient tumors and non-tumor cirrhotic tissues. Unsupervised clustering of gene expression data revealed a gradual suppression of local tumor immunity that coincided with disease progression, indicating an increasingly immunosuppressive tumor environment during HCC disease advancement. IHC examination of the spatial distribution of CD8+ T cells in tumors revealed distinct intra- and peri-tumoral subsets. Differential gene expression analysis revealed an 85-gene signature that was significantly upregulated in the peri-tumoral CD8+ T cell-excluded tumors. Notably, this signature was highly enriched with components of underlying extracellular matrix, fibrosis, and epithelial-mesenchymal transition (EMT). Further analysis condensed this signature to a core set of 23 genes that are associated with CD8+ T cell localization, and were prospectively validated in an independent cohort of HCC specimens. These findings suggest a potential association between elevated fibrosis, possibly modulated by TGF-β, PDGFR, SHH or Notch pathway, and the T cell-excluded immune phenotype. Indeed, targeting fibrosis using a TGF-β neutralizing antibody in the STAM™ model of murine HCC, we found that ameliorating the fibrotic environment could facilitate redistribution of CD8+ lymphocytes into tumors. Our results provide a strong rationale for utilizing immunotherapies in HCC earlier during treatment, potentially in combination with anti-fibrotic therapies.
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Affiliation(s)
- K. Okrah
- Department of Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. Tarighat
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - B. Liu
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - H. Koeppen
- Department of Research Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. C. Wagle
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - G. Cheng
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - C. Sun
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - A. Dey
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. T. Chang
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - T. Sumiyoshi
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - Z. Mounir
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - C. Cummings
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - G. Hampton
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - L. Amler
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - J. Fridlyand
- Department of Biostatistics, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - P. S. Hegde
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. J. Turley
- Department of Research, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - M. R. Lackner
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
| | - S. M. Huang
- Department of Oncology Biomarker Development, Genentech, 1 DNA Way, South San Francisco, CA 94080 USA
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Huang G, Jiang H, Lin Y, Wu Y, Cai W, Shi B, Luo Y, Jian Z, Zhou X. Prognostic value of plasma fibrinogen in hepatocellular carcinoma: a meta-analysis. Cancer Manag Res 2018; 10:5027-5041. [PMID: 30464603 PMCID: PMC6214315 DOI: 10.2147/cmar.s175780] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Elevated plasma fibrinogen levels have been associated with tumor progression in several malignancies. Our study aims to characterize the clinical significance of elevated plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). Materials and methods Relevant published articles were systematically searched in electronic databases including PubMed, Embase, and Web of Science. The pooled differences in plasma fibrinogen levels among HCC, cirrhotic, and control groups were expressed as weighted mean differences (WMDs) and their corresponding 95% CIs. The associations between elevated fibrinogen and overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS) were expressed as HRs and their 95% CIs, whereas the associations between elevated fibrinogen and various types of clinical characteristic of patients with HCC were expressed as ORs and their corresponding 95% CIs. Results Results showed that the plasma fibrinogen levels in patients with HCC were not significantly different than that in healthy controls (WMD = 0.50, 95% CI = [−0.82, 1.82], P = 0.457) or patients with cirrhosis (WMD = −0.62, 95% CI = [−1.56, 0.33], P = 0.200). However, our results showed that compared to those with normal levels, patients with HCC and elevated plasma fibrinogen levels showed poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and DFS/RFS (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Results of trial sequential analysis of the OS indicated that currently available studies were sufficient to validate the negative prognostic value of elevated plasma fibrinogen in patients with HCC. Clinicopathological analyses showed that high plasma fibrinogen levels were associated with tumor progression as indicated by advanced tumor stage, larger tumor size, increased tumor number, and the presence of vascular invasion. Conclusion Elevated plasma fibrinogen levels are associated with poor prognosis and advanced tumor progression. Plasma fibrinogen may serve as a negative prognostic biomarker in patients with HCC.
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Affiliation(s)
- Guanqun Huang
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China
| | - Hui Jiang
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China,
| | - Ye Lin
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People's Republic of China,
| | - Yanpeng Wu
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China
| | - Weilong Cai
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China
| | - Boyun Shi
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China,
| | - Yuanwei Luo
- Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China
| | - Zhixiang Jian
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People's Republic of China,
| | - Xinke Zhou
- Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People's Republic of China,
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Fekry B, Ribas-Latre A, Baumgartner C, Deans JR, Kwok C, Patel P, Fu L, Berdeaux R, Sun K, Kolonin MG, Wang SH, Yoo SH, Sladek FM, Eckel-Mahan K. Incompatibility of the circadian protein BMAL1 and HNF4α in hepatocellular carcinoma. Nat Commun 2018; 9:4349. [PMID: 30341289 PMCID: PMC6195513 DOI: 10.1038/s41467-018-06648-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of liver-specific gene expression with potent tumor suppressor activity, yet many liver tumors express HNF4α. This study reveals that P1-HNF4α, the predominant isoform expressed in the adult liver, inhibits expression of tumor promoting genes in a circadian manner. In contrast, an additional isoform of HNF4α, driven by an alternative promoter (P2-HNF4α), is induced in HNF4α-positive human hepatocellular carcinoma (HCC). P2-HNF4α represses the circadian clock gene ARNTL (BMAL1), which is robustly expressed in healthy hepatocytes, and causes nuclear to cytoplasmic re-localization of P1-HNF4α. We reveal mechanisms underlying the incompatibility of BMAL1 and P2-HNF4α in HCC, and demonstrate that forced expression of BMAL1 in HNF4α-positive HCC prevents the growth of tumors in vivo. These data suggest that manipulation of the circadian clock in HNF4α-positive HCC could be a tractable strategy to inhibit tumor growth and progression in the liver.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Corrine Baumgartner
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Jonathan R Deans
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Christopher Kwok
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Pooja Patel
- Department of Pediatrics, Molecular and Cellular Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Loning Fu
- Department of Pediatrics, Molecular and Cellular Biology, Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Rebecca Berdeaux
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Kai Sun
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Sidney H Wang
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Seung-Hee Yoo
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Kristin Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA.
- Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, 77030, USA.
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50
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Zhang J, Fang C, Qu M, Wu H, Wang X, Zhang H, Ma H, Zhang Z, Huang Y, Shi L, Liang S, Gao Z, Song W, Wang X. CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents. Front Pharmacol 2018; 9:1042. [PMID: 30258365 PMCID: PMC6144529 DOI: 10.3389/fphar.2018.01042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 08/27/2018] [Indexed: 12/20/2022] Open
Abstract
Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.
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Affiliation(s)
- Jian Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Chunyan Fang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Meihua Qu
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Huina Wu
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xuejuan Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hongan Zhang
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Hui Ma
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Zhaolin Zhang
- Weifang Bochuang International Biological Medicinal Institute, Weifang, China
| | - Yongxue Huang
- Weifang Bochuang International Biological Medicinal Institute, Weifang, China
| | - Lihong Shi
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Shujuan Liang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zhiqin Gao
- School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Weiguo Song
- School of Pharmacy, Weifang Medical University, Weifang, China
| | - Xuejian Wang
- School of Pharmacy, Weifang Medical University, Weifang, China
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