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Zhang Q, Chan WL, Fung SY, Pang L, Ding T, Teo JMN, Zhou Y, Wu CMA, Siu KL, Bi J, Ling GS, Jin DY, Man K, Ching YP. Centrosome protein TAX1BP2 mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in hepatocellular carcinoma. Mol Ther 2025:S1525-0016(25)00047-4. [PMID: 39881544 DOI: 10.1016/j.ymthe.2025.01.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 12/19/2024] [Accepted: 01/24/2025] [Indexed: 01/31/2025] Open
Abstract
Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered that a hallmark of low TAX1BP2 expression in HCC tumors is T cell exclusion, whereas re-depression of TAX1BP2 in preclinical models restores antitumor immunity and potentiates anti-PD-1 efficacy. Mechanistically, we identified that reconstitution of intratumor TAX1BP2 triggers the type I interferon (IFN-I) response and subsequent facilitation of a subtype of CD27+CD8+ T cell recruitment. Furthermore, we demonstrated that Intratumor TAX1BP2 upregulates STING by inhibiting the hyperactivation of DNMT1, and EZH2 is linked to endogenous LKB1 activity.
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Affiliation(s)
- Qingmei Zhang
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China; Department of Surgery, HKU-Shenzhen Hospital and Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | - Wing-Lim Chan
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Sin-Yee Fung
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Li Pang
- Department of Surgery, HKU-Shenzhen Hospital and Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China; Organ Transplantation Center, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tao Ding
- Department of Surgery, HKU-Shenzhen Hospital and Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China
| | | | - Yuan Zhou
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Chung Ming Alex Wu
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Kam-Leung Siu
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Jiacheng Bi
- The CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Guang Sheng Ling
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Dong-Yan Jin
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China
| | - Kwan Man
- Department of Surgery, HKU-Shenzhen Hospital and Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Yick Pang Ching
- School of Biomedical Sciences, University of Hong Kong, Hong Kong SAR, China; State Key Laboratory of Liver Research (University of Hong Kong), Hong Kong SAR, China.
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Li W, Chen G, Peng H, Zhang Q, Nie D, Guo T, Zhu Y, Zhang Y, Lin M. Research Progress on Dendritic Cells in Hepatocellular Carcinoma Immune Microenvironments. Biomolecules 2024; 14:1161. [PMID: 39334927 PMCID: PMC11430656 DOI: 10.3390/biom14091161] [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: 07/17/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/30/2024] Open
Abstract
Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in initiating immune responses by cross-presenting relevant antigens to initial T cells. The activation of DCs is a crucial step in inducing anti-tumor immunity. Upon recognition and uptake of tumor antigens, activated DCs present these antigens to naive T cells, thereby stimulating T cell-mediated immune responses and enhancing their ability to attack tumors. It is particularly noted that DCs are able to cross-present foreign antigens to major histocompatibility complex class I (MHC-I) molecules, prompting CD8+ T cells to proliferate and differentiate into cytotoxic T cells. In the malignant progression of hepatocellular carcinoma (HCC), the inactivation of DCs plays an important role, and the activation of DCs is particularly important in anti-HCC immunotherapy. In this review, we summarize the mechanisms of DCs activation in HCC, the involved regulatory factors and strategies to activate DCs in HCC immunotherapy. It provides a basis for the study of HCC immunotherapy through DCs activation.
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Affiliation(s)
- Wenya Li
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Guojie Chen
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Medical School, Nantong University, Nantong 226019, China
| | - Hailin Peng
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Qingfang Zhang
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Dengyun Nie
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ting Guo
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yinxing Zhu
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
| | - Yuhan Zhang
- The First School of Clinical Medicine Southern Medical University, Guangzhou 510515, China
| | - Mei Lin
- The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou 225300, China
- Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Gu D, Zhao X, Song J, Xiao J, Zhang L, Deng G, Li D. Expression and clinical significance of interleukin-6 pathway in cholangiocarcinoma. Front Immunol 2024; 15:1374967. [PMID: 38881895 PMCID: PMC11176422 DOI: 10.3389/fimmu.2024.1374967] [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: 02/01/2024] [Accepted: 05/15/2024] [Indexed: 06/18/2024] Open
Abstract
Background Cholangiocarcinoma (CCA) is a typical inflammation-induced malignancy, and elevated serum interleukin-6 (IL-6) levels have been reported to be linked to the onset and progression of CCA. We aim to investigate the potential prognostic value of the IL-6 pathway for CCA. Methods We detected the expressions of IL-6, IL-6R, glycoprotein (gp130), C-reactive protein (CRP), Janus kinase 2 (JAK2), and signal transducer and activator of transcription 3 (STAT3) in CCA tissue microarray using multiplex immunofluorescence. Furthermore, the clinical associations and prognostic values were assessed. Finally, single-cell transcriptome analysis was performed to evaluate the expression level of IL-6 pathway genes in CCA. Results The results revealed that the expression of IL-6 was lower, while the expression of STAT3 was higher in tumor tissues compared to normal tissues. Especially in tumor microenvironment, the expression of IL-6 pathway genes was generally downregulated. Importantly, gp130 was strongly correlated with JAK2 in tumor tissues, while it was moderately correlated with JAK2 in normal tissue. Although none of the gene expressions were directly associated with overall survival and disease-free survival, our study found that IL-6, IL-6R, CRP, gp130, and JAK2 were inversely correlated with vascular invasion, which is a risk factor for poor prognosis in patients with CCA. Conclusion The findings from this study suggest that the IL-6 signaling pathway may have a potential prognostic value for CCA. Further investigation is needed to understand the underlying molecular mechanisms of the IL-6 pathway in CCA.
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Affiliation(s)
- Dongqing Gu
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Viral Infectious Diseases, Chongqing, China
| | - Xin Zhao
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Jing Song
- Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University (CHCMU), Chongqing, China
| | - Jianmei Xiao
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Viral Infectious Diseases, Chongqing, China
| | - Leida Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Guohong Deng
- Department of Infectious Diseases, First Affiliated Hospital, Army Medical University, Chongqing, China
- Chongqing Key Laboratory of Viral Infectious Diseases, Chongqing, China
| | - Dajiang Li
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Army Medical University, Chongqing, China
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Liu CR, Li YP, Wang YK, Zhang W, Hao M, Wang WJ, Li T, Dang SS. Peripheral blood T cell and cytokine levels in HBV-related liver disease patients. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:293-301. [DOI: 10.11569/wcjd.v32.i4.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
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Tylutka A, Walas Ł, Zembron-Lacny A. Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis. Front Immunol 2024; 15:1330386. [PMID: 38495887 PMCID: PMC10943692 DOI: 10.3389/fimmu.2024.1330386] [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: 10/30/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction Chronic low-grade inflammation is an important aspect of morbidity and mortality in older adults. The level of circulating pro-inflammatory cytokines (interleukin (IL)-6, tumor necrosis factor (TNF) or IL-1β) is a risk factor in cardiovascular and neurodegenerative diseases and is also associated with sarcopenia and frailties. The objective of this study was to assess each cytokine: IL-6, TNF, and IL-1β separately in the elderly with comorbidities against controls without diseases according to the data published in the available literature. Methods The electronic bibliographic PubMed database was systematically searched to select all the relevant studies published up to July 2023. The total number of the subjects involved in the meta-analysis included patients with diseases (n=8154) and controls (n=33967). Results The overall concentration of IL-6 was found to be higher in patients with diseases compared to controls and the difference was statistically significant, with a p-value of <0.001 (SMD, 0.16; 95% CI, 0.12-0.19). The heterogeneity was considerable with Q = 109.97 (P <0.0001) and I2 = 79.2%. The potential diagnostic usefulness of IL-6 was confirmed by odds ratio (OR) analysis (OR: 1.03, 95% CI (1.01; 1.05), p=0.0029). The concentration of both TNF and IL-1β was elevated in the control group compared to patients and amounted to SMD -0.03; 95% CI, -0.09-0.02, p-value 0.533 and SMD-0.29; 95% CI, -0.47- -0.12; p = 0.001, respectively. For TNF, however, the difference was statistically insignificant. Discussion IL-6, unlike TNF and IL-1β, could be a useful and convenient marker of peripheral inflammation in older adults with various comorbidities.
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Affiliation(s)
- Anna Tylutka
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, Zielona Gora, Poland
| | - Łukasz Walas
- Institute of Dendrology, Polish Academy of Sciences, Kórnik, Poland
| | - Agnieszka Zembron-Lacny
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, Zielona Gora, Poland
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Savage TM, Fortson KT, de Los Santos-Alexis K, Oliveras-Alsina A, Rouanne M, Rae SS, Gamarra JR, Shayya H, Kornberg A, Cavero R, Li F, Han A, Haeusler RA, Adam J, Schwabe RF, Arpaia N. Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis. Immunity 2024; 57:303-318.e6. [PMID: 38309273 PMCID: PMC10922825 DOI: 10.1016/j.immuni.2024.01.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/20/2023] [Accepted: 01/10/2024] [Indexed: 02/05/2024]
Abstract
Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.
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Affiliation(s)
- Thomas M Savage
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | - Katherine T Fortson
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | | | | | - Mathieu Rouanne
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | - Sarah S Rae
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | | | - Hani Shayya
- Mortimer B. Zuckerman Mind, and Brain and Behavior Institute, Columbia University, New York, NY, USA
| | - Adam Kornberg
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA
| | - Renzo Cavero
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | - Fangda Li
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA
| | - Arnold Han
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA; Columbia Center for Translational Immunology, Columbia University, New York, NY, USA; Department of Medicine, Columbia University, New York, NY, USA
| | - Rebecca A Haeusler
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Julien Adam
- Pathology Department, Hopital Paris Saint-Joseph, Paris, France; INSERM U1186, Gustave Roussy, Villejuif, France
| | | | - Nicholas Arpaia
- Department of Microbiology & Immunology, Columbia University, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
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Khan S, Anwer A, Sevak JK, Trehanpati N, Kazim SN. Cytokines Expression Compared to the Determinants of Cellular Apoptosis Prominently Attributes to the Deleterious Effects of 'A' Determinant Surface Gene Mutations in HBV Transfected Hepatoma Cell Line. Immunol Invest 2024; 53:224-240. [PMID: 38095846 DOI: 10.1080/08820139.2023.2288841] [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] [Indexed: 03/23/2024]
Abstract
BACKGROUND Previous studies have explored the role of AKT protein in anti-apoptotic/proliferative activities. However, there has been a lack of information regarding the role of Akt in association with cytokines expression in HBV-related (wild type HBV and HBV with mutations of 'a' determinant region) studies either in the case of HBV infection or in transfected hepatoma cells. The present study tries to determine the role of Akt and cytokines expression in the presence of small surface gene mutants in the hepatoma cell line. METHODS Mutations of 'a' determinant region, viz. sA128V and sG145R, were created in wild-type pHBV1.3 by site-directed mutagenesis and transfected in hepatoma cell line. Secretory levels of HBsAg in the wild type as well as in both the mutants were analyzed by ELISA. Apoptotic analysis of transfected cells was studied by flow cytometry. Expression analysis of Akt and cytokines (TNF-alpha, IL-6, and IFN-gamma) was done by qPCR. RESULTS The presence of significantly more alive cells in sG145R than sA128V transfected cells may be due to the up-regulation of the Akt gene expression. Cytokines expression was nearly similar between sA128V and wild-type pHBV1.3 transfected cells. Presence of sG145R showed dramatically high cytokines expression than sA128V and wild-type pHBV1.3. CONCLUSION Cytokines expression predominantly contributes to the detrimental effects associated with the 'a' determinant region mutations particularly sG145R mutant. It may also be inferred that mechanisms associated with cellular apoptosis apparently do not play any major role to assign the 'a' determinant small surface gene mutation(s) for their pathological outcome.
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Affiliation(s)
- Saniya Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Ayesha Anwer
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Jayesh Kumar Sevak
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Syed Naqui Kazim
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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Paul C, Besch C, Artzner T, Michard B, Cusumano C, Addeo P, Bachellier P, Faitot F. Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation. Cytokine 2023; 169:156286. [PMID: 37385083 DOI: 10.1016/j.cyto.2023.156286] [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: 04/10/2023] [Revised: 06/13/2023] [Accepted: 06/24/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND & AIMS Inflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT. The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. METHODS From 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). RESULTS High IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010). Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013). Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). CONCLUSIONS IL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.
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Affiliation(s)
- Chloé Paul
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - Camille Besch
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Thierry Artzner
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Baptiste Michard
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Caterina Cusumano
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Pietro Addeo
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France
| | - Philippe Bachellier
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - François Faitot
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France.
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Chamseddine S, Mohamed YI, Lee SS, Yao JC, Hu ZI, Tran Cao HS, Xiao L, Sun R, Morris JS, Hatia RI, Hassan M, Duda DG, Diab M, Mohamed A, Nassar A, Datar S, Amin HM, Kaseb AO. Clinical and Prognostic Biomarker Value of Blood-Circulating Inflammatory Cytokines in Hepatocellular Carcinoma. Oncology 2023; 101:730-737. [PMID: 37467732 PMCID: PMC10614568 DOI: 10.1159/000531870] [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: 03/14/2023] [Accepted: 06/20/2023] [Indexed: 07/21/2023]
Abstract
INTRODUCTION Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients. METHODS We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% confidence interval [CI]: 52.5, 83.3). Biomarker association with OS was evaluated by the log-rank method. RESULTS The median OS in this cohort was 14.2 months (95% CI: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18. CONCLUSION Our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC.
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Affiliation(s)
- Shadi Chamseddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,
| | - Yehia I Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sunyoung S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - James C Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zishuo Ian Hu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hop S Tran Cao
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeffrey S Morris
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rikita I Hatia
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Manal Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Dan G Duda
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Maria Diab
- Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
| | - Amr Mohamed
- Division of Hematology/Oncology, Department of Medicine, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Ahmed Nassar
- Department of Surgery, Emory University, Atlanta, Georgia, USA
| | - Saumil Datar
- Department of Internal Medicine University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Hesham M Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ahmed Omar Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Shahini E, Pasculli G, Solimando AG, Tiribelli C, Cozzolongo R, Giannelli G. Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int J Mol Sci 2023; 24:ijms24054286. [PMID: 36901717 PMCID: PMC10001986 DOI: 10.3390/ijms24054286] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
- Correspondence: ; Tel.: +39-0804994249
| | - Giuseppe Pasculli
- National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), University of Bari “A. Moro”, 70121 Bari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Director, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
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Liu Y, Xu Q, Deng F, Zheng Z, Luo J, Wang P, Zhou J, Lu X, Zhang L, Chen Z, Zhang Q, Chen Q, Zuo D. HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway. J Exp Clin Cancer Res 2023; 42:38. [PMID: 36721234 PMCID: PMC9890722 DOI: 10.1186/s13046-023-02609-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 01/19/2023] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis. METHODS RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan-Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development. RESULTS We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model. CONCLUSION Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.
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Affiliation(s)
- Yunzhi Liu
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Clinical Oncology Center, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, Guangdong, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Qishan Xu
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Fan Deng
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Zhuojun Zheng
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jialiang Luo
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Ping Wang
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jia Zhou
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Xiao Lu
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Liyun Zhang
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Zhengliang Chen
- Guangdong Province Key Laboratory of Proteomics, Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Qifan Zhang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Qingyun Chen
- Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
| | - Daming Zuo
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Guangdong Province Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, Guangdong, China.
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Tabakhiyan F, Mir A, Vahedian V. Potential tumor marker for hepatocellular carcinoma identification: PI3K and pro-inflammatory cytokines (TGF-β, IL-1, and IL-6). Horm Mol Biol Clin Investig 2022; 43:389-396. [PMID: 35709206 DOI: 10.1515/hmbci-2022-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC), the most common form of liver cancer, is a leading cause of tumor-associated mortality worldwide. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The progression of HCC is often associated with chronic inflammation, expression levels of inflammatory mediators, chemokine, and cytokines. In this study, we try to evaluate the PI3K and pro-inflammatory cytokines, TGF-β, IL-1, and IL-6 expression level in patients with liver cancer. MATERIALS AND METHODS The kupffer cells were isolated from patient's specimens. Real-time PCR was applied to evaluate the expression level of PI3K in cell lines or tumors. The concentrations of TGF-β, IL-1, and IL-6 were measured by the quantitative ELISA kit. RESULTS PI3K mRNA expression in cancer cells was increased markedly vs. normal cells. The ELISA results demonstrated over expression of TGF-β, IL-1, and IL-6 in patients and positive correlation between tumor size and stage. DISCUSSION This study suggests that targeting the expression level of PI3K and pro-inflammatory chemokine and cytokines, TGF-β, IL-1, and IL-6, may be a potential diagnostic strategy in HCC patients.
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Affiliation(s)
| | - Amirabbas Mir
- Institute of Nano Science and Nano Technology, University of Kashan, Kashan, Islamic Republic of Iran
| | - Vahid Vahedian
- Cancer Biology Research Group, Faculty of Medicine Institute of Biotechnology (FMB-IBTEC) Sao Paulo State University (UNESP), Sao Paulo, Brazil
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13
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da Cruz NS, Pasquarelli-do-Nascimento G, e Oliveira ACP, Magalhães KG. Inflammasome-Mediated Cytokines: A Key Connection between Obesity-Associated NASH and Liver Cancer Progression. Biomedicines 2022; 10:2344. [PMID: 36289606 PMCID: PMC9598450 DOI: 10.3390/biomedicines10102344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 09/18/2022] [Indexed: 11/18/2022] Open
Abstract
Liver cancer is one of the most lethal malignancies and is commonly diagnosed as hepatocellular carcinoma (HCC), a tumor type that affects about 90% of patients. Non-alcoholic steatohepatitis (NASH) and obesity are both risk factors for this disease. HCC initiation and progression are deeply linked with changes in the hepatic microenvironment, with cytokines playing key roles. The understanding of the pathogenic pathways that connect these disorders to liver cancer remains poor. However, the inflammasome-mediated cytokines associated with both diseases are central actors in liver cancer progression. The release of the pro-inflammatory cytokines IL-1β and IL-18 during inflammasome activation leads to several detrimental effects on the liver microenvironment. Considering the critical crosstalk between obesity, NASH, and HCC, this review will present the connections of IL-1β and IL-18 from obesity-associated NASH with HCC and will discuss approaches to using these cytokines as therapeutic targets against HCC.
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Affiliation(s)
| | | | | | - Kelly Grace Magalhães
- Laboratory of Immunology and Inflammation, Department of Cell Biology, University of Brasilia, Brasilia 70910-900, Brazil
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14
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Harris BHL, Macaulay VM, Harris DA, Klenerman P, Karpe F, Lord SR, Harris AL, Buffa FM. Obesity: a perfect storm for carcinogenesis. Cancer Metastasis Rev 2022; 41:491-515. [PMID: 36038791 PMCID: PMC9470699 DOI: 10.1007/s10555-022-10046-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/08/2022] [Indexed: 12/14/2022]
Abstract
Obesity-related cancers account for 40% of the cancer cases observed in the USA and obesity is overtaking smoking as the most widespread modifiable risk factor for carcinogenesis. Here, we use the hallmarks of cancer framework to delineate how obesity might influence the carcinogenic hallmarks in somatic cells. We discuss the effects of obesity on (a) sustaining proliferative signaling; (b) evading growth suppressors; (c) resisting cell death; (d) enabling replicative immortality; (e) inducing angiogenesis; (f) activating invasion and metastasis; (g) reprogramming energy metabolism; and (h) avoiding immune destruction, together with its effects on genome instability and tumour-promoting inflammation. We present the current understanding and controversies in this evolving field, and highlight some areas in need of further cross-disciplinary focus. For instance, the relative importance of the many potentially causative obesity-related factors is unclear for each type of malignancy. Even within a single tumour type, it is currently unknown whether one obesity-related factor consistently plays a predominant role, or if this varies between patients or, even in a single patient with time. Clarifying how the hallmarks are affected by obesity may lead to novel prevention and treatment strategies for the increasingly obese population.
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Affiliation(s)
- Benjamin H L Harris
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
- St Anne's College, 56 Woodstock Rd, Oxford, OX2 6HS, UK.
| | - Valentine M Macaulay
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK
| | | | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK
| | - Simon R Lord
- Early Phase Clinical Trials Unit, Churchill Hospital, Oxford, OX3 7LE, UK
| | - Adrian L Harris
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
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15
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Buddham R, Chauhan S, Narad P, Mathur P. Reconstruction and Exploratory Analysis of mTORC1 Signaling Pathway and Its Applications to Various Diseases Using Network-Based Approach. J Microbiol Biotechnol 2022; 32:365-377. [PMID: 35001007 PMCID: PMC9628786 DOI: 10.4014/jmb.2108.08007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 12/15/2022]
Abstract
Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (PI3K) pathway, which is involved in multiple biological functions by transcriptional and translational control. mTOR is a downstream mediator in the PI3K/Akt signaling pathway and plays a critical role in cell survival. In cancer, this pathway can be activated by membrane receptors, including the HER (or ErbB) family of growth factor receptors, the insulin-like growth factor receptor, and the estrogen receptor. In the present work, we congregated an electronic network of mTORC1 built on an assembly of data using natural language processing, consisting of 470 edges (activations/interactions and/or inhibitions) and 206 nodes representing genes/proteins, using the Cytoscape 3.6.0 editor and its plugins for analysis. The experimental design included the extraction of gene expression data related to five distinct types of cancers, namely, pancreatic ductal adenocarcinoma, hepatic cirrhosis, cervical cancer, glioblastoma, and anaplastic thyroid cancer from Gene Expression Omnibus (NCBI GEO) followed by pre-processing and normalization of the data using R & Bioconductor. ExprEssence plugin was used for network condensation to identify differentially expressed genes across the gene expression samples. Gene Ontology (GO) analysis was performed to find out the over-represented GO terms in the network. In addition, pathway enrichment and functional module analysis of the protein-protein interaction (PPI) network were also conducted. Our results indicated NOTCH1, NOTCH3, FLCN, SOD1, SOD2, NF1, and TLR4 as upregulated proteins in different cancer types highlighting their role in cancer progression. The MCODE analysis identified gene clusters for each cancer type with MYC, PCNA, PARP1, IDH1, FGF10, PTEN, and CCND1 as hub genes with high connectivity. MYC for cervical cancer, IDH1 for hepatic cirrhosis, MGMT for glioblastoma and CCND1 for anaplastic thyroid cancer were identified as genes with prognostic importance using survival analysis.
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Affiliation(s)
- Richa Buddham
- Centre for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh Noida-201313, India
| | - Sweety Chauhan
- Centre for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh Noida-201313, India
| | - Priyanka Narad
- Centre for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh Noida-201313, India
| | - Puniti Mathur
- Centre for Computational Biology and Bioinformatics, Amity Institute of Biotechnology, Amity University Uttar Pradesh Noida-201313, India,Corresponding author Phone: +91-120-4392204 E-mail:
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16
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Öcal O, Schütte K, Kupčinskas J, Morkunas E, Jurkeviciute G, de Toni EN, Ben Khaled N, Berg T, Malfertheiner P, Klümpen HJ, Sengel C, Basu B, Valle JW, Benckert J, Gasbarrini A, Palmer D, Seidensticker R, Wildgruber M, Sangro B, Pech M, Ricke J, Seidensticker M. Baseline Interleukin-6 and -8 predict response and survival in patients with advanced hepatocellular carcinoma treated with sorafenib monotherapy: an exploratory post hoc analysis of the SORAMIC trial. J Cancer Res Clin Oncol 2022; 148:475-485. [PMID: 33855585 PMCID: PMC8800931 DOI: 10.1007/s00432-021-03627-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 03/30/2021] [Indexed: 11/14/2022]
Abstract
PURPOSE To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. METHODS A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. RESULTS Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). CONCLUSION IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.
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Affiliation(s)
- Osman Öcal
- Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
| | - Juozas Kupčinskas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Egidijus Morkunas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Gabija Jurkeviciute
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Enrico N de Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Najib Ben Khaled
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Thomas Berg
- Klinik Und Poliklinik Für Gastroenterologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany
| | | | - Heinz Josef Klümpen
- Department of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Christian Sengel
- Radiology Department, Grenoble University Hospital, La Tronche, France
| | - Bristi Basu
- Department of Oncology, University of Cambridge, Cambridge, UK
| | - Juan W Valle
- Division of Cancer Sciences and Department of Medical Oncology, The Christie NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Julia Benckert
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany
| | - Antonio Gasbarrini
- Fondazione Policlinico Universitario Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Roma, Italy
| | - Daniel Palmer
- Molecular and Clinical Cancer Medicine, University Hospitals and Clatterbridge, University of Liverpool, Liverpool, UK
| | - Ricarda Seidensticker
- Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra, Pamplona, Spain
| | - Maciej Pech
- Departments of Radiology and Nuclear Medicine, University of Magdeburg, Magdeburg, Germany
| | - Jens Ricke
- Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, Ludwig Maximilian University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
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Srivastava A, Sharma H, Khanna S, Sadhu Balasundaram T, Chowdhury S, Chowdhury R, Mukherjee S. Interleukin-6 Induced Proliferation Is Attenuated by Transforming Growth Factor-β-Induced Signaling in Human Hepatocellular Carcinoma Cells. Front Oncol 2022; 11:811941. [PMID: 35127527 PMCID: PMC8810489 DOI: 10.3389/fonc.2021.811941] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is often associated with an inflammatory setting. A plethora of cytokines are secreted in this milieu, actively contributing to the progression of the disease; however, the extent of cytokine interaction and how it contributes to HCC development remains an enigma. In this regard, our analysis of available patient-derived data suggests that cytokines like interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β) are enriched in HCC. We further analyzed the effect of these cytokines independently or in combination on HCC cells. Importantly, IL-6 was found to induce a STAT-3-dependent proliferation and mediate its pro-proliferative effects through activation and direct interaction with the p65 subunit of NFkB. Alternatively, TGF-β was found to induce a SMAD-dependent induction of epithelial to mesenchymal transition (EMT) coupled to growth arrest in these cells. Interestingly, the simultaneous addition of IL-6 and TGF-β failed to profoundly impact EMT markers but resulted in attenuation of IL-6-induced pro-proliferative effects. Analysis of the putative molecular mechanism revealed a decrease in IL-6 receptor (IL-6R) transcript levels, reduced expression of IL-6-induced STAT-3, and its nuclear localization upon addition of TGF-β along with IL-6. Consequently, a reduced p65 activation was also observed in combination treatment. Importantly, SMAD levels were unperturbed and the cells showed more TGF-β-like features under combination treatment. Finally, we observed that TGF-β resulted in enrichment of repressive chromatin mark (H3K27me3) coupled to growth arrest, while IL-6 induced an open chromatin signature (H3K4me3) associated with an enhanced expression of EZH2. Overall, for the first time, we show that TGF-β attenuates IL-6-induced effects by regulating the receptor level, downstream signaling, and the epigenome. Understanding the complex interactions between these cytokines can be imperative to a better understanding of the disease, and manipulation of cytokine balance can act as a prospective future therapeutic strategy.
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Affiliation(s)
| | | | | | | | | | | | - Sudeshna Mukherjee
- Department of Biological Sciences, Birla Institute of Technology and Science (BITS) Pilani, Rajasthan, India
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EMT and Inflammation: Crossroads in HCC. J Gastrointest Cancer 2022; 54:204-212. [PMID: 35020133 DOI: 10.1007/s12029-021-00801-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/29/2021] [Indexed: 10/19/2022]
Abstract
Hepatocellular carcinoma is one of the major causes of cancer-related deaths worldwide and is associated with several inflammatory mediators, since 90% of HCCs occur based on chronic hepatitis B or C, alcoholism or increasingly metabolic syndrome-associated inflammation. EMT is a physiological process, with coordinated changes in epithelial gene signatures and is regulated by multiple factors, including cytokines and growth factors such as TGFβ, EGF, and FGF. Recent reports propose a strong association between EMT and inflammation, which is also correlated with tumor aggressiveness and poor outcomes. Cellular heterogeneity results collectively as an outcome of EMT, inflammation, and the tumor microenvironment, and it plays a fundamental role in the progression, complexity of cancer, and chemoresistance. In this review, we highlight recent developments concerning the association of EMT and inflammation in the context of HCC progression. Identifying potential EMT-related biomarkers and understanding EMT regulatory molecules will likely contribute to promising developments in clinical practice and will be a valuable tool for predicting metastasis in general and specifically in HCC.
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Wang CI, Chu PM, Chen YL, Lin YH, Chen CY. Chemotherapeutic Drug-Regulated Cytokines Might Influence Therapeutic Efficacy in HCC. Int J Mol Sci 2021; 22:ijms222413627. [PMID: 34948424 PMCID: PMC8707970 DOI: 10.3390/ijms222413627] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/04/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second leading cause of cancer-related mortality worldwide. Processes involved in HCC progression and development, including cell transformation, proliferation, metastasis, and angiogenesis, are inflammation-associated carcinogenic processes because most cases of HCC develop from chronic liver damage and inflammation. Inflammation has been demonstrated to be a crucial factor inducing tumor development in various cancers, including HCC. Cytokines play critical roles in inflammation to accelerate tumor invasion and metastasis by mediating the migration of immune cells into damaged tissues in response to proinflammatory stimuli. Currently, surgical resection followed by chemotherapy is the most common curative therapeutic regimen for HCC. However, after chemotherapy, drug resistance is clearly observed, and cytokine secretion is dysregulated. Various chemotherapeutic agents, including cisplatin, etoposide, and 5-fluorouracil, demonstrate even lower efficacy in HCC than in other cancers. Tumor resistance to chemotherapeutic drugs is the key limitation of curative treatment and is responsible for treatment failure and recurrence, thus limiting the ability to treat patients with advanced HCC. Therefore, the capability to counteract drug resistance would be a major clinical advancement. In this review, we provide an overview of links between chemotherapeutic agents and inflammatory cytokine secretion in HCC. These links might provide insight into overcoming inflammatory reactions and cytokine secretion, ultimately counteracting chemotherapeutic resistance.
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Affiliation(s)
- Chun-I Wang
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan;
| | - Pei-Ming Chu
- Department of Anatomy, School of Medicine, China Medical University, Taichung 404, Taiwan;
| | - Yi-Li Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
| | - Yang-Hsiang Lin
- Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan;
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan;
- Correspondence: ; Tel./Fax: +886-6-2353535 (ext. 5329)
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20
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Zhong Y, Wang X, Zha R, Wang C, Zhang H, Wang Y, Li C. Dual-wavelength responsive photoelectrochemical aptasensor based on ionic liquid functionalized Zn-MOFs and noble metal nanoparticles for the simultaneous detection of multiple tumor markers. NANOSCALE 2021; 13:19066-19075. [PMID: 34757368 DOI: 10.1039/d1nr05782k] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
A single tumor marker may correspond to a variety of diseases, and a specific disease requires the joint detection of multiple tumor markers for improving the accuracy of diagnoses. An ionic liquid-functionalized metal-organic framework (Zn-MOF microspheres) was used as the substrate to capture the aptamer (Ab1), and noble metal nanoparticles were used to label a signal aptamer (Ab2) to construct a dual-wavelength responsive sandwich-type photoelectrochemical (PEC) aptasensor. Due to the size effect, plasma resonance and the response of the noble metal nanoparticle enhancement system to different excitation wavelengths, the simultaneous detection of CEA and CA153 tumor markers was realized. Under the optimized conditions, CA153 and CEA at concentrations of 0.05-100 U mL-1 and 0.005-10 ng mL-1 were detected by the PEC aptasensor. Detection limits calculated for CA153 and CEA determinations were 0.0275 U mL-1 and 2.85 pg mL-1 (S/N = 3), respectively. CA153 and CEA in serum samples were detected by the PEC aptasensor, and their concentrations were well consistent with that obtained from the ELISA. In addition, the PEC aptasensor exhibited a recovery rate of 96.98%-103.4%, and a relative standard deviation of 1.1%-3.6%, indicating good practical value and accuracy, further confirming its potential for clinical diagnosis.
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Affiliation(s)
- Yingying Zhong
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
| | - Xian Wang
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
| | - Ruyan Zha
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
| | - Chen Wang
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
| | - Huijuan Zhang
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
| | - Yanying Wang
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
- Experimental Teaching and Laboratory Management Center, South-Central University for Nationalities, Wuhan 430074, China.
| | - Chunya Li
- Key Laboratory of Catalysis and Energy Materials Chemistry of Ministry of Education & Hubei Key Laboratory of Catalysis and Materials Science & Key Laboratory of Analytical Chemistry of the State Ethnic Affairs Commission, South-Central University for Nationalities, Wuhan 430074, China.
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21
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Intestinal Intervention Strategy Targeting Myeloid Cells to Improve Hepatic Immunity during Hepatocarcinoma Development. Biomedicines 2021; 9:biomedicines9111633. [PMID: 34829862 PMCID: PMC8615385 DOI: 10.3390/biomedicines9111633] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023] Open
Abstract
Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter pro-tumorigenic conditions, at the early stages of HCC development, it was used as an established model of diethylnitrosamine/thioacetamide-injured liver fed with a standard diet (STD) or high-fat diet (42%) (HFD). The administration of SETIs improved survival and ameliorated tumor burden via modulation of monocyte-derived macrophages as key effectors involved in diet-induced HCC development. RT-qPCR analyses of hepatic tissue evidenced a diet-independent downregulatory effect of SETIs on the transcripts of CD36, FASN, ALOX15, and SREBP1c; however, animals fed with an STD showed opposing effects for PPAR and NRLP3 levels. These effects were accompanied by a decreased production of IL-6 and IL-17 but increased that of TNF in animals receiving SETIs. Moreover, only animals fed an HFD displayed increased concentrations of the stem cell factor. Overall, SETIs administration decreased the hepatic contents of lysophosphatydilcholine, phosphatidylinositol, phosphatidylcholine, and phosphatidyl ethanolamine. Notably, animals that received SETIs exhibited increased hepatic proportions of CD68+CX3CR1+CD74+ cells and at a higher rate in those animals fed an HFD. Altogether, the data evidence that oral administration of SETIs modulates the tumor microenvironment, improving hepatic innate immune response(s) and favoring a better antitumoral environment. It represents a path forward in developing coadjutant strategies to pharmacological therapies, with either a preventive or therapeutic character, to counter physiopathological conditions at early stages of HCC development.
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Shriki A, Lanton T, Sonnenblick A, Levkovitch-Siany O, Eidelshtein D, Abramovitch R, Rosenberg N, Pappo O, Elgavish S, Nevo Y, Safadi R, Peled A, Rose-John S, Galun E, Axelrod JH. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis. Cancer Res 2021; 81:4766-4777. [PMID: 34117031 DOI: 10.1158/0008-5472.can-21-0321] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/05/2021] [Accepted: 06/10/2021] [Indexed: 11/16/2022]
Abstract
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2-/-) mouse model to elucidate potential roles of IL6 in chronic hepatitis-associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling-deficient Mdr2-/- strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These findings reveal a crucial suppressive role for IL6/Stat3 signaling in chronic hepatitis-associated hepatocarcinogenesis by impeding protumorigenic NASH-associated phenotypes and by reinforcing the antitumorigenic effects of the SASP. SIGNIFICANCE: These findings describe a context-dependent role of IL6 signaling in hepatocarcinogenesis and predict that increased IL6-neutralizing sgp130 levels in some patients with NASH may herald early HCC development.See related commentary by Huynh and Ernst, p. 4671.
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Affiliation(s)
- Anat Shriki
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Tali Lanton
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amir Sonnenblick
- Oncology Division, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Orr Levkovitch-Siany
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Dana Eidelshtein
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Rinat Abramovitch
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- The Wohl Institute for Translational Medicine, Human Biology Research Center, Hadassah University Medical Center, Jerusalem, Israel
| | - Nofar Rosenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Orit Pappo
- Department of Pathology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Sharona Elgavish
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Yuval Nevo
- Bioinformatics Unit, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Hadassah Medical School, Ein Karem, Jerusalem, Israel
| | - Rifaat Safadi
- Liver Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Stefan Rose-John
- Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Eithan Galun
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
| | - Jonathan H Axelrod
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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23
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Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells. REPORTS 2021. [DOI: 10.3390/reports4020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.
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Leone P, Solimando AG, Fasano R, Argentiero A, Malerba E, Buonavoglia A, Lupo LG, De Re V, Silvestris N, Racanelli V. The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment. Vaccines (Basel) 2021; 9:vaccines9050532. [PMID: 34065489 PMCID: PMC8160723 DOI: 10.3390/vaccines9050532] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/19/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.
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Affiliation(s)
- Patrizia Leone
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
| | - Antonio Giovanni Solimando
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Rossella Fasano
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | | | - Eleonora Malerba
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- Department of Experimental Diagnostic and Specialty Medicine, “L. and A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
| | - Alessio Buonavoglia
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
| | - Luigi Giovanni Lupo
- Department of General Surgery and Liver Transplantation, University of Bari, 70124 Bari, Italy;
| | - Valli De Re
- Immunopathology and Cancer Biomarkers—Bio-Proteomics Facility, CRO Aviano National Cancer Institute, 33081 Aviano, Italy;
| | - Nicola Silvestris
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Vito Racanelli
- Unit of Internal Medicine “Guido Baccelli”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, 70124 Bari, Italy; (P.L.); (A.G.S.); (R.F.); (E.M.); (A.B.); (N.S.)
- Correspondence: ; Tel.: +39-080-5478050
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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Chen Y, Yang W, Chen Q, Liu Q, Liu J, Zhang Y, Li B, Li D, Nan J, Li X, Wu H, Xiang X, Peng Y, Wang J, Su S, Wang Z. Prediction of hepatocellular carcinoma risk in patients with chronic liver disease from dynamic modular networks. J Transl Med 2021; 19:122. [PMID: 33757544 PMCID: PMC7989040 DOI: 10.1186/s12967-021-02791-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 03/16/2021] [Indexed: 12/17/2022] Open
Abstract
Background Discovering potential predictive risks in the super precarcinomatous phase of hepatocellular carcinoma (HCC) without any clinical manifestations is impossible under normal paradigm but critical to control this complex disease. Methods In this study, we utilized a proposed sequential allosteric modules (AMs)-based approach and quantitatively calculated the topological structural variations of these AMs. Results We found the total of 13 oncogenic allosteric modules (OAMs) among chronic hepatitis B (CHB), cirrhosis and HCC network used SimiNEF. We obtained the 11 highly correlated gene pairs involving 15 genes (r > 0.8, P < 0.001) from the 12 OAMs (the out-of-bag (OOB) classification error rate < 0.5) partial consistent with those in independent clinical microarray data, then a three-gene set (cyp1a2-cyp2c19-il6) was optimized to distinguish HCC from non-tumor liver tissues using random forests with an average area under the curve (AUC) of 0.973. Furthermore, we found significant inhibitory effect on the tumor growth of Bel-7402, Hep 3B and Huh7 cell lines in zebrafish treated with the compounds affected those three genes. Conclusions These findings indicated that the sequential AMs-based approach could detect HCC risk in the patients with chronic liver disease and might be applied to any time-dependent risk of cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02791-9.
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Affiliation(s)
- Yinying Chen
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixian Ge, Xicheng District, Beijing, 100053, China.,Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China.,Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Yang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Qilong Chen
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai, 201203, China
| | - Qiong Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Jun Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Yingying Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Bing Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China
| | - Dongfeng Li
- School of Mathematical Sciences, Peking University, Beijing, China
| | - Jingyi Nan
- Shandong Danhong Pharmaceutical Co. Ltd., Heze, China
| | - Xiaodong Li
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Huikun Wu
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, China
| | - Xinghua Xiang
- School of Mathematics and Computational Science, Hunan University of Science and Technology, Xiangtan, China
| | - Yehui Peng
- School of Mathematics and Computational Science, Hunan University of Science and Technology, Xiangtan, China
| | - Jie Wang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No. 5 Beixian Ge, Xicheng District, Beijing, 100053, China.
| | - Shibing Su
- Research Center for Traditional Chinese Medicine Complexity System, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong, Shanghai, 201203, China.
| | - Zhong Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimen, Beijing, 100700, China.
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Tang S, Huang Z, Jiang J, Gao J, Zhao C, Tai Y, Ma X, Zhang L, Ye Y, Gan C, Su W, Jia X, Liu R, Wu H, Tang C. Celecoxib ameliorates liver cirrhosis via reducing inflammation and oxidative stress along spleen-liver axis in rats. Life Sci 2021; 272:119203. [PMID: 33577848 DOI: 10.1016/j.lfs.2021.119203] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/13/2021] [Accepted: 01/31/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Splenomegaly is usually taken as a consequence of liver cirrhosis. However, as a risk factor for cirrhosis, the impacts of spleen-liver axis on the development of cirrhosis are largely unknown. This study focused on the impacts of splenomegaly on the development of cirrhosis and assessment of the effects of celecoxib, a selective COX-2 inhibitor, on the splenomegaly and cirrhotic liver. MATERIALS AND METHODS Liver cirrhosis was induced by thioacetamide (TAA). Sixty rats were randomly divided into control, TAA-16w, TAA + celecoxib groups and normal, TAA + sham, TAA + splenectomy groups. Hepatic stellate cells (HSCs) or hepatocytes were co-cultured with splenocytes from those groups. RESULTS Splenocytes of cirrhotic rats stimulated the HSCs activation and induced hepatocyte apoptosis via enhancing oxidative stress. The hepatic levels of NOX-4 and the in situ O2- were profoundly reduced in TAA + splenectomy group by 50.6% and 18.5% respectively, p < 0.05. Celecoxib significantly decreased the hepatic fibrotic septa induced with TAA by 50.8%, p < 0.05. Splenic lymphoid tissue proliferation and proinflammatory cytokines of the cirrhotic rats were also obviously suppressed by celecoxib, p < 0.05. Compared with the HSC or hepatocyte cell line co-cultured with the cirrhotic splenocytes, the expression of alpha-SMA, NOX-4, in situ O2- or the levels of cleaved caspase3 and NOX-4 were significantly decreased in those cell lines co-cultured with cirrhotic splenocytes treated by celecoxib, p < 0.05. CONCLUSION Splenomegaly contributed to the development of liver cirrhosis through enhancing oxidative stress in liver. Celecoxib could effectively ameliorate liver cirrhosis via reducing inflammatory cytokines and immune cells derived from spleen and suppressing oxidative stress.
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Affiliation(s)
- Shihang Tang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyin Huang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jingsun Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Gao
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Chong Zhao
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Tai
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao Ma
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Linhao Zhang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yanting Ye
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Can Gan
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Su
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xintong Jia
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Liu
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
| | - Chengwei Tang
- Lab. of gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, China; Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
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Bachmann M, Lamprecht L, Gonther S, Pfeilschifter J, Mühl H. A murine cellular model of necroinflammation displays RAGE-dependent cytokine induction that connects to hepatoma cell injury. J Cell Mol Med 2020; 24:10356-10366. [PMID: 32697038 PMCID: PMC7521286 DOI: 10.1111/jcmm.15649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/28/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Unresolved inflammation maintained by release of danger‐associated molecular patterns, particularly high‐mobility group box‐1 (HMGB1), is crucial for hepatocellular carcinoma (HCC) pathogenesis. To further characterize interactions between leucocytes and necrotic cancerous tissue, a cellular model of necroinflammation was studied in which murine Raw 264.7 macrophages or primary splenocytes were exposed to necrotic lysates (N‐lys) of murine hepatoma cells or primary hepatocytes. In comparison to those derived from primary hepatocytes, N‐lys from hepatoma cells were highly active—inducing in macrophages efficient expression of inflammatory cytokines like C‐X‐C motif ligand‐2 , tumor necrosis factor‐α, interleukin (IL)‐6 and IL‐23‐p19. This activity associated with higher levels of HMGB1 in hepatoma cells and was curbed by pharmacological blockage of the receptor for advanced glycation end product (RAGE)/HMGB1 axis or the mitogen‐activated protein kinases ERK1/2 pathway. Analysis of murine splenocytes furthermore demonstrated that N‐lys did not comprise of functionally relevant amounts of TLR4 agonists. Finally, N‐lys derived from hepatoma cells supported inflammatory splenic Th17 and Th1 polarization as detected by IL‐17, IL‐22 or interferon‐γ production. Altogether, a straightforward applicable model was established which allows for biochemical characterization of immunoregulation by HCC necrosis in cell culture. Data presented indicate a remarkably inflammatory capacity of necrotic hepatoma cells that, at least partly, depends on the RAGE/HMGB1 axis and may shape immunological properties of the HCC microenvironment.
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Affiliation(s)
- Malte Bachmann
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Laura Lamprecht
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Sina Gonther
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Josef Pfeilschifter
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
| | - Heiko Mühl
- pharmazentrum frankfurt/ZAFES, Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Frankfurt am Main, Germany
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Wang ST, Huang SW, Liu KT, Lee TY, Shieh JJ, Wu CY. Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway. Cell Death Discov 2020; 6:17. [PMID: 32257389 PMCID: PMC7105491 DOI: 10.1038/s41420-020-0252-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 03/02/2020] [Accepted: 03/10/2020] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of STAT3 but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of STAT3 phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated STAT3 rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-STAT3, and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/STAT3 pathway.
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Affiliation(s)
- Sin-Ting Wang
- Division of Translational Research and Center of Excellence for Cancer Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shi-Wei Huang
- Center for Cell Therapy and Translation Research, China Medical University Hospital, Taichung, Taiwan
| | - Kuang-Ting Liu
- Department of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Pathology & Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Teng-Yu Lee
- Division of Gastroenterology and Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jeng-Jer Shieh
- Department of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Life Sciences and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chun-Ying Wu
- Division of Translational Research and Center of Excellence for Cancer Research, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Biomedical Informatics, Institute of Clinical Medicine, and Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
- Department of Public Health, China Medical University, Taichung, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
- Taiwan Microbiota Consortium, Taipei, Taiwan
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Goodus MT, McTigue DM. Hepatic dysfunction after spinal cord injury: A vicious cycle of central and peripheral pathology? Exp Neurol 2019; 325:113160. [PMID: 31863731 DOI: 10.1016/j.expneurol.2019.113160] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 11/17/2019] [Accepted: 12/18/2019] [Indexed: 02/06/2023]
Abstract
The liver is essential for numerous physiological processes, including filtering blood from the intestines, metabolizing fats, proteins, carbohydrates and drugs, and regulating iron storage and release. The liver is also an important immune organ and plays a critical role in response to infection and injury throughout the body. Liver functions are regulated by autonomic parasympathetic innervation from the brainstem and sympathetic innervation from the thoracic spinal cord. Thus, spinal cord injury (SCI) at or above thoracic levels disrupts major regulatory mechanisms for hepatic functions. Work in rodents and humans shows that SCI induces liver pathology, including hepatic inflammation and fat accumulation characteristic of a serious form of non-alcoholic fatty liver disease (NAFLD) called non-alcoholic steatohepatitis (NASH). This hepatic pathology is associated with and likely contributes to indices of metabolic dysfunction often noted in SCI individuals, such as insulin resistance and hyperlipidemia. These occur at greater rates in the SCI population and can negatively impact health and quality of life. In this review, we will: 1) Discuss acute and chronic changes in human and rodent liver pathology and function after SCI; 2) Describe how these hepatic changes affect systemic inflammation, iron regulation and metabolic dysfunction after SCI; 3) Describe how disruption of the hepatic autonomic nervous system may be a key culprit in post-injury chronic liver pathology; and 4) Preview ongoing and future research that aims to elucidate mechanisms driving liver and metabolic dysfunction after SCI.
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Affiliation(s)
- Matthew T Goodus
- The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
| | - Dana M McTigue
- The Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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Huang Z, Lu W, Yu N, Yang G, Xu H, Liu H. Systemic inflammatory response predicts poor prognoses in Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma with transarterial chemoembolization: a prospective study. Transl Cancer Res 2019; 8:2552-2563. [PMID: 35117012 PMCID: PMC8798496 DOI: 10.21037/tcr.2019.10.18] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Accepted: 10/09/2019] [Indexed: 01/14/2023]
Abstract
Background Chronic inflammation has been demonstrated to be an important factor in the initiation, promotion, and progression of hepatocellular carcinoma (HCC). The aim of this study was to investigate the prognostic values of systemic inflammation markers in Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC. Methods A prospective non-randomized study was performed from June 2016 to May 2017; 51 of 123 BCLC stage B/C HCC patients were enrolled and received transarterial chemoembolization (TACE). Clinical and laboratory data were recorded. Serum IL-6, IL-10, C-reactive protein (CRP), and blood-neutrophil-to-lymphocyte ratio (NLR) levels were analyzed during the perioperative period. Patient prognosis was investigated. Twenty-eight stage A cases and 10 stage B/C patients who received resection were also collected as controls. Results Compared to the stage A group, the BCLC stage B/C HCC patients had significantly higher serum IL-6, CRP, and blood NLR levels. Serum IL-6, IL-10, CRP, and blood NLR levels increased significantly 3 days after treatment (TACE/resection) and returned to baseline levels after 30 days. By univariate analyses, tumor size, high pretreatment serum IL-6, CRP, and blood NLR levels predicted worse progression-free survival (PFS) after TACE (log-rank test P<0.001, P=0.007, P=0.001, respectively). Multivariate analysis revealed that both high serum IL-6 (P=0.018) and CRP (P=0.042) were independent predictors of worse PFS, meanwhile blood NLR was the only inflammatory factor associated to overall survival (OS) (P=0.046). Conclusions Serum IL-6, CRP, and blood NLR levels were significantly elevated in stage B/CHCC. Serum IL-6 and CRP were independent predictors of poor PFS while NLR independently predicted worse OS in BCLC stage B/C HCC.
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Affiliation(s)
- Zhiliang Huang
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.,Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou 510095, China
| | - Weiqun Lu
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.,Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou 510095, China
| | - Nanrong Yu
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.,Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Guangzhou 510095, China
| | - Guohua Yang
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Houwei Xu
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Haiying Liu
- Department of Gastrointestinal Surgical Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
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Preoperative Serum IL6, IL8, and TNF- α May Predict the Recurrence of Hepatocellular Cancer. Gastroenterol Res Pract 2019; 2019:6160783. [PMID: 31781194 PMCID: PMC6855033 DOI: 10.1155/2019/6160783] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 09/15/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023] Open
Abstract
Purpose As we all know, curative resection remains the only effective treatment for hepatocellular cancer (HCC). However, systemic inflammatory response syndrome always correlates with surgery, which may impose an impact on the clinical outcome of HCC patients who had undergone curative treatment. The present study is aimed at exploring the correlation between perioperative inflammatory mediators and recurrence risk of HCC. Methods This study retrospectively included 157 histologically confirmed single HCC patients (88 patients developed HCC again) who had received radical hepatectomy between January 2016 and May 2018 at the Department of Hepatobiliary Surgery, the People's Liberation Army General Hospital (PLAGH), China. The cut-off values for predicting recurrence were determined by receiver operating characteristic (ROC) curve analysis with estimation of the Youden index. Recurrence-free survival (RFS) was assessed using the Kaplan-Meier method, and the difference was compared between groups by the log-rank test. Univariate/multivariate analysis was performed to identify independent risk factors of postoperative tumor recurrence. Results The perioperative serum IL1, IL2, and IL10 levels showed no difference between groups, whereas the serum IL6, IL8, and TNF-α levels showed significant differences between groups. High preoperative serum IL6, IL8, and TNF-α levels were significantly associated with shorter RFS. Multivariate analysis revealed that preoperative serum IL6 > 8.45 pg/ml, preoperative serum IL8 > 68 pg/ml, preoperative serum TNF − α > 14.9 pg/ml, microvascular invasion (MVI), and maximum tumor size > 6 cm were independent predictors of RFS. Conclusions The present study confirmed that high preoperative serum IL6, IL8, and TNF-α levels were distinctly correlated with the postoperative tumor recurrence risk of HCC patients.
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Li A, Wu J, Zhai A, Qian J, Wang X, Qaria MA, Zhang Q, Li Y, Fang Y, Kao W, Song W, Zhang Z, Zhang F. HBV triggers APOBEC2 expression through miR‑122 regulation and affects the proliferation of liver cancer cells. Int J Oncol 2019; 55:1137-1148. [PMID: 31485598 DOI: 10.3892/ijo.2019.4870] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 07/15/2019] [Indexed: 11/05/2022] Open
Abstract
Hepatitis B virus (HBV) infection is responsible for 50% of liver cancer cases globally; this disease is one of the leading causes of cancer‑associated mortality. One reported mechanism underlying the development of liver cancer is the mutation of tumor suppressor genes induced by the overexpression of apolipoprotein B mRNA‑editing enzyme catalytic subunit 2 (APOBEC2) in hepatocytes. In addition, it has been observed that HBV inhibited microRNA (miR)‑122 expression in hepatocytes; however, the molecular mechanisms involved in liver cancer development remain unknown and further investigations are required. In the present study, the mechanistic roles of HBV infection in modulating the expression of miR‑122 and APOBEC2, and the development of liver cancer, were investigated. Reverse transcription‑quantitative PCR and western blot analyses revealed that APOBEC2 expression was markedly upregulated following HBV infection. Of note, the expression profile of APOBEC2 in the Huh7 and HepG2 liver cancer cell lines opposed that of miR‑122; this miR is the most abundant miRNA in the liver and has been associated with hepatocarcinogenesis. Mechanistically, it was demonstrated via a dual‑luciferase assay that miR‑122 could specifically bind to the 3'‑untranslated region (3'UTR) of APOBEC2 mRNA, inhibiting its expression. Collectively, the findings of the present study may provide insight into the mechanistic role of HBV infection in modulating the expression of miR‑122, which targets the 3'UTR of APOBEC2 mRNA, subsequently inducing liver carcinogenesis.
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Affiliation(s)
- Aimei Li
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jing Wu
- Hangzhou Key Laboratory of Inflammation and Immunoregulation, Department of Basic Medical Science, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310000, P.R. China
| | - Aixia Zhai
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Jun Qian
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Xinyang Wang
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Majjid A Qaria
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Qingmeng Zhang
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yujun Li
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Yong Fang
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Wenping Kao
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Wuqi Song
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Zhiyi Zhang
- Department of Rheumatology, The First Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
| | - Fengmin Zhang
- Wu Lien‑Teh Institute, Department of Microbiology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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Badawy AA, Othman G, Elabbasy LM, Abd Elsalam M, Shrief R, Fahmy EM, Kamel NM, Osman A, Zaki ME. IL-6 -572G/C and -174G/C polymorphisms association with hepatitis C virus-induced hepatocellular carcinoma. Br J Biomed Sci 2019; 76:201-204. [PMID: 31314698 DOI: 10.1080/09674845.2019.1642562] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- A A Badawy
- Medical Biochemistry Department, Mansoura University, Mansoura, Egypt
| | - G Othman
- Medical Biochemistry Department, Mansoura University, Mansoura, Egypt
| | - L M Elabbasy
- Medical Biochemistry Department, Mansoura University, Mansoura, Egypt
| | - M Abd Elsalam
- Internal Medicine Department, Nephrology and Dialysis Unit, Mansoura University, Mansoura, Egypt
| | - R Shrief
- Medical Microbiology and Immunology Department, Mansoura University, Mansoura, Egypt
| | - E M Fahmy
- Medical Microbiology and Immunology Department, Aswan University, Aswan, Egypt
| | - N M Kamel
- Clinical Pathology Department, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - A Osman
- Clinical Pathology Department, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - M E Zaki
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Wu Y, Fan W, Xue M, Zhong B, Zhang S, Wang Y, Yao W, Zhao Y, Li J. Postintervention Interleukin-6 (IL-6) Level, Rather than the Pretreatment or Dynamic Changes of IL-6, as an Early Practical Marker of Tumor Response in Hepatocellular Carcinoma Treated with Transarterial Chemoembolization. Oncologist 2019; 24:e1489-e1495. [PMID: 31249138 DOI: 10.1634/theoncologist.2018-0669] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 04/23/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of this study was to determine the potential prognostic roles of the perioperative interleukin-6 (IL-6) level and its dynamic changes in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). MATERIALS AND METHODS Sixty patients with hepatitis B virus-associated HCC receiving TACE were enrolled in the study. Serum IL-6 levels were determined at baseline and 1 day after TACE by immunoassay. Response to TACE was evaluated after a 4-6-week interval. Factors associated with tumor response were analyzed by univariate and multivariate analysis in a Cox regression model. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive performance of the included variables on tumor response in patients with HCC undergoing TACE. RESULTS The serum IL-6 level was significantly elevated 1 day after TACE. Patients in the low postintervention IL-6 level group had a high probability of achieving an objective response (OR) (66.7% vs. 18.8%, p = .021). Post-TACE IL-6 level (≤12.7 pg/mL) and post-/pre-TACE neutrophils ratio (>2.47) were independently correlated with OR after TACE. ROC curve analysis showed that a combined index based on those two factors exhibited optimal predictive power of tumor response among all the included variables (area under the curve = 0.740, 95% confidence interval: 0.601-0.879). Additionally, high post-TACE plasma IL-6 level was associated with maximum tumor size, vascular invasion, post-TACE aspartate aminotransferase, and Barcelona Clinic Liver Cancer stage. CONCLUSION Our study suggests that the post-treatment serum IL-6 level, rather than pretreatment or dynamic changes of IL-6, serves as a powerful predictor for tumor response. These findings provide evidence to help discriminate between patients who will particularly benefit from TACE and those who require more personalized therapeutic regimens and rigorous surveillance. IMPLICATIONS FOR PRACTICE Transarterial chemoembolization (TACE) is a major therapeutic regimen for advanced hepatocellular carcinoma. Thus, identification of early practical markers of tumor response to TACE is of high importance. This study indicated that the post-treatment serum interleukin-6 (IL-6) level, rather than the pretreatment or dynamic changes of IL-6, serves as a powerful predictor for tumor response. A combined index based on the post-TACE IL-6 level and post-/pre-TACE neutrophils ratio is optimal for predetermining an objective response after TACE, which may be helpful in guiding individualized treatments and surveillance.
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Affiliation(s)
- Yanqin Wu
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Wenzhe Fan
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Miao Xue
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Bihui Zhong
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Shenghong Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yu Wang
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Wang Yao
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yue Zhao
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Jiaping Li
- Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China
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Ribera J, Rodríguez-Vita J, Cordoba B, Portolés I, Casals G, Casals E, Jiménez W, Puntes V, Morales-Ruiz M. Functionalized cerium oxide nanoparticles mitigate the oxidative stress and pro-inflammatory activity associated to the portal vein endothelium of cirrhotic rats. PLoS One 2019; 14:e0218716. [PMID: 31233564 PMCID: PMC6590813 DOI: 10.1371/journal.pone.0218716] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 06/07/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The occurrence of endothelial alterations in the liver and in the splanchnic vasculature of cirrhotic patients and experimental models of liver diseases has been demonstrated. However, the pathological role of the portal vein endothelium in this clinical context is scarcely studied and, therefore, deserves attention. In this context, we aimed to investigate whether pathological endothelial activation occurs in the portal vein of cirrhotic rats. METHODS Cirrhosis was induced in wistar rats by CCl4 inhalation. We generated immortalized endothelial cells from the portal vein of control (CT-iPVEC) and cirrhotic rats (CH-iPVEC) by retroviral transduction of the SV40 T antigen. We assessed differential gene expression and intracellular reactive oxygen species (ROS) levels in iPVECs and in portal veins of control and cirrhotic rats. Finally, we assessed the therapeutic effectiveness of cerium oxide nanoparticles (CeO2NP) on reversing PVEC activation and macrophage polarization. RESULTS CH-iPVECs overexpressed collagen-I, endothelin-1, TIMP-1, TIMP-2, IL-6 and PlGF genes. These results were consistent with the differential expression showed by whole portal veins from cirrhotic rats. In addition, CH-iPVECs showed a significant increase in intracellular ROS and the capacity of potentiating M1 polarization in macrophages. The treatment of CH-iPVECs with CeO2NPs blocked intracellular ROS formation and IL-6 and TIMP-2 gene overexpression. In agreement with the in vitro results, the chronic treatment of cirrhotic rats with CeO2NPs also resulted in the blockade of both ROS formation and IL-6 gene overexpression in whole portal veins. CONCLUSIONS Endothelial cells from portal vein of cirrhotic rats depicted an abnormal phenotype characterized by a differential gene expression and the induction of M1 polarization in macrophages. We identified the excess of intracellular reactive oxygen species (ROS) as a major contributor to this altered phenotype. In addition, we demonstrated the utility of the nanomaterial cerium oxide as an effective antioxidant capable of reverse some of these pathological features associated with the portal vein in the cirrhosis condition.
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Affiliation(s)
- Jordi Ribera
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Juan Rodríguez-Vita
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- German Cancer Research Center, Heidelberg, Germany
| | - Bernat Cordoba
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Irene Portolés
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Gregori Casals
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Eudald Casals
- Catalan Institute of Nanotechnology (ICN), Bellaterra, Spain
| | - Wladimiro Jiménez
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Department of Biomedicine-Biochemistry Unit, School of Medicine University of Barcelona, Barcelona, Spain
| | - Victor Puntes
- Catalan Institute of Nanotechnology (ICN), Bellaterra, Spain
| | - Manuel Morales-Ruiz
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
- Department of Biomedicine-Biochemistry Unit, School of Medicine University of Barcelona, Barcelona, Spain
- * E-mail:
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Zhang Y, Zhao W, Li S, Lv M, Yang X, Li M, Zhang Z. CXCL11 promotes self-renewal and tumorigenicity of α2δ1 + liver tumor-initiating cells through CXCR3/ERK1/2 signaling. Cancer Lett 2019; 449:163-171. [PMID: 30771435 DOI: 10.1016/j.canlet.2019.02.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/07/2019] [Accepted: 02/09/2019] [Indexed: 12/18/2022]
Abstract
Tumor-initiating cells (TICs), which are responsible for sustaining tumor growth and recurrence, rely on several regulatory factors. However, the mechanism of inflammation-related molecules in the acquisition and maintenance of TIC properties in hepatocellular carcinoma (HCC) remains elusive. We previously demonstrated that the voltage-gated calcium channel α2δ1 subunit is a functional surface marker of HCC TICs. Here, we found that the expression of an inflammation-related molecule C-X-C motif chemokine 11 (CXCL11) was significantly upregulated in α2δ1+ HCC TICs and that CXCL11 induced the expression of stem cell-related genes, such as BMI1, NANOG, MDR1, ABCG2, and CACNA2D1. Furthermore, CXCL11 could promote the acquisition and maintenance of self-renewal, tumorigenic, and chemoresistance properties of α2δ1+ HCC TICs by activating the extracellular signal-regulated kinase (ERK1/2) through its affinity receptor CXCR3. Collectively, our results suggest that CXCL11 may positively regulate the stemness of α2δ1+ HCC TICs via ERK1/2 activation through an autocrine signaling pathway.
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Affiliation(s)
- Yuan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Wei Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Sheng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Mengzhu Lv
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Xiaodan Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Meng Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Zhiqian Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cell Biology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing, 100142, China.
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Roomi MW, Kalinovsky T, Bhanap B, Niedzwiecki A, Rath M. In Vitro Effect of Cytokines, Inducers, and Inhibitors on the Secretion of MMP-2 and MMP-9 in Hepatocarcinoma Cell Line SK-Hep-1. Integr Cancer Ther 2019. [PMCID: PMC6902378 DOI: 10.1177/1534735419889155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The prognosis of hepatocellular carcinoma (HCC) remains dismal despite any treatment. Matrix metalloproteinases (MMPs) have been researched for their role in tumor invasion and metastasis. Various cytokines, mitogens, growth factors, inducers, and inhibitors control MMP activities. In this article, we investigated the roles of these in the regulation of MMP-2, -9 secretions in HCC. Human HCC SK-Hep-1 was grown in appropriate media. At near confluence, the cells were washed with phosphate-buffered saline and incubated in serum-free media with PMA; TNF-α, IL-1β; lipopolysaccharide; epigallocatechin gallate (EGCG) and doxycycline (Dox) at various doses with and without PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid, and EGCG with and without PMA at; and actinomycin D and cycloheximide at different doses. After 24 hours, the media were removed and analyzed. SK-Hep-1 expressed bands corresponding to MMP-2 and MMP-9. TNF-α showed an insignificant effect on MMP-2 at doses below 25 at which dose MMP-2 was virtually blocked and a moderate dose-dependent effect on MMP-9. Interleukin-1β demonstrated an insignificant effect on MMP-2 at doses below 25 at which dose MMP-2 was completely blocked and enhanced effects on MMP-9. Lipopolysaccharide showed dose-dependent inhibition of MMP-2 and MMP-9. EGCG, Dox, and NM, without and with PMA, downregulated the expression of MMP-2 and MMP-9. Actinomycin D and cycloheximide also had dose-dependent inhibitory effects on MMPs. Our results showed that cytokines, mitogens, and inhibitors modulated SK-Hep-1 MMP-2 and MMP-9 secretion, suggesting the clinical use of especially potent and nontoxic MMP inhibitor as the NM in management of HCC.
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Obesity-Induced TNFα and IL-6 Signaling: The Missing Link between Obesity and Inflammation-Driven Liver and Colorectal Cancers. Cancers (Basel) 2018; 11:cancers11010024. [PMID: 30591653 PMCID: PMC6356226 DOI: 10.3390/cancers11010024] [Citation(s) in RCA: 158] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/20/2018] [Accepted: 12/21/2018] [Indexed: 02/06/2023] Open
Abstract
Obesity promotes the development of numerous cancers, such as liver and colorectal cancers, which is at least partly due to obesity-induced, chronic, low-grade inflammation. In particular, the recruitment and activation of immune cell subsets in the white adipose tissue systemically increase proinflammatory cytokines, such as tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). These proinflammatory cytokines not only impair insulin action in metabolic tissues, but also favor cancer development. Here, we review the current state of knowledge on how obesity affects inflammatory TNFα and IL-6 signaling in hepatocellular carcinoma and colorectal cancers.
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Hu J, Zuo J, Chen Z, Fu L, Lv X, Hu S, Shi X, Jing Y, Wang Y, Wang Z, Mi R, Huang Y, Liu D, Qi K, Han X. Use of a modified bacterial ghost lysis system for the construction of an inactivated avian pathogenic Escherichia coli vaccine candidate. Vet Microbiol 2018; 229:48-58. [PMID: 30642598 DOI: 10.1016/j.vetmic.2018.12.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 12/16/2018] [Accepted: 12/17/2018] [Indexed: 12/18/2022]
Abstract
Vaccination is an effective strategy to prevent avian colibacillosis. Bacterial ghosts (BGs) are prepared by the controlled expression of the phiX174 gene E, which mediates the lysis of Gram-negative bacteria. Staphylococcal nuclease A may be used to produce BGs for further inactivation of host bacteria and elimination of residual genetic material. In this study, the double promoter lysis plasmid (pUC19-ΔcI857-E-rrnB-pL-SN) was successfully constructed and BGs were prepared at 37 °C. The cleavage efficiency of Escherichia coli BGs was 99.9%. Furthermore, to evaluate the immunological effects of the BG vaccines in chickens, a BG vaccine was prepared using the serotype O2 avian pathogenic Escherichia coli deletion strain (DE17ΔluxSΔaroA). The results showed that the BG vaccine was able to achieve over 90% immune protection against virulent challenge using the same serotype O2 strain (DE17 or CE35), while it showed poor cross-protection against serotypes O1 and O78 (data not shown). The enzyme-linked immunosorbent assay results showed that the antibody levels in the immunized groups were higher than in the control group (p < 0.05), with the BG group being the highest. The cytokine tests showed that the levels of interferon-γ in the BG immune group were higher than in the phosphate-buffered saline (PBS) control group (non-immune) (p < 0.01) and the formalin-inactivated vaccine immune group (p < 0.05), and the levels of tumor necrosis factor-α in the BG group were higher than in the formalin-inactivated vaccine (p > 0.05) and the PBS control groups (p < 0.05). In addition, pathological analysis revealed that the PBS control group showed typical fibrinous pericarditis and perihepatitis, whereas the immune group showed no obvious pathological changes. In summary, our findings provide a new strategy for the prevention and control of avian colibacillosis.
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Affiliation(s)
- Jiangang Hu
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China; College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, PR China; College of Animal Science, Southwest University, Chongqing, 402460, PR China
| | - Jiakun Zuo
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Zhaoguo Chen
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Lixia Fu
- College of Animal Science and Technology, Yangzhou University, Yangzhou, 225009, PR China
| | - Xiaolong Lv
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China; College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, PR China
| | - Shijun Hu
- College of Animal Science, Southwest University, Chongqing, 402460, PR China
| | - Xingchi Shi
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China; College of Animal Science, Southwest University, Chongqing, 402460, PR China
| | - Yawei Jing
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Yalei Wang
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Zhihao Wang
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China; College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, PR China
| | - Rongsheng Mi
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Yan Huang
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China
| | - Dahai Liu
- Sino-british sippr/bklab animal ltd testing evaluation center, Shanghai, 200241, PR China
| | - Kezong Qi
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, PR China.
| | - Xiangan Han
- Shanghai Veterinary Research Institute, the Chinese Academy of Agricultural Sciences (CAAS), 518 Ziyue Road, Shanghai, 200241, PR China.
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Shakiba E, Ramezani M, Sadeghi M. Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis. Clin Exp Hepatol 2018; 4:182-190. [PMID: 30324143 PMCID: PMC6185933 DOI: 10.5114/ceh.2018.78122] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 12/26/2017] [Indexed: 02/07/2023] Open
Abstract
AIM OF THE STUDY This meta-analysis evaluated serum interleukin-6 (IL-6) levels in hepatocellular carcinoma (HCC) patients compared with healthy controls and hepatitis and cirrhotic patients. MATERIAL AND METHODS The three databases PubMed, Scopus, and Web of Science were searched for assessment of IL-6 levels in HCC patients (without cirrhosis and hepatitis) compared with healthy controls (without HCC, cirrhosis and hepatitis) and the studies were selected based on inclusion and exclusion criteria. A random-effect meta-analysis was performed with RevMan 5.3 software, using mean difference (MD) and 95% confidence intervals (CIs). RESULTS Out of 503 studies searched in databases, 18 studies were included in the meta-analysis. The pooled analysis with continuous data demonstrated that the IL-6 level in HCC patients was significantly higher than that in healthy controls (MD = 12.44; 95% CI: 9.02-15.85; p < 0.00001). Also, the pooled analysis demonstrated that the IL-6 levels in cirrhotic patients (MD = -6.98; 95% CI: -12.91-1.05; p < 0.02) and patients with hepatitis (MD = -8.43; 95% CI: -11.91-4.95; p < 0.00001) were significantly lower than the level in HCC patients, and the subgroup analyses had high heterogeneity. CONCLUSIONS The elevated IL-6 levels in HCC patients compared with hepatitis and cirrhosis patients and healthy controls may show a significant association of this cytokine with increased risk of HCC and its potential as a diagnostic marker for HCC in future diagnostic and therapeutic strategies.
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Affiliation(s)
- Ebrahim Shakiba
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mazaher Ramezani
- Molecular Pathology Research Center, Emam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Song J, Zhang X, Ge Q, Yuan C, Chu L, Liang HF, Liao Z, Liu Q, Zhang Z, Zhang B. CRISPR/Cas9-mediated knockout of HBsAg inhibits proliferation and tumorigenicity of HBV-positive hepatocellular carcinoma cells. J Cell Biochem 2018; 119:8419-8431. [PMID: 29904948 PMCID: PMC6221038 DOI: 10.1002/jcb.27050] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/23/2018] [Indexed: 12/20/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). High HBV surface antigen (HBsAg) levels are highly correlated with hepatocarcinogenesis and HBV‐associated HCC development. However, the role and detailed mechanisms associated with HBsAg in HCC development remain elusive. In this study, we designed specific single guide RNAs (sgRNAs) targeting the open reading frames, preS1/preS2/S, of the HBV genome and established HBsAg knockout HCC cell lines using the CRISPR/Cas9 system. We showed that knockout of HBsAg in HCC cell lines decreased HBsAg expression and significantly attenuated HCC proliferation in vitro, as well as tumorigenicity in vivo. We also found that overexpression of HBsAg, including the large (LHBs), middle (MHBs), and small (SHBs) surface proteins promoted proliferation and tumor formation in HCC cells. Moreover, we demonstrated that knockout of HBsAg in HCC cells decreased interleukin (IL)‐6 production and inhibited signal transducer and activator of transcription 3 (STAT3) signaling, while overexpression of HBsAg induced a substantial accumulation of pY‐STAT3. Collectively, these results highlighted the tumorigenic role of HBsAg and implied that the IL‐6‐STAT3 pathway may be implicated in the HBsAg‐mediated malignant potential of HBV‐associated HCC.
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Affiliation(s)
- Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Xiaochao Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Qianyun Ge
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Chaoyi Yuan
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, China
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Yakut M, Özkan H, F Karakaya M, Erdal H. Diagnostic and Prognostic Role of Serum Interleukin-6 in Malignant Transformation of Liver Cirrhosis. Euroasian J Hepatogastroenterol 2018; 8:23-30. [PMID: 29963457 PMCID: PMC6024044 DOI: 10.5005/jp-journals-10018-1253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 01/28/2018] [Indexed: 12/15/2022] Open
Abstract
Aim Alpha-fetoprotein (AFP) is still the most commonly used and the single most recommended marker in the diagnosis of hepatocellular carcinoma (HCC). Interleukin (IL)-6 is a circular cytokine and its role on carcinogenesis in various hematological and solid tumors is clearly documented. A combination of serum IL-6 and AFP may provide beneficial information regarding early diagnosis of HCC. In this study, the effect of plasma IL-6 level in the diagnosis of HCC was investigated. Materials and methods A total of 130 patients with liver cirrhosis, together with 30 control cases were enrolled in the trial. A diagnosis of HCC was present in 75 patients (57.6%) in the liver cirrhosis group. Blood samples were obtained from the enrolled study and control cases. Alpha-fetoprotein was quantified by chemiluminescent method. Plasma IL-6 levels of samples obtained at -80°C were quantified by human IL-6 BMS213/2 BMS213/2TEN kit. Results The HCC patients were older than the patients in the cirrhosis group (p = 0.016). On comparison of the HCC patients with the control group, AFP (p < 0.001) and IL-6 (p < 0.001) were significantly higher among the HCC patients. Comparison of HCC patients with liver cirrhosis cases with no diagnosis of HCC revealed significantly high AFP (p < 0.001) and IL-6 levels (p < 0.001) in HCC group. Cutoff value for IL-6 was calculated as 5.73 (pg/mL). No difference was detected in AFP (p = 0.600) and IL-6 (0.344) in all three subgroups. A total of 17 patients died during a mean follow-up period of 32.9 months. No correlation was found between mean AFP values and IL-6 values and survival rates. Conclusion Plasma IL-6 level was found to be significant in the diagnosis of HCC. Alpha-fetoprotein and IL-6 provided no advantage in terms of early diagnosis of HCC and no correlation was observed between these markers and survival. How to cite this article: Yakut M, Özkan H, Karakaya MF, Erdal H. Diagnostic and Prognostic Role of Serum Interleukin-6 in Malignant Transformation of Liver Cirrhosis. Euroasian J Hepato-Gastroenterol 2018;8(1):23-30.
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Affiliation(s)
- Mustafa Yakut
- Department of Gastroenterology, Memorial Diyarbakir Hospital, Diyarbakir, Turkey
| | - Hasan Özkan
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Muhammed F Karakaya
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Harun Erdal
- Department of Gastroenterology, Düzce Public Hospital, Düzce, Turkey
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Stone TW, McPherson M, Gail Darlington L. Obesity and Cancer: Existing and New Hypotheses for a Causal Connection. EBioMedicine 2018; 30:14-28. [PMID: 29526577 PMCID: PMC5952217 DOI: 10.1016/j.ebiom.2018.02.022] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/12/2018] [Accepted: 02/23/2018] [Indexed: 02/07/2023] Open
Abstract
Existing explanations of obesity-associated cancer emphasise direct mutagenic effects of dietary components or hormonal imbalance. Some of these hypotheses are reviewed briefly, but recent evidence suggests a major role for chronic inflammation in cancer risk, possibly involving dietary content. These ideas include the inflammation-induced activation of the kynurenine pathway and its role in feeding and metabolism by activation of the aryl hydrocarbon receptor (AHR) and by modulating synaptic transmission in the brain. Evidence for a role of the kynurenine pathway in carcinogenesis then provides a potentially major link between obesity and cancer. A second new hypothesis is based on evidence that serine proteases can deplete cells of the tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin. These enzymes include mammalian chymotryptic proteases released by pro-inflammatory neutrophils and macrophages. Blood levels of chymotrypsin itself increase in parallel with food intake. The mechanistically similar bacterial enzyme subtilisin is widespread in the environment, animal probiotics, meat processing and cleaning products. Simple public health schemes in these areas, with selective serine protease inhibitors and AHR antagonists and could prevent a range of intestinal and other cancers.
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Affiliation(s)
- Trevor W Stone
- The Kennedy Institute, University of Oxford, Oxford OX3 7FY, UK; Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
| | - Megan McPherson
- School of Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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Chen Y, Zeng Z, Lu Y. Is mIndy a mediator of energy metabolism reprogramming in hepatocellular carcinoma induced by interleukin-6/signal transducer and activator of transcription 3 signaling? Hepatology 2018; 67:451-452. [PMID: 29023910 DOI: 10.1002/hep.29592] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 10/03/2017] [Indexed: 12/07/2022]
Affiliation(s)
- Yan Chen
- Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing, China
| | - Zhen Zeng
- Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, Beijing 302 Hospital, Beijing, China
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Wang CC, Yuan JR, Wang CF, Yang N, Chen J, Liu D, Song J, Feng L, Tan XB, Jia XB. Anti-inflammatory Effects of Phyllanthus emblica L on Benzopyrene-Induced Precancerous Lung Lesion by Regulating the IL-1β/miR-101/Lin28B Signaling Pathway. Integr Cancer Ther 2017; 16:505-515. [PMID: 27562754 PMCID: PMC5739133 DOI: 10.1177/1534735416659358] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/25/2016] [Accepted: 06/03/2016] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Phyllanthus emblica L (PEL), a well-known medical plant, has been used in Asian countries for a long time. Increasing evidence suggests that it can prevent the tumorigenesis of cancer associated with nonresolving inflammation. However, the possible anti-inflammatory mechanism responsible for preventing tumorigenesis of precancerous lung lesions is not well elucidated. MATERIALS AND METHODS Male A/J mice were randomly divided into 5 groups with 10 mice in each group: (1) blank group (saline), (2) benzo(a)pyrene [B(a)P] group, (3) and (4) B(a)P + PEL (5 g/kg/d, 10 g/kg/d, administered by gavage), (5) B(a)P + celecoxib (30 mg/kg/d, administered by gavage). Nodes on the lung surface were observed and calculated. The levels of macrophage inflammatory protein (MIP-2), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA) kits. Cyclo-oxygenase-2 (COX-2), hypoxia-inducible factor-1 (HIF-α), IL-1β, miR-101, and Lin28B protein levels were evaluated by immunohistochemistry and Western blotting. RESULTS PEL extract treatment significantly reduced the number of nodes on the lung surface and attenuated B(a)P-induced levels of proinflammatory cytokines MIP-2, TNF-α, IL-6, and IL-1β in lung tissue. The protein expressions of COX-2 and HIF-α were significantly decreased by the treatment of PEL. In addition, both PEL extract and celecoxib markedly upregulate the expression of miR-101 while downregulating IL-1β and Lin28B levels. CONCLUSION Our study indicated that treatment with PEL extract can not only protect the lung from inflammatory injury but effectively prevent precancerous lung lesions through regulating the IL-1β/miR-i101/Lin28B signaling pathway.
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Affiliation(s)
- Cheng-cheng Wang
- Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Jia-rui Yuan
- Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Chun-fei Wang
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
- Anhui University of Chinese Medicine, Hefei, China
| | - Nan Yang
- Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Juan Chen
- Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Dan Liu
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Jie Song
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Liang Feng
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
- Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Xiao-bin Tan
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
- Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
| | - Xiao-bin Jia
- Jiangsu Provincial Academy of Chinese Medicine, Jiangsu Nanjing, P R China
- Third School of Clinical Medical of Nanjing University of Chinese Medicine, Jiangsu Nanjing, P R China
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Hochnadel I, Kossatz-Boehlert U, Jedicke N, Lenzen H, Manns MP, Yevsa T. Cancer vaccines and immunotherapeutic approaches in hepatobiliary and pancreatic cancers. Hum Vaccin Immunother 2017; 13:2931-2952. [PMID: 29112462 PMCID: PMC5718787 DOI: 10.1080/21645515.2017.1359362] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary and pancreatic cancers along with other gastrointestinal malignancies remain the leading cause of cancer-related deaths worldwide. Strategies developed in the recent years on immunotherapy and cancer vaccines in the setting of primary liver cancer as well as in pancreatic cancer are the scope of this review. Significance of orthotopic and autochthonous animal models which mimic and/or closely reflect human malignancies allowing for a prompt and trustworthy analysis of new therapeutics is underlined. Combinational approaches that on one hand, specifically target a defined cancer-driving pathway, and on the other hand, restore the functions of immune cells, which effector functions are often suppressed by a tumor milieu, are shown to have the strongest perspectives and future directions. Among combinational immunotherapeutic approaches a personalized- and individual cancer case-based therapy is of special importance.
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Affiliation(s)
- Inga Hochnadel
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Uta Kossatz-Boehlert
- b Institute for Neuroanatomy, Eberhard-Karls University Tuebingen , Tuebingen , Germany
| | - Nils Jedicke
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Henrike Lenzen
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Michael P Manns
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
| | - Tetyana Yevsa
- a Department of Gastroenterology , Hepatology and Endocrinology, Hannover Medical School , Hannover , Germany
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Guerra AD, Yeung OW, Qi X, Kao WJ, Man K. The Anti-Tumor Effects of M1 Macrophage-Loaded Poly (ethylene glycol) and Gelatin-Based Hydrogels on Hepatocellular Carcinoma. Am J Cancer Res 2017; 7:3732-3744. [PMID: 29109772 PMCID: PMC5667344 DOI: 10.7150/thno.20251] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Accepted: 07/03/2017] [Indexed: 12/26/2022] Open
Abstract
Background and Aims: Recently we reported that direct injection of M1 macrophages significantly caused tumor regression in vivo. Despite the promising result, a major limitation in translating this approach is the induction of acute inflammatory response. To improve the strategy, a biocompatible scaffold for cell presentation and support is essential to control cell fate. Here, we aimed to elucidate the anti-tumor effects of a poly(ethylene glycol) diacrylate (PEGdA) and thiolated gelatin poly(ethylene glycol) (Gel-PEG-Cys) cross-linked hydrogels capsulated with M1 macrophages in both in vitro and in vivo disease models. Methods: Hydrogels were made at 0.5% (w/v) Iragcure 2959 photoinitiator, 10% (w/v) PEGdA, and 10% (w/v) Gel-PEG-Cys. Monocytic THP-1 cells were loaded into hydrogels and differentiated into M1 macrophages with lipopolysaccharide (LPS) and interferon gamma (IFN-γ). The M1 hydrogels were then cocultivated with HCC cell-lines Hep3B and MHCC97L to investigate the anti-tumor capacities and the associated molecular profiles in vitro. A nude mice ectopic liver cancer model with dorsal window chamber (DWC) and a subcutaneous tumor model were both performed to validate the in vivo application of M1 hydrogels. Results: M1 hydrogels significantly decreased the viability of HCC cells (MHCC97L: -46%; Hep3B: -56.9%; P<0.05) compared to the control in vitro. In response to HCC cells, the hydrogel embedded M1 macrophages up-regulated nitrite and tumor necrosis factor alpha (TNF-α) activating caspase-3 induced apoptosis in the tumor cells. Increased tumor necrosis was observed in DWC filled with M1 hydrogels. In addition, mice treated with M1 hydrogels exhibited a significant 2.4-fold decrease in signal intensity of subcutaneous HCC tumor compared to control (P=0.036). Conclusion: M1 hydrogels induced apoptosis in HCC cells and tumor regression in vivo. Continuous development of the scaffold-based cancer immunotherapy may provide an alternative and innovative strategy against HCC.
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Rao S, Zaidi S, Banerjee J, Jogunoori W, Sebastian R, Mishra B, Nguyen BN, Wu RC, White J, Deng C, Amdur R, Li S, Mishra L. Transforming growth factor-β in liver cancer stem cells and regeneration. Hepatol Commun 2017; 1:477-493. [PMID: 29404474 PMCID: PMC5678904 DOI: 10.1002/hep4.1062] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/27/2017] [Accepted: 06/01/2017] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells have established mechanisms that contribute to tumor heterogeneity as well as resistance to therapy. Over 40% of hepatocellular carcinomas (HCCs) are considered to be clonal and arise from a stem-like/cancer stem cell. Moreover, HCC is the second leading cause of cancer death worldwide, and an improved understanding of cancer stem cells and targeting these in this cancer are urgently needed. Multiple studies have revealed etiological patterns and multiple genes/pathways signifying initiation and progression of HCC; however, unlike the transforming growth factor β (TGF-β) pathway, loss of p53 and/or activation of β-catenin do not spontaneously drive HCC in animal models. Despite many advances in cancer genetics that include identifying the dominant role of TGF-β signaling in gastrointestinal cancers, we have not reached an integrated view of genetic mutations, copy number changes, driver pathways, and animal models that support effective targeted therapies for these common and lethal cancers. Moreover, pathways involved in stem cell transformation into gastrointestinal cancers remain largely undefined. Identifying the key mechanisms and developing models that reflect the human disease can lead to effective new treatment strategies. In this review, we dissect the evidence obtained from mouse and human liver regeneration, and mouse genetics, to provide insight into the role of TGF-β in regulating the cancer stem cell niche. (Hepatology Communications 2017;1:477-493).
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Affiliation(s)
- Shuyun Rao
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Sobia Zaidi
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Jaideep Banerjee
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Wilma Jogunoori
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Raul Sebastian
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Bibhuti Mishra
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Ray-Chang Wu
- Department of Biochemistry and Molecular Medicine George Washington University Washington DC
| | - Jon White
- Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
| | - Chuxia Deng
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Health Sciences University of Macau Taipa Macau China
| | - Richard Amdur
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC
| | - Shulin Li
- Department of Pediatrics The University of Texas MD Anderson Cancer Center Houston TX
| | - Lopa Mishra
- Center for Translational Medicine Department of Surgery, George Washington University Washington DC.,Institute for Clinical Research, Veterans Affairs Medical Center Washington DC
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Gao Y, Li W, Liu R, Guo Q, Li J, Bao Y, Zheng H, Jiang S, Hua B. Norcantharidin inhibits IL-6-induced epithelial‑mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells. Oncol Rep 2017; 38:1224-1232. [PMID: 28677802 DOI: 10.3892/or.2017.5775] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 06/19/2017] [Indexed: 11/06/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT), plays a vital role in hepatocellular carcinoma (HCC) development and metastasis. Norcantharidin (NCTD; 7-oxabicyclo (2.2.1) heptane-2,3-dicarboxylic anhydride) plays anticancer roles in the regulation of tumor cell proliferation, apoptosis and migration. However, the molecular mechanism of HCC EMT and the effects of NCTD in the HCC EMT process have been either poorly elucidated or not studied. In this study, HCC EMT was induced by the treatment of IL-6 and various concentrations of NCTD (0, 30, 60 and 120 µM) were treated with HCC cell lines, HCCLM3 and SMMC-7721. We investigated the effect of NCTD on the invasion of HCC cells by using Transwell assay. Immunofluorescence staining, western blot analysis and quantitative RT-PCR were performed to evaluate the protein and mRNA expression levels of HCC cells. Here, using cell line models, our data demonstrated that interleukin 6 (IL-6) induced EMT through the JAK/STAT3/TWIST pathway in HCC. Moreover, our studies revealed that NCTD markedly inhibited IL-6-induced EMT and cell invasiveness. Signaling studies revealed that NCTD sufficiently suppressed JAK/STAT3/TWIST signaling to reverse the IL-6-promoting effects. Collectively, these data provide evidence for the use of NCTD as a potential anticancer drug in HCC metastatic patients.
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Affiliation(s)
- Yebo Gao
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Weidong Li
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Rui Liu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Qiujun Guo
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Jie Li
- Department of Oncology, Jining First People's Hospital, Jining, Shandong 272111, P.R. China
| | - Yanju Bao
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Honggang Zheng
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Shulong Jiang
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Baojin Hua
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
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