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Eresen A, Zhang Z, Yu G, Hou Q, Chen Z, Yu Z, Yaghmai V, Zhang Z. Sorafenib plus memory-like natural killer cell immunochemotherapy boosts treatment response in liver cancer. BMC Cancer 2024; 24:1215. [PMID: 39350084 PMCID: PMC11443676 DOI: 10.1186/s12885-024-12718-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 07/26/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Heterogeneity of hepatocellular carcinoma (HCC) presents significant challenges for therapeutic strategies and necessitates combinatorial treatment approaches to counteract suppressive behavior of tumor microenvironment and achieve improved outcomes. Here, we employed cytokines to induce memory-like behavior in natural killer (NK) cells, thereby enhancing their cytotoxicity against HCC. Additionally, we evaluated the potential benefits of combining sorafenib with this newly developed memory-like NK cell (pNK) immunochemotherapy in a preclinical model. METHODS HCC tumors were grown in SD rats using subcapsular implantation. Interleukin 12/18 cytokines were supplemented to NK cells to enhance cytotoxicity through memory activation. Tumors were diagnosed using MRI, and animals were randomly assigned to control, pNK immunotherapy, sorafenib chemotherapy, or combination therapy groups. NK cells were delivered locally via the gastrointestinal tract, while sorafenib was administered systemically. Therapeutic responses were monitored with weekly multi-parametric MRI scans over three weeks. Afterward, tumor tissues were harvested for histopathological analysis. Structural and functional changes in tumors were evaluated by analyzing MRI and histopathology data using ANOVA and pairwise T-test analyses. RESULTS The tumors were allowed to grow for six days post-cell implantation before treatment commenced. At baseline, tumor diameter averaged 5.27 mm without significant difference between groups (p = 0.16). Both sorafenib and combination therapy imposed greater burden on tumor dimensions compared to immunotherapy alone in the first week. By the second week of treatment, combination therapy had markedly expanded its therapeutic efficacy, resulting in the most significant tumor regression observed (6.05 ± 1.99 vs. 13.99 ± 8.01 mm). Histological analysis demonstrated significantly improved cell destruction in the tumor microenvironment associated with combination treatment (63.79%). Interestingly, we observed fewer viable tumor regions in the sorafenib group (38.9%) compared to the immunotherapy group (45.6%). Notably, there was a significantly higher presence of NK cells in the tumor microenvironment with combination therapy (34.79%) compared to other groups (ranging from 2.21 to 26.50%). Although the tumor sizes in the monotherapy groups were similar, histological analysis revealed a stronger response in pNK cell immunotherapy group compared to the sorafenib group. CONCLUSIONS Experimental results indicated that combination therapy significantly enhanced treatment response, resulting in substantial tumor growth reduction in alignment with histological analysis.
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Affiliation(s)
- Aydin Eresen
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
| | - Zigeng Zhang
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
| | - Guangbo Yu
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - Qiaoming Hou
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
| | - Zhilin Chen
- Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Zeyang Yu
- Information School, University of Washington, Seattle, WA, USA
| | - Vahid Yaghmai
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA
| | - Zhuoli Zhang
- Department of Radiological Sciences, University of California Irvine, Irvine, CA, USA.
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA.
- Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, USA.
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Kim EY, Yoon YC, Hong TH. The role of natural killer cell activity as a milestone in oncologic outcome after curative resection of pancreatic adenocarcinoma. J Surg Oncol 2023; 128:1353-1364. [PMID: 37650829 DOI: 10.1002/jso.27432] [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: 04/05/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND The objective of this study was to investigate differences in oncologic outcomes of patients with pancreas cancer according to natural killer cell activity (NKA). METHODS A total of 118 patients who underwent curative resection for primary pancreas cancer in two hospitals were analyzed. NKA change pattern was analyzed. Difference in disease-free survival or overall survival was investigated by dividing subjects into two groups based on a normal NKA value for each period. RESULTS NKA value decreased after surgery compared to the value measured at admission. It recovered to normal levels at 5 weeks postoperatively. The low NKA (less than 250 pg/mL) group at admission, 5 weeks postoperatively, and before 1st chemotherapy had significantly poorer disease-free survival than the normal NKA group. In multivariate analysis, NKA values less than 250 pg/mL at admission (odds ratio = 2.267, p = 0.023) and N 1 or N2 category (odds ratio = 2.478, p = 0.023) were significant factors associated with recurrence after curative resection. CONCLUSIONS NKA in patients with pancreatic cancer demonstrated noticeable changes after surgery. Immunologically predisposed patients with a low NKA value had a high risk of early recurrence and a poor prognosis, although pancreatic cancer was surgically removed.
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Affiliation(s)
- Eun Young Kim
- Division of Trauma and Surgical Critical Care, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Young Chul Yoon
- Division of Hepatobiliary, Pancreas, and Abdominal Organ Transplant, Department of Surgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Tae Ho Hong
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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He H, Wu Y, Jia Z, Xu H, Pan Y, Cao D, Zhang Y, Tao X, Zhao T, Lv H, Yi J, Wang Y, Gao Y, Kou C, Niu J, Jiang J. Risk-stratified approach by aMAP score for community population infected with hepatitis B and C to guide subsequent liver cancer screening practice: A cohort study with 10-year follow-up. J Viral Hepat 2023; 30:859-869. [PMID: 37723945 DOI: 10.1111/jvh.13884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/12/2023] [Accepted: 08/14/2023] [Indexed: 09/20/2023]
Abstract
The aim of this study was to determine whether the age-Male-ALBI-Platelet (aMAP) score is applicable in community settings and how to maximise its role in risk stratification. A total of thousand five hundred and three participants had an aMAP score calculated at baseline and were followed up for about 10 years to obtain information on liver cancer incidence and death. After assessing the ability of aMAP to predict liver cancer incidence and death in terms of differentiation and calibration, the optimal risk stratification threshold of the aMAP score was explored, based on absolute and relative risks. The aMAP score achieved higher area under curves (AUCs) (almost all above 0.8) within 10 years and exhibited a better calibration within 5 years. Regarding absolute risk, the risk of incidence of and death from liver cancer showed a rapid increase after an aMAP score of 55. The cumulative incidence (5-year: 8.3% vs. 1.3% and 10-year: 20.9% vs. 3.6%) and mortality (5-year: 6.7% vs. 1.1% and 10-year: 17.5% vs. 3.1%) of liver cancer in individuals with an aMAP score of ≥55 were significantly higher than in those with a score of <55 (Grey's test p < .001). In terms of relative risk, the risk of death from liver cancer surpassed that from other causes after an aMAP score of ≥55 [HR = 1.38(1.02-1.87)]. Notably, the two types of death risk had opposite trends between the subpopulation with an aMAP score of ≥55 and < 55. To conclude, this study showed the value of the aMAP score in community settings and recommends using 55 as a new risk stratification threshold to guide subsequent liver cancer screening.
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Affiliation(s)
- Hua He
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Yanhua Wu
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Zhifang Jia
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Hongqin Xu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
| | - Yuchen Pan
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
| | - Donghui Cao
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Yangyu Zhang
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Xuerong Tao
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Tianye Zhao
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Haiyong Lv
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Jiaxin Yi
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
| | - Yuehui Wang
- Department of Geriatrics, the First Hospital of Jilin University, Changchun, China
| | - Yanhang Gao
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
| | - Changgui Kou
- Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Junqi Niu
- Department of Hepatology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
| | - Jing Jiang
- Department of Clinical Epidemiology, the First Hospital of Jilin University, Changchun, China
- Center of Infectious Diseases and Pathogen Biology, the First Hospital of Jilin University, Changchun, China
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Han Q, Wang M, Dong X, Wei F, Luo Y, Sun X. Non-coding RNAs in hepatocellular carcinoma: Insights into regulatory mechanisms, clinical significance, and therapeutic potential. Front Immunol 2022; 13:985815. [PMID: 36300115 PMCID: PMC9590653 DOI: 10.3389/fimmu.2022.985815] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/23/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a complex and heterogeneous malignancy with high incidence and poor prognosis. In addition, owing to the lack of diagnostic and prognostic markers, current multimodal treatment options fail to achieve satisfactory outcomes. Tumor immune microenvironment (TIME), angiogenesis, epithelial-mesenchymal transition (EMT), invasion, metastasis, metabolism, and drug resistance are important factors influencing tumor development and therapy. The intercellular communication of these important processes is mediated by a variety of bioactive molecules to regulate pathophysiological processes in recipient cells. Among these bioactive molecules, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), account for a large part of the human transcriptome, and their dysregulation affects the progression of HCC. The purpose of this review is to evaluate the potential regulatory mechanisms of ncRNAs in HCC, summarize novel biomarkers from somatic fluids (plasma/serum/urine), and explore the potential of some small-molecule modulators as drugs. Thus, through this review, we aim to contribute to a deeper understanding of the regulatory mechanisms, early diagnosis, prognosis, and precise treatment of HCC.
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Affiliation(s)
- Qin Han
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mengchen Wang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Dong
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Fei Wei
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory for Research and Evaluation of Pharmacovigilance, Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun,
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Wang J, Liu X, Jin T, Cao Y, Tian Y, Xu F. NK cell immunometabolism as target for liver cancer therapy. Int Immunopharmacol 2022; 112:109193. [PMID: 36087507 DOI: 10.1016/j.intimp.2022.109193] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 08/04/2022] [Accepted: 08/22/2022] [Indexed: 11/29/2022]
Abstract
Natural killer (NK) cells are being used effectively as a potential candidate in tumor immunotherapy. However, the migration and transport of NK cells to solid tumors is inadequate. NK cell dysfunction, tumor invasiveness, and metastasis are associated with altered metabolism of NK cells in the liver cancer microenvironment. However, in liver cancers, metabolic impairment of NK cells is still not understood fully. Evidence from various sources has shown that the interaction of NK cell's immune checkpoints with its metabolic checkpoints is responsible for the regulation of the development and function of these cells. How immune checkpoints contribute to metabolic programming is still not fully understood, and how this can be beneficial needs a better understanding, but they are emerging to be incredibly compelling to rebuilding the function of NK cells in the tumor. It is expected to represent a potential aim that focuses on improving the efficacy of therapies based on NK cells for treating liver cancer. Here, the recent advancements made to understand the NK cell's metabolic reprogramming in liver cancer have been summarized, along with the possible interplay between the immune and the metabolic checkpoints in NK cell function. Finally, an overview of some potential metabolic-related targets that can be used for liver cancer therapy treatment has been presented.
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Affiliation(s)
- Junqi Wang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiaolin Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang, China
| | - Tianqiang Jin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yuqing Cao
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yu Tian
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Feng Xu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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Mantovani S, Varchetta S, Mele D, Maiello R, Donadon M, Soldani C, Franceschini B, Torzilli G, Tartaglia G, Maestri M, Piccolo G, Barabino M, Opocher E, Bernuzzi S, Mondelli MU, Oliviero B. Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells. Cancers (Basel) 2022; 14:4060. [PMID: 36011052 PMCID: PMC9406989 DOI: 10.3390/cancers14164060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. METHODS Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. RESULTS sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. CONCLUSIONS We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.
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Affiliation(s)
- Stefania Mantovani
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Stefania Varchetta
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Dalila Mele
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Roberta Maiello
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Matteo Donadon
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Cristiana Soldani
- Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Barbara Franceschini
- Laboratory of Hepatobiliary Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Guido Torzilli
- Department of Biomedical Science, Humanitas University, Pieve Emanuele, 20090 Milan, Italy
- Department of Hepatobiliary and General Surgery, IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy
| | - Giuseppe Tartaglia
- Division of General Surgery 1, Department of Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Marcello Maestri
- Division of General Surgery 1, Department of Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Gaetano Piccolo
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Matteo Barabino
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Enrico Opocher
- Unit of HepatoBilioPancreatic and Digestive Surgery, Department of Health Sciences, San Paolo Hospital, University of Milan, 20142 Milan, Italy
| | - Stefano Bernuzzi
- Immunohematology and Transfusion Service, Department of Diagnostic Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
| | - Mario U. Mondelli
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Barbara Oliviero
- Division of Clinical Immunology-Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy
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Chen J, Chen X, Li T, Wang L, Lin G. Identification of chromatin organization-related gene signature for hepatocellular carcinoma prognosis and predicting immunotherapy response. Int Immunopharmacol 2022; 109:108866. [PMID: 35691273 DOI: 10.1016/j.intimp.2022.108866] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 04/26/2022] [Accepted: 05/12/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chromatin organization is associated with tumorigenesis; however, information on its role in hepatocellular carcinoma (HCC) is limited. Moreover, although immune checkpoint inhibitors (ICIs) have proven effective against HCC, the optimal index remains unknown. In this study, we aimed to construct a chromatin organization-related gene signature (CORGS) for prognosis and predicting response to ICIs in HCC. METHODS HCC-related data were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Construction (ICGC). Chromatin organization-related genes (CORGs) were retrieved from Gene Set Enrichment Analysis. Differentially expressed genes (DEGs) and prognostic genes were then applied to select candidate genes using advanced statistical methods, including learning vector quantization, random forest, and lasso regression. Subsequently, the CORGS was established based on chromatin organization-related hub genes using multivariate Cox regression analysis, evaluated with Kaplan-Meier survival curves, and verified in 64 samples of HCC patients from Fujian Provincial Hospital (FPH) via quantitative PCR. Subsequently, functional enrichment analysis, tumor somatic mutation analysis, and tumor immune analysis were performed to evaluate the potential value of the CORGS. RESULTS Three hundred and thirty-nine CORGs were identified as DEGs, and 186 were associated with HCC prognosis (all P < 0.05). Four intersection genes were selected to establish the CORGS using TCGA cohort, which was found to serve as an independent risk factor for HCC patients. CORGS was then validated in an ICGC cohort. In addition, CORGS reliability was verified in 64 samples from HCC patients and 26 adjacent non-tumorous tissues, collected from the FPH. The CORGS was also associated with tumor immune microenvironment characteristics and ICI response. Moreover, data from "IMvigor 210" revealed that more patients in the low CORGS group responded to atezolizumab compared to high CORGS patients (P < 0.05). Finally, a nomogram of tumor characteristics and the CORGS was established, exhibiting superior discrimination and calibration compared to the current staging system and published models. CONCLUSIONS CORGS may serve as an effective predictive biomarker for HCC as well as a potential index of the tumor immune microenvironment and ICI response.
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Affiliation(s)
- Jingbo Chen
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Xingte Chen
- Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Ting Li
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Lei Wang
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China; Department of Radiation Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China.
| | - Guishan Lin
- Department of Oncology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.
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Cai S, Du R, Zhang Y, Yuan Z, Shang J, Yang Y, Han B, Zhong W, Yuan H, Li Z. Construction and Comprehensive Analysis of ceRNA Networks and Tumor-Infiltrating Immune Cells in Hepatocellular Carcinoma With Vascular Invasion. FRONTIERS IN BIOINFORMATICS 2022; 2:836981. [PMID: 36304284 PMCID: PMC9580849 DOI: 10.3389/fbinf.2022.836981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/23/2022] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is a common malignant cancer. Metastasis plays a critical role in tumor progression, and vascular invasion is considered one of the most crucial factors for HCC metastasis. However, comprehensive analysis focusing on competitive endogenous RNA (ceRNA) and immune infiltration in the vascular invasion of HCC is lacking. Methods: The gene expression profiles of 321 samples, including 210 primary HCC cases and 111 HCC cases with vascular invasion, were downloaded from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma project, and used in identifying significant differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs). The RNAs associated with vascular invasion were used in constructing a ceRNA network. A multigene-based risk signature was constructed using the least absolute shrinkage and selection operator algorithm. We detected the fractions of 28 immune cell types in HCC through single-sample gene set enrichment analysis (ssGSEA). Finally, the relationship between the ceRNA network and immune cells was determined through correlation analysis and used in clarifying the potential mechanism involved in vascular invasion. Results: Overall, 413 DElncRNAs, 27 DEmiRNAs, and 397 DEmRNAs were recognized in HCC. A specific ceRNA network based on the interaction among 3 lncRNA–miRNA pairs and 24 miRNA–mRNA pairs were established. A ceRNA-based prognostic signature was constructed and used in dividing samples into high- and low-risk subgroups. The signature showed significant efficacy; its 3- and 5-year areas under the receiver operating characteristic curves were 0.712 and 0.653, respectively. ceRNA and ssGSEA integration analysis demonstrated that PART1 (p = 0, R = −0.33) and CDK5R2 (p = 0.01, R = −0.15) were negatively correlated to natural killer cells. Conclusion: This study demonstrated that vascular invasion in HCC might be related to PART1, and its role in regulating CDK5R2 and NK cells. A nomogram was developed to predict the prognosis of patients with HCC and demonstrated the value of the ceRNA network and tumor-infiltrating immune cells value in improving personalized management.
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Affiliation(s)
- Shijiao Cai
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Renle Du
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yuan Zhang
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhengyi Yuan
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Shang
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Yang Yang
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Bin Han
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
| | - Weilong Zhong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Weilong Zhong, ; Hengjie Yuan, ; Zhengxiang Li,
| | - Hengjie Yuan
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Weilong Zhong, ; Hengjie Yuan, ; Zhengxiang Li,
| | - Zhengxiang Li
- Department of Pharmacy, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Weilong Zhong, ; Hengjie Yuan, ; Zhengxiang Li,
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9
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Han J, Ke C, Jiang B, Zhou H, Xu H, Xie X. Down-regulation of PR/SET domain 10 underlies natural killer cell dysfunction in hepatocellular carcinoma. Clin Exp Immunol 2021; 206:366-377. [PMID: 34562314 DOI: 10.1111/cei.13666] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/07/2021] [Accepted: 09/21/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the world's leading cause of tumor-related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down-regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)-γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10-deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over-expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN-γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over-expression down-regulated and up-regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down-regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function.
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Affiliation(s)
- Jiantao Han
- The Department of Hepatobiliary and Pancreatic Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Chao Ke
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Bin Jiang
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Hongjian Zhou
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Hanbin Xu
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Xingwang Xie
- The Department of Hepatobiliary and Pancreatic Surgery, Tongren Hospital of Wuhan University, Wuhan, Hubei Province, China
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Mehrabi M, Amini F, Mehrabi S. Kill and Clearance in HCC: An Approach Based on NK Cells and Macrophages. Front Oncol 2021; 11:693076. [PMID: 34557407 PMCID: PMC8453146 DOI: 10.3389/fonc.2021.693076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/23/2021] [Indexed: 11/15/2022] Open
Affiliation(s)
| | | | - Shima Mehrabi
- Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
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11
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A Novel Orthotopic Liver Cancer Model for Creating a Human-like Tumor Microenvironment. Cancers (Basel) 2021; 13:cancers13163997. [PMID: 34439154 PMCID: PMC8394300 DOI: 10.3390/cancers13163997] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma is the most common form of liver cancer. The lack of models that resemble actual tumor development in patients, limits the research to improve the diagnosis rate and develop new treatments. This study describes a novel mouse model that involves organoid formation and an implantation technique. This mouse model shares human genetic profiles and factors around the tumor, resembling the actual tumor development in patients. We demonstrate the roles of different cell types around the tumor, in promoting tumor growth, using this model. This model will be useful to understand the tumor developmental process, drug testing, diagnosis, prognosis, and treatment development. Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer. This study aims to develop a new method to generate an HCC mouse model with a human tumor, and imitates the tumor microenvironment (TME) of clinical patients. Here, we have generated functional, three-dimensional sheet-like human HCC organoids in vitro, using luciferase-expressing Huh7 cells, human iPSC-derived endothelial cells (iPSC-EC), and human iPSC-derived mesenchymal cells (iPSC-MC). The HCC organoid, capped by ultra-purified alginate gel, was implanted into the disrupted liver using an ultrasonic homogenizer in the immune-deficient mouse, which improved the survival and engraftment rate. We successfully introduced different types of controllable TME into the model and studied the roles of TME in HCC tumor growth. The results showed the role of the iPSC-EC and iPSC-MC combination, especially the iPSC-MC, in promoting HCC growth. We also demonstrated that liver fibrosis could promote HCC tumor growth. However, it is not affected by non-alcoholic fatty liver disease. Furthermore, the implantation of HCC organoids to humanized mice demonstrated that the immune response is important in slowing down tumor growth at an early stage. In conclusion, we have created an HCC model that is useful for studying HCC development and developing new treatment options in the future.
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12
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Lee HA, Goh HG, Lee YS, Jung YK, Kim JH, Yim HJ, Lee MG, An H, Jeen YT, Yeon JE, Byun KS, Seo YS. Natural killer cell activity is a risk factor for the recurrence risk after curative treatment of hepatocellular carcinoma. BMC Gastroenterol 2021; 21:258. [PMID: 34118869 PMCID: PMC8199695 DOI: 10.1186/s12876-021-01833-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/24/2021] [Indexed: 12/12/2022] Open
Abstract
Background Natural killer (NK) cells have been known to contribute to surveillance and control of hepatocellular carcinoma (HCC). However, the association of NK cell activity with stage and recurrence risk of HCC have not been fully evaluated. Methods Untreated patients with newly diagnosed HCC were prospectively enrolled. Peripheral blood mononuclear cells were isolated at the time of diagnosis. Patients who had undergone surgery or radiofrequency ablation were classified as the curative treatment group, and their blood samples were collected again at 1 month after treatment. Results A total of 80 patients with HCC were enrolled. The mean age was 62.5 years. At baseline, interferon (IFN)-γ producing NK cell proportion was significantly lower in patients with Barcelona clinic liver cancer (BCLC) stage B, C, or D than in those with BCLC stage 0 (42.9% vs. 56.8%, P = 0.045). Among all patients, 56 patients had undergone curative treatment, and 42 patients re-visited at 1 month after curative treatment. There was no significant change in total NK cell and IFN-γ producing NK cell proportion from baseline to 1 month after treatment (all P > 0.05). During a median follow-up of 12.4 months, HCC recurred in 14 patients (33.3%). When patients were classified according to the IFN-γ producing NK cell proportion (group 1, ≥ 45%; and group 2, < 45%), HCC recurrence rate did not differ according to the IFN-γ producing NK cell proportion at baseline (log-rank test, P = 0.835). However, patients with < 45% IFN-γ producing NK cell proportion at 1 month after treatment had a significantly higher HCC recurrence rate than patients with that of ≥ 45% (log-rank test, P < 0.001). Multivariate analysis revealed that BCLC stage B (hazard ratio [HR] = 3.412, P = 0.045) and < 45% IFN-γ producing NK cell proportion at 1 month after treatment (HR = 6.934, P = 0.001) independently predicted an increased risk of HCC recurrence. Conclusions Decreased NK cell activity is significantly associated with the advanced stage of HCC, and the increased recurrence risk of HCC after curative treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01833-2.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea.,Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Hyun Gil Goh
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Min-Goo Lee
- Department of Physiology, Korea University College of Medicine, Seoul, Korea
| | - Hyunggin An
- Department of Biostatistics, Korea University College of Medicine, Seoul, Korea
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-Gu, Seoul, Korea.
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13
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Yang J, Eresen A, Scotti A, Cai K, Zhang Z. Combination of NK-based immunotherapy and sorafenib against hepatocellular carcinoma. Am J Cancer Res 2021; 11:337-349. [PMID: 33575075 PMCID: PMC7868752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/07/2020] [Indexed: 06/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver, which is considered the fourth leading cause of cancer-related death in the United States. Liver transplant and surgical resection are curative treatments for HCC, but only 10-15% of HCC patients are eligible candidates. The FDA-approved sorafenib is a multi-kinase inhibitor systemic therapy for advanced HCC that extends the overall survival by over 3 months when compared with placebo. Adoptive transfer of Natural Killer (NK) cells holds great promise for clinical cancer treatment. However, only limited clinical benefit has been achieved in cancer patients. Therefore, there is currently considerable interest in development of the combination of sorafenib and NK cells for the treatment of HCC patients. However, the mechanism of how sorafenib affects the function of NK cells remains to be comprehensively clarified. In this paper, we will discuss NK cell-based immunotherapies that are currently under preclinical and clinical investigation and its potential combination with sorafenib for improving the survival of HCC patients.
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Affiliation(s)
- Jia Yang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
| | - Aydin Eresen
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
| | - Alessandro Scotti
- Department of Radiology, University of Illinois at ChicagoChicago, IL, 60612, USA
- Department of Bioengineering, University of Illinois at ChicagoChicago, IL, 60612, USA
| | - Kejia Cai
- Department of Radiology, University of Illinois at ChicagoChicago, IL, 60612, USA
- Department of Bioengineering, University of Illinois at ChicagoChicago, IL, 60612, USA
| | - Zhuoli Zhang
- Department of Radiology, Feinberg School of Medicine, Northwestern UniversityChicago, IL, 60611, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL, 60611, USA
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14
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Sung PS, Shin EC. Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection. J Clin Med 2021; 10:E221. [PMID: 33435135 PMCID: PMC7827927 DOI: 10.3390/jcm10020221] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 02/08/2023] Open
Abstract
Direct-acting antiviral agents (DAAs) that allow for rapid clearance of hepatitis C virus (HCV) may evoke immunological changes. Some cases of rapid de novo hepatocellular carcinoma (HCC) development or early recurrence of HCC after DAA treatment have been reported. During chronic HCV infection, natural killer (NK) cells exhibited a deviant functional phenotype with decreased production of antiviral cytokines and increased cytotoxicity; however, DAA treatment rapidly decreased their cytotoxic function. Effective DAA therapy also suppressed the intrahepatic activation of macrophages/monocytes. This was followed by a decrease in mucosal-associated invariant T (MAIT) cell cytotoxicity without normalization of cytokine production. Rapid changes in the phenotypes of NK and MAIT cells after DAA treatment may attenuate the cytotoxicity of these cells against cancer cells. Moreover, DAA treatment did not normalize the increased frequencies of regulatory T cells even after clearance of HCV infection. Thus, the persistently increased frequency of regulatory T cells may contribute to a local immunosuppressive milieu and hamper the clearance of cancer cells. This review will focus on recent studies describing the changes in innate and adaptive immune responses after DAA treatment in patients with chronic HCV infection in the context of de novo occurrence or recurrence of HCC.
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Affiliation(s)
- Pil Soo Sung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea
- The Catholic Liver Research Center, The Catholic University of Korea, Seoul 06591, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
- The Center for Epidemic Preparedness, KAIST Institute, Daejeon 34141, Korea
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15
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Mantovani S, Varchetta S, Mele D, Donadon M, Torzilli G, Soldani C, Franceschini B, Porta C, Chiellino S, Pedrazzoli P, Santambrogio R, Barabino M, Cigala C, Piccolo G, Opocher E, Maestri M, Sangiovanni A, Bernuzzi S, Lhospice F, Kraiem M, Mondelli MU, Oliviero B. An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:3583. [PMID: 33266137 PMCID: PMC7761065 DOI: 10.3390/cancers12123583] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 12/29/2022] Open
Abstract
Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL). A group of patients treated with sorafenib because of clinically advanced HCC was also studied. A humanized anti-MICA/B monoclonal antibody (mAb) was used in in vitro experiments to examine NK cell-mediated antibody-dependent cellular cytotoxicity. Serum concentrations of soluble MICA/B were evaluated by ELISA. IL-15 stimulation increased NKG2D-dependent activity which, however, remained dysfunctional in PB NK cells from HCC patients, in line with the reduced NKG2D expression on NK cells. NK-TIL showed a lower degranulation ability than NK-LIL, which was restored by IL-15 stimulation. Moreover, in vitro IL-15 stimulation enhanced degranulation and interferon-γ production by PB NK from patients at month one of treatment with sorafenib. Anti-MICA/B mAb associated with IL-15 was able to induce PB NK cytotoxicity for primary HCC cells in HD and patients with HCC, who also showed NK-TIL degranulation for autologous primary HCC cells. Our findings highlight the key role of the NKG2D-MICA/B axis in the regulation of NK cell responses in HCC and provide evidence in support of a potentially important role of anti-MICA/B mAb and IL-15 stimulation in HCC immunotherapy.
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Affiliation(s)
- Stefania Mantovani
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Stefania Varchetta
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Dalila Mele
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
| | - Matteo Donadon
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Guido Torzilli
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Cristiana Soldani
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Barbara Franceschini
- Department of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Humanitas University, 20089 Rozzano, Italy; (M.D.); (G.T.); (C.S.); (B.F.)
| | - Camillo Porta
- Department of Medical Sciences and Human Oncology, “Aldo Moro” University of Bari and Policlinico Consorziale, 70124 Bari, Italy;
| | - Silvia Chiellino
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | - Paolo Pedrazzoli
- Division of Medical Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.C.); (P.P.)
| | | | - Matteo Barabino
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Claudia Cigala
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Gaetano Piccolo
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Enrico Opocher
- Division of Gastrointestinal Surgery, ASST Santi Paolo e Carlo, and State University of Milan, 20142 Milan, Italy; (M.B.); (C.C.); (G.P.); (E.O.)
| | - Marcello Maestri
- Division of General Surgery, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, CRC “A. M. and A. Migliavacca” Center for Liver Disease, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Stefano Bernuzzi
- Immunohematology and Transfusion Service, Centre of Transplantation Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | | | - Manel Kraiem
- Innate Pharma, 13009 Marseille, France; (F.L.); (M.K.)
| | - Mario Umberto Mondelli
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
- Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Barbara Oliviero
- Division of Infectious Diseases and Immunology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy; (S.M.); (S.V.); (D.M.); (B.O.)
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Lu H, Zhang H, Xiao Y, Chingin K, Dai C, Wei F, Wang N, Frankevich V, Chagovets V, Zhou F, Chen H. Comparative study of alterations in phospholipid profiles upon liver cancer in humans and mice. Analyst 2020; 145:6470-6477. [PMID: 32856629 DOI: 10.1039/d0an01080d] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Comparative studies of molecular alterations upon cancer between mice and humans are of great importance in order to determine the relevance of research involving mouse cancer models to the development of diagnostic and therapeutic approaches in clinical practice as well as for the mechanistic studies of pathology in humans. Herein, using molecular fingerprinting by internal extractive electrospray ionization mass spectrometry (iEESI-MS), we identified 50 differential signals in mouse liver tissue and 62 differential signals in human liver tissue that undergo significant intensity alterations (variable importance in the project (VIP) >1.0) upon liver cancer, out of which only 27 were common in both mouse and human tissues. Out of the 27 common differential signals, six types of phospholipids were also identified to undergo significant alterations in human serum upon liver cancer, including PC(34:2), PC(36:4), PC(38:6), PC(36:2), PC(38:4) and PC(42:9). Statistical analysis of the relative intensity distribution of these six identified phospholipids in serum allowed confident determination of liver cancer in humans (sensitivity 91.0%, specificity 88.0%, and accuracy 90.0%). Our results indicate that, despite the significant difference in the overall alterations of phospholipid profiles upon liver cancer between humans and mice, the six identified 'core' differential phospholipids of liver cancer found in the liver tissues of both humans and mice as well as in human serum show high potential as a minimal panel for the rapid targeted diagnosis of liver cancer with high accuracy, sensitivity and specificity using direct mass spectrometry (MS) analysis.
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Affiliation(s)
- Haiyan Lu
- State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012, P. R. China
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Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches. Cancers (Basel) 2020; 12:cancers12040926. [PMID: 32283827 PMCID: PMC7226319 DOI: 10.3390/cancers12040926] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.
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18
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Animal Models of Hepatocellular Carcinoma: The Role of Immune System and Tumor Microenvironment. Cancers (Basel) 2019; 11:cancers11101487. [PMID: 31581753 PMCID: PMC6826986 DOI: 10.3390/cancers11101487] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 09/28/2019] [Accepted: 09/30/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has one of the highest mortality rates of solid cancers. Ninety percent of HCCs are associated with liver fibrosis or cirrhosis developed from chronic liver injuries. The immune system of the liver contributes to the severity of the necrotic-inflammatory tissue damage, the establishment of fibrosis and cirrhosis, and the disease progression towards HCC. Immunotherapies have emerged as an exciting strategy for HCC treatment, but their effect is limited, and an extensive translation research is urgently needed to enhance anti-tumor efficacy and clinical success. Establishing HCC animal models that are analogous to human disease settings, i.e., mimicking the tumor microenvironment of HCC, is extremely challenging. Hence, this review discusses different animal models of HCC by summarizing their advantages and their limits with a specific focus on the role of the immune system and tumor microenvironment.
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Angenard G, Merdrignac A, Louis C, Edeline J, Coulouarn C. Expression of long non-coding RNA ANRIL predicts a poor prognosis in intrahepatic cholangiocarcinoma. Dig Liver Dis 2019; 51:1337-1343. [PMID: 31040073 DOI: 10.1016/j.dld.2019.03.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/05/2019] [Accepted: 03/22/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a deadly cancer worldwide associated with an increased incidence, limited therapeutic options and absence of reliable prognostic biomarkers. Long non-coding RNAs (lncRNA) emerge as relevant biomarkers in cancer being associated with tumor progression. However, lncRNA have been poorly investigated in iCCA. AIM To identify lncRNA significantly associated with the survival of patients with iCCA after tumor resection for curative intent. METHODS Gene expression profiling and Q-RT-PCR were performed from a cohort of 39 clinically well-annotated iCCA. Univariate Cox proportional hazards model with Wald Statistic was used to identify lncRNA significantly associated with overall (OS) and/or disease-free (DFS) survival. RESULTS A signature made of 9 lncRNA was identified to be significantly (P < 0.05) associated with OS and DFS, including 4 lncRNA (lnc-CDK9-1, XLOC_l2_009441, CDKN2B-AS1, HOXC13-AS) highly expressed in poor prognosis iCCA and 5 lncRNA (lnc-CCHCR1-1, lnc-AF131215.3.1, lnc-CBLB-5, COL18A1-AS2, lnc-RELL2-1) highly expressed in better prognosis iCCA. We further validated CDKN2B-AS1 (ANRIL) as a poor prognosis biomarker, not only in iCCA, but also in hepatocellular carcinoma, kidney renal clear cell carcinoma and uterine corpus endometrial carcinoma. CONCLUSIONS We report a prognosis lncRNA signature in iCCA and the clinical relevance of CDKN2B-AS1 (ANRIL) overexpression in several cancers.
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Affiliation(s)
- Gaëlle Angenard
- Inserm, Univ Rennes, Inra, Institut NuMeCan (Nutrition Metabolisms and Cancer), CHU Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Aude Merdrignac
- Inserm, Univ Rennes, Inra, Institut NuMeCan (Nutrition Metabolisms and Cancer), CHU Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Corentin Louis
- Inserm, Univ Rennes, Inra, Institut NuMeCan (Nutrition Metabolisms and Cancer), CHU Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Julien Edeline
- Inserm, Univ Rennes, Inra, Institut NuMeCan (Nutrition Metabolisms and Cancer), CHU Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
| | - Cédric Coulouarn
- Inserm, Univ Rennes, Inra, Institut NuMeCan (Nutrition Metabolisms and Cancer), CHU Rennes, Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France.
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20
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Mikulak J, Bruni E, Oriolo F, Di Vito C, Mavilio D. Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology. Front Immunol 2019; 10:946. [PMID: 31114585 PMCID: PMC6502999 DOI: 10.3389/fimmu.2019.00946] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/12/2019] [Indexed: 12/16/2022] Open
Abstract
The liver is considered a preferential tissue for NK cells residency. In humans, almost 50% of all intrahepatic lymphocytes are NK cells that are strongly imprinted in a liver-specific manner and show a broad spectrum of cellular heterogeneity. Hepatic NK (he-NK) cells play key roles in tuning liver immune response in both physiological and pathological conditions. Therefore, there is a pressing need to comprehensively characterize human he-NK cells to better understand the related mechanisms regulating their effector-functions within the dynamic balance between immune-tolerance and immune-surveillance. This is of particular relevance in the liver that is the only solid organ whose parenchyma is constantly challenged on daily basis by millions of foreign antigens drained from the gut. Therefore, the present review summarizes our current knowledge on he-NK cells in the light of the latest discoveries in the field of NK cell biology and clinical relevance.
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Affiliation(s)
- Joanna Mikulak
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Elena Bruni
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Ferdinando Oriolo
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Clara Di Vito
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
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21
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Zhuang L, Fulton RJ, Rettman P, Sayan AE, Coad J, Al-Shamkhani A, Khakoo SI. Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma. Hepatol Int 2019; 13:75-83. [PMID: 30467624 PMCID: PMC6513806 DOI: 10.1007/s12072-018-9909-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 10/30/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is common, but remains difficult to treat. Natural killer (NK) cells are cells of the innate immune system that have potent anti-cancer activity. Recent work has shown that stimulation with IL-12/15/18 leads to the generation of NK cells with enhanced functional and putative "memory" properties. We have investigated the activity of these NK cells against HCC cell lines in vitro and in a mouse model. METHODS NK cells from healthy donors or individuals with HCC were activated with IL-12/15/18 in vitro and tested for cytotoxic activity against a panel of human HCC cell lines. IL-12/15/18 primed murine NK cells were then infused into a murine model of spontaneously arising HCC to test for anti-tumor activity. RESULTS NK cells from patients and healthy controls had similar expression levels of activating and inhibitory NK cell receptors. However, proliferation of NK cells from HCC patients was weaker than healthy controls in response to IL-12/15/18 and IL-2 (p < 0.001 at day 9). In vitro, NK cells from both groups of individuals killed HCC targets to similar levels and this was unrelated to NKG2D expression. In a spontaneous model of HCC, IL-12/15/18 activated NK cells trafficked to the liver and resulted in lower levels of spontaneous HCC formation (p < 0.01). CONCLUSION Cytokine-primed NK cells from patients with HCC have similar levels of activity against HCC cell lines as those from healthy controls. This type of activated NK cell has immunotherapeutic potential against hepatocellular carcinoma.
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Affiliation(s)
- Lihui Zhuang
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - Rebecca J. Fulton
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - Pauline Rettman
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - A. Emre Sayan
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - Jonathan Coad
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - Aymen Al-Shamkhani
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
| | - Salim I. Khakoo
- Faculty of Medicine, Southampton General Hospital, University of Southampton, Tremona Road, Southampton, SO16 6YD UK
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22
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Wang T, Liu Y, Liu Q, Cummins S, Zhao M. Integrative proteomic analysis reveals potential high-frequency alternative open reading frame-encoded peptides in human colorectal cancer. Life Sci 2018; 215:182-189. [PMID: 30419281 DOI: 10.1016/j.lfs.2018.11.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/31/2018] [Accepted: 11/08/2018] [Indexed: 11/30/2022]
Abstract
Identification of alternative open reading frame-encoded peptides (AEPs) for the diagnosis of colorectal cancer at the proteome level is largely unexplored because of a lack of comprehensive proteomics data. Here, we performed a comprehensive integrative analysis of mass spectral data published by Clinical Proteomic Tumor Analysis Consortium and characterized 93 high-confident AEPs encoded within 75 genes. There are four cancer-related genes appeared to have AEPs identified frequently in >20 out of 95 colorectal cancer samples, including ABCF2, AR, RBM10 and NRG1. Further network analysis of the identified AEPs found the enrichment of novel AEPs within hormone androgen receptor and a highly-modularised network with 42 genes associated with patient survival. Our results not only suggested a mechanistic view of how AEPs work in cancer progression, but also shed light on somatic amino acid mutations in AEPs, which might be overlooked previously because of their low frequencies. In particular, potential high-frequency mutations in 77 samples associated with EDARADD may contribute to the discovery of new biomarkers and the development of innovative therapeutic approaches.
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Affiliation(s)
- Tianfang Wang
- School of Science and Engineering, University of the Sunshine Coast, Maroochydore DC, Queensland, 4558, Australia.
| | - Yining Liu
- The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou 510182, China
| | - Qi Liu
- Department of Biomedical Informatics, School of Medicine, Vanderbilt University, Nashville, TN 37232, United States; Center for Quantitative Sciences, School of Medicine, Vanderbilt University, Nashville, TN 37232, United States
| | - Scott Cummins
- School of Science and Engineering, University of the Sunshine Coast, Maroochydore DC, Queensland, 4558, Australia
| | - Min Zhao
- School of Science and Engineering, University of the Sunshine Coast, Maroochydore DC, Queensland, 4558, Australia.
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23
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Sung PS, Jang JW. Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications. Int J Mol Sci 2018; 19:3648. [PMID: 30463262 PMCID: PMC6274919 DOI: 10.3390/ijms19113648] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/16/2018] [Accepted: 11/16/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.
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Affiliation(s)
- Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
| | - Jeong Won Jang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
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24
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Siu EHL, Chan AWH, Chong CCN, Chan SL, Lo KW, Cheung ST. Treatment of advanced hepatocellular carcinoma: immunotherapy from checkpoint blockade to potential of cellular treatment. Transl Gastroenterol Hepatol 2018; 3:89. [PMID: 30603725 DOI: 10.21037/tgh.2018.10.16] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 10/29/2018] [Indexed: 12/16/2022] Open
Abstract
The absence of potent therapeutic option accounts for the dismal prognosis of advanced hepatocellular carcinoma (HCC) with high mortality and recurrence rate. For a decade, sorafenib is the only approved systemic drug in the first-line setting and warrants as the standard-of-care for HCC in the advanced stage. Given the common failures of chemotherapies and targeted therapies in the field of HCC treatment, promising breakthroughs were eagerly needed and until recently, immunotherapies have opened a new era of anticancer treatment. The liver organ is perceived as "immunotolerant" owing to its functional role, and the hepatic immune balance is found to be deregulated during chronic liver inflammation and HCC tumorigenesis. Restoring a competent immunity by mitigation of immunosuppression signals is a contemporary approach. In this regard, novel immune checkpoint inhibitors have revolutionized cancer pharmacological treatment options with remarkable clinical outcomes in hematologic malignancy and multiple solid tumors including advanced HCC. Nivolumab, an immunotherapeutic agent to block programmed cell death protein 1 (PD-1), showed high efficacy potential for patients progressed with sorafenib and granted accelerated approval by the US Food and Drug Administration (FDA) recently. The development of this class of immunotherapeutic drug is currently based on myriad studies established on the role of T-cell mediated immunosuppression through immune checkpoints. Heterogeneous results have led to further explorations to the profile of oncogenic processes and signaling pathways associated with PD1/PD-L1 axis. Emerging evidence from preclinical studies implicate natural killer (NK) cells as a mediator to the PD-1 checkpoint signaling immunoevasion. The strategy of adopting immunomodulating ability of NK cells by immune checkpoints inhibitors is potential to additive effects in stimulating anticancer immunity. This idea is not entirely newfound but has recently gained prominence because of advances in defining phenotypic heterogeneity of NK cell populations. The physiological significance and synergistic value of NK cells await further investigation in clinical trials. In this review, an overview of the treatment paradigm shift of HCC management is presented. Current knowledge concerning immunological mechanisms of immune checkpoints attributed to T cell is further discussed and relevant ongoing clinical trials are summarized. We proposed that NK cells should be viewed as part of the network of checkpoint immunoevasion and delineate current evidence of translational clinical research in this area. It is conceivable that immune checkpoint inhibitors in combination with NK cell-based therapeutic strategies will be great promise for treatment of advanced HCC.
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Affiliation(s)
- Elaine Hon-Lam Siu
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
| | - Anthony Wing-Hung Chan
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | | | - Stephen Lam Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Kwok-Wai Lo
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China
| | - Siu Tim Cheung
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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25
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Gong Z, Ma Q, Wang X, Cai Q, Gong X, Genchev GZ, Lu H, Zeng F. A Herpes Simplex Virus Thymidine Kinase-Induced Mouse Model of Hepatocellular Carcinoma Associated with Up-Regulated Immune-Inflammatory-Related Signals. Genes (Basel) 2018; 9:E380. [PMID: 30060537 PMCID: PMC6115908 DOI: 10.3390/genes9080380] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/19/2018] [Accepted: 07/23/2018] [Indexed: 12/11/2022] Open
Abstract
Inflammation and fibrosis in human liver are often precursors to hepatocellular carcinoma (HCC), yet none of them is easily modeled in animals. We previously generated transgenic mice with hepatocyte-specific expressed herpes simplex virus thymidine kinase (HSV-tk). These mice would develop hepatitis with the administration of ganciclovir (GCV)(Zhang, 2005 #1). However, our HSV-tk transgenic mice developed hepatitis and HCC tumor as early as six months of age even without GCV administration. We analyzed the transcriptome of the HSV-tk HCC tumor and hepatitis tissue using microarray analysis to investigate the possible causes of HCC. Gene Ontology (GO) enrichment analysis showed that the up-regulated genes in the HCC tissue mainly include the immune-inflammatory and cell cycle genes. The down-regulated genes in HCC tumors are mainly concentrated in the regions related to lipid metabolism. Gene set enrichment analysis (GSEA) showed that immune-inflammatory-related signals in the HSV-tk mice are up-regulated compared to those in Notch mice. Our study suggests that the immune system and inflammation play an important role in HCC development in HSV-tk mice. Specifically, increased expression of immune-inflammatory-related genes is characteristic of HSV-tk mice and that inflammation-induced cell cycle activation maybe a precursory step to cancer. The HSV-tk mouse provides a suitable model for the study of the relationship between immune-inflammation and HCC, and their underlying mechanism for the development of therapeutic application in the future.
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Affiliation(s)
- Zhijuan Gong
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
| | - Qingwen Ma
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
| | - Xujun Wang
- SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
| | - Qin Cai
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
| | - Xiuli Gong
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
| | - Georgi Z Genchev
- SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
| | - Hui Lu
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
- SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
| | - Fanyi Zeng
- Shanghai Institute of Medical Genetics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China.
- Department of Histo-Embryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
- Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China.
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26
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27
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Wahid B, Ali A, Rafique S, Saleem K, Waqar M, Wasim M, Idrees M. Role of altered immune cells in liver diseases: a review. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:377-388. [PMID: 29605453 DOI: 10.1016/j.gastrohep.2018.01.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 01/12/2018] [Accepted: 01/22/2018] [Indexed: 12/17/2022]
Abstract
Immune cells play an important role in controlling liver tumorigenesis, viral hepatitis, liver fibrosis and contribute to pathogenesis of liver inflammation and injury. Accumulating evidence suggests the effectiveness of natural killer (NK) cells and Kupffer cells (KCs) against viral hepatitis, hepatocellular damage, liver fibrosis, and carcinogenesis. Activation of natural killer cells provides a novel therapeutic strategy to cure liver related diseases. This review discusses the emerging roles of immune cells in liver disorders and it will provide baseline data to scientists to design better therapies for treatment.
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Affiliation(s)
- Braira Wahid
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan; Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Amjad Ali
- Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Shazia Rafique
- Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Komal Saleem
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan; Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Muhammad Waqar
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan; Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan
| | - Muhammad Wasim
- Department of Medicine, Khyber Teaching Hospital Peshawar KPK, Pakistan
| | - Muhammad Idrees
- Centre for Applied Molecular Biology (CAMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan; Genome Centre for Molecular Based Diagnostics and Research, Al-Sudais Plaza Abdalian Cooperative Society, Lahore, Pakistan; Department of Medicine, Khyber Teaching Hospital Peshawar KPK, Pakistan; Division of Molecular Virology and Diagnostics Center of Excellence in Molecular Biology (CEMB), 87-West Canal Bank Road Thokar Niaz Baig, University of the Punjab, Lahore, Pakistan; Vice Chancellor Hazara University Mansehra, Pakistan.
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28
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Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches. Front Med 2017; 11:509-521. [DOI: 10.1007/s11684-017-0546-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 04/26/2017] [Indexed: 12/21/2022]
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29
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Menegon S, Columbano A, Giordano S. The Dual Roles of NRF2 in Cancer. Trends Mol Med 2016; 22:578-593. [PMID: 27263465 DOI: 10.1016/j.molmed.2016.05.002] [Citation(s) in RCA: 486] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/06/2016] [Accepted: 05/09/2016] [Indexed: 12/19/2022]
Abstract
NRF2 has been traditionally considered as a tumor suppressor because its cytoprotective functions are deemed to be the main cellular defense mechanism against exogenous and endogenous insults, including xenobiotics and oxidative stress. However, several recent studies demonstrate that hyperactivation of the NRF2 pathway creates an environment that favors the survival of normal as well as malignant cells, protecting them against oxidative stress, chemotherapeutic agents, and radiotherapy. In a rapidly advancing field, this review summarizes some of the known mechanisms by which NRF2 can exert its oncogenic functions, and describes the current status of NRF2 inhibitors, providing a clear rationale for the consideration of NRF2 as a powerful putative therapeutic target in cancer treatment.
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Affiliation(s)
- Silvia Menegon
- University of Torino, Department of Oncology, Candiolo Cancer Institute-FPO, IRCCS, Strada Provinciale 142, 10060 Candiolo, Torino, Italy.
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy.
| | - Silvia Giordano
- University of Torino, Department of Oncology, Candiolo Cancer Institute-FPO, IRCCS, Strada Provinciale 142, 10060 Candiolo, Torino, Italy.
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30
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Han H, Li W, Shen H, Zhang J, Zhu Y, Li Y. microRNA-129-5p, a c-Myc negative target, affects hepatocellular carcinoma progression by blocking the Warburg effect. J Mol Cell Biol 2016; 8:400-410. [PMID: 27001970 DOI: 10.1093/jmcb/mjw010] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Revised: 12/03/2015] [Accepted: 12/25/2015] [Indexed: 01/09/2023] Open
Abstract
Deregulation of microRNAs (miRNAs) and c-Myc (Myc) contributes to hepatocellular carcinoma (HCC) progression, but how miRNAs and Myc regulate each other in hepatocarcinogenesis is still poorly understood. Using a functional screen, we identified miR-129-5p as a miRNA that inhibits HCC cell growth. miR-129-5p targets the mitochondrial matrix protein pyruvate dehydrogenase kinase 4 (PDK4), which leads to decreased phosphorylation of the E1α subunit of pyruvate dehyrogenase (PDH) complex, inhibition of glycolysis, retarded tumor growth, and impaired lung colonization. Enforced expression of PDK4 refractory to inhibition by miR-129-5p rescued all of these phenotypes. Targeting PDK4 by shRNA recapitulated the effects caused by miR-129-5p. miR-129-5p is transcriptionally repressed by a complex comprised of Myc, histone deacetylase 3 (HDAC3), and enhancer of zeste 2 polycomb repressive complex 2 (EZH2). Levels of miR-129-5p negatively correlated with clinical stages in human HCC. Restoring miR-129-5p expression suppressed the diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Thus, we concluded that miR-129-5p, which is a negative target of Myc, blocks glycolysis to retard hepatocarcinogenesis via targeting PDK4. The critical link between miR-129-5p and PDK4 in the progression of HCC suggests potential points of therapeutic intervention for this disease.
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Affiliation(s)
- Han Han
- College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Wenjuan Li
- College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Hongxing Shen
- College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Jinxiang Zhang
- Department of Surgery, Wuhan Union Hospital, Wuhan 430022, China
| | - Yahui Zhu
- College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Youjun Li
- College of Life Sciences, Medical Research Institute, Wuhan University, Wuhan 430072, China
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31
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Zavattari P, Perra A, Menegon S, Kowalik MA, Petrelli A, Angioni MM, Follenzi A, Quagliata L, Ledda-Columbano GM, Terracciano L, Giordano S, Columbano A. Nrf2, but not β-catenin, mutation represents an early event in rat hepatocarcinogenesis. Hepatology 2015; 62:851-62. [PMID: 25783764 DOI: 10.1002/hep.27790] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 03/16/2015] [Indexed: 12/24/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). CONCLUSION In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development.
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Affiliation(s)
- Patrizia Zavattari
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Silvia Menegon
- University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo, Torino, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Annalisa Petrelli
- University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo, Torino, Italy
| | | | - Antonia Follenzi
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Luca Quagliata
- Institute of Pathology, University Hospital, Basel, Switzerland
| | | | | | - Silvia Giordano
- University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo, Torino, Italy
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
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Sachdeva M, Chawla YK, Arora SK. Immunology of hepatocellular carcinoma. World J Hepatol 2015; 7:2080-2090. [PMID: 26301050 PMCID: PMC4539401 DOI: 10.4254/wjh.v7.i17.2080] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 05/28/2015] [Accepted: 07/22/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is primarily a malignancy of the liver, advancing from a damaged, cirrhotic liver to HCC. Globally, HCC is the sixth most prevalent cancer and the third-most prevalent reason for neoplastic disease-related deaths. A diverse array of infiltrating immunocytes regulates the development and progression of HCC, as is the case in many other cancers. An understanding of the various immune components during HCC becomes necessary so that novel therapeutic strategies can be designed to combat the disease. A dysregulated immune system (including changes in the number and/or function of immune cells, cytokine levels, and the expression of inhibitory receptors or their ligands) plays a key role in the development of HCC. Alterations in either the innate or adaptive arm of the immune system and cross-talk between them make the immune system tolerant to tumors, leading to disease progression. In this review, we have discussed the status and roles of various immune effector cells (e.g., dendritic cells, natural killer cells, macrophages, and T cells), their cytokine profile, and the chemokine-receptor axis in promoting or impeding HCC.
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Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM, Giordano S, Columbano A. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology 2014; 59:228-41. [PMID: 23857252 DOI: 10.1002/hep.26616] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 06/29/2013] [Indexed: 12/17/2022]
Abstract
UNLABELLED Studies on gene and/or microRNA (miRNA) dysregulation in the early stages of hepatocarcinogenesis are hampered by the difficulty of diagnosing early lesions in humans. Experimental models recapitulating human hepatocellular carcinoma (HCC) are then used to perform this analysis. We performed miRNA and gene expression profiling to characterize the molecular events involved in the multistep process of hepatocarcinogenesis in the resistant-hepatocyte rat model. A high percentage of dysregulated miRNAs/genes in HCC were similarly altered in early preneoplastic lesions positive for the stem/progenitor cell marker cytokeratin-19, indicating that several HCC-associated alterations occur from the very beginning of the carcinogenic process. Our analysis also identified miRNA/gene-target networks aberrantly activated at the initial stage of hepatocarcinogenesis. Activation of the nuclear factor erythroid related factor 2 (NRF2) pathway and up-regulation of the miR-200 family were among the most prominent changes. The relevance of these alterations in the development of HCC was confirmed by the observation that NRF2 silencing impaired while miR-200a overexpression promoted HCC cell proliferation in vitro. Moreover, T3-induced in vivo inhibition of the NRF2 pathway accompanied the regression of cytokeratin-19-positive nodules, suggesting that activation of this transcription factor contributes to the onset and progression of preneoplastic lesions towards malignancy. The finding that 78% of genes and 57% of dysregulated miRNAs in rat HCC have been previously associated with human HCC as well underlines the translational value of our results. CONCLUSION This study indicates that most of the molecular changes found in HCC occur in the very early stages of hepatocarcinogenesis. Among these, the NRF2 pathway plays a relevant role and may represent a new therapeutic target.
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Affiliation(s)
- Annalisa Petrelli
- IRCC, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Torino, Italy
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Wallace MC, Friedman SL. Hepatic fibrosis and the microenvironment: fertile soil for hepatocellular carcinoma development. Gene Expr 2014; 16:77-84. [PMID: 24801168 PMCID: PMC8750341 DOI: 10.3727/105221614x13919976902057] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma is an emerging worldwide health threat that has few curative treatment options and poor overall survival. Progressive hepatic fibrosis is a common pathway for all forms of chronic liver disease and is closely linked epidemiologically to hepatocellular carcinoma risk. However, the molecular events that predispose a fibrotic liver to cancer development remain elusive. Nonetheless, a permissive hepatic microenvironment provides fertile soil for transition of damaged hepatocytes into hepatocellular carcinoma. Key predisposing features include alterations in the extracellular matrix, bidirectional signaling pathways between parenchymal and nonparenchymal cells, and immune dysfunction. Emerging research into the contributions of autophagy, tumor-associated fibroblasts, and hepatocellular carcinoma progenitor cells to this dangerous milieu also provides new mechanistic underpinnings to explain the contribution of fibrosis to cancer. As effective antifibrotic therapies are developed, these approaches could attenuate the rising surge of hepatocellular carcinoma associated with chronic liver disease.
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Affiliation(s)
- Michael C. Wallace
- *Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
- †School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia
| | - Scott L. Friedman
- *Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
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35
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Scolastici C, de Conti A, Cardozo MT, Ong TP, Purgatto E, Horst MA, Heidor R, Furtado KS, Bassoli BK, Moreno FS. β-ionone inhibits persistent preneoplastic lesions during the early promotion phase of rat hepatocarcinogenesis: TGF-α, NF-κB, and p53 as cellular targets. Nutr Cancer 2013; 66:234-41. [PMID: 24364727 DOI: 10.1080/01635581.2014.863364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Dietary isoprenic derivatives such as β-ionone (βI) are a promising class of chemopreventive agents. In this study, cellular aspects of βI protective activities during early hepatocarcinogenesis were evaluated. Male Wistar rats were submitted to "resistant hepatocyte" model and then received daily 16 mg/100 g body weight (b.w.) of βI (βI group) or only 0.25 mL/100 g b.w. of corn oil (vehicle, control group [CO]) during 4 wk, specifically during early promotion phase. Compared to controls, βI inhibited (P < 0.05) the development of persistent preneoplastic lesions (pPNL), considered to be potential hepatocellular carcinoma (HCC) progression sites, and increased remodeling PNL (rPNL) (P < 0.05) that tend to regress to a normal phenotype. Increased βI hepatic levels (P < 0.05), in the βI group, were associated with its chemopreventive actions. Compared to control rats, βI reduced the frequency of both pPNL and rPNL positive for tumor growth factor (TGF)-α (P < 0.05), reduced the frequency of pPNL stained for p65 (nuclear factor-kappaB; NF-κB) (P < 0.05), and reduced the frequency of pPNL positive for cytoplasmic p53 (P < 0.05). Our data demonstrated that βI targets TGF-α, NF-κB, and p53 in initial phases of hepatocarcinogenesis and specifically inhibits PNL with increased probability to progress to HCC. This isoprenoid may represent a chemopreventive agent of choice for HCC control.
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Affiliation(s)
- Clarissa Scolastici
- a Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences , University of São Paulo , São Paulo , Brazil
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36
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Abstract
NAFLD affects a large proportion of the US population and its incidence and prevalence are increasing to epidemic proportions around the world. As with other liver diseases that cause cirrhosis, NAFLD increases the risk of liver cancer, a disease with poor outcomes and limited therapeutic options. The incidences of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma are also rising, and HCC is now the leading cause of obesity-related cancer deaths in middle-aged men in the USA. In this Review, we summarize the correlations between liver cancer and NAFLD-related cirrhosis, and the role of the metabolic syndrome in the development of liver cancer from diverse aetiologies, including HCV-mediated cirrhosis. Recent advances in understanding the progression of NAFLD to HCC from preclinical models will also be discussed. Targeted genetic manipulation of certain metabolic or stress-response pathways, including one-carbon metabolism, NF-κB, PTEN and microRNAs, has been valuable in elucidating the pathways that regulate carcinogenesis in NAFLD. Although tremendous advances have occurred in the identification of diagnostic and therapeutic opportunities to reduce the progression of NAFLD, considerable gaps in our knowledge remain with regard to the mechanisms by which NAFLD and its risk factors promote liver cancer.
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Affiliation(s)
- Gregory A Michelotti
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 595 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC 27710, USA
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37
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Mossanen JC, Tacke F. Role of lymphocytes in liver cancer. Oncoimmunology 2013; 2:e26468. [PMID: 24498546 PMCID: PMC3906418 DOI: 10.4161/onci.26468] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 09/10/2013] [Accepted: 09/11/2013] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) typically occurs in patients with chronic inflammatory liver diseases, such as viral hepatitis or (non-)alcoholic steatohepatitis. Inflammation appears indeed as a crucial factor in hepatocarcinogenesis. Nevertheless, sophisticated animal models and studies of human samples revealed that the HCC also elicits antitumor immune responses. Patrolling and infiltrating lymphocytes (e.g., NKT and T cells, respectively) can exert decisive functions in the transition from chronic hepatic inflammation to cancer as well as in antitumor immune responses. An improved understanding of the cellular and molecular mechanisms whereby inflammation promotes or restricts hepatocarcinogenesis will open new avenues for therapeutic approaches to liver cancer.
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Affiliation(s)
- Jana C Mossanen
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
| | - Frank Tacke
- Department of Medicine III; RWTH-University Hospital Aachen; Aachen, Germany
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38
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Ayub A, Ashfaq UA, Haque A. HBV induced HCC: major risk factors from genetic to molecular level. BIOMED RESEARCH INTERNATIONAL 2013; 2013:810461. [PMID: 23991421 PMCID: PMC3749539 DOI: 10.1155/2013/810461] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 07/09/2013] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is a deadly and emerging disease leading to death in Asian countries. High hepatitis B virus (HBV) load and chronic hepatitis B (CHB) infection increase the risk of developing HCC. HBV is a DNA virus that can integrate DNA into host genome thereby increase the yield of transactivator protein HBxAg that may deregulate many pathways involving in metabolism of cells. Several monogenic and polygenic risk factors are also involved in HCC development. This review summarizes the mechanism involved in HCC development and discusses some promising therapies to make HCC curative.
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Affiliation(s)
- Ambreen Ayub
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
| | - Asma Haque
- Department of Bioinformatics and Biotechnology, Government College University Faisalabad (GCUF), Faisalabad 38000, Pakistan
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39
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Han H, Sun D, Li W, Shen H, Zhu Y, Li C, Chen Y, Lu L, Li W, Zhang J, Tian Y, Li Y. A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis. Hepatology 2013; 57:2378-2389. [PMID: 23389829 DOI: 10.1002/hep.26302] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 01/12/2013] [Indexed: 12/24/2022]
Abstract
UNLABELLED c-Myc (Myc) plays an important role in normal liver development and tumorigenesis. We show here that Myc is pathologically activated in and essential for promoting human hepatocellular carcinoma (HCC). Myc induces HCC through a novel, microRNA (miRNA)-mediated feedback loop comprised of miR-148a-5p, miR-363-3p, and ubiquitin-specific protease 28 (USP28). Myc directly binds to conserved regions in the promoters of the two miRNAs and represses their expression. miR-148a-5p directly targets and inhibits Myc, whereas miR-363-3p destabilizes Myc by directly targeting and inhibiting USP28. Inhibition of miR-148a-5p or miR-363-3p induces hepatocellular tumorigenesis by promoting G1 to S phase progression, whereas activation of them has the opposite effects. The Myc-miRNA feedback loop is dysregulated in human HCC. CONCLUSION These results define miR-148a-5p and miR-363-3p as negative regulators of Myc, thus revealing their heretofore unappreciated roles in hepatocarcinogenesis. (HEPATOLOGY 2013;57:2378-2389).
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Affiliation(s)
- Han Han
- College of Life Sciences, State Key Laboratory of Virology, Wuhan University, Wuhan, China
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40
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Tian Z, Chen Y, Gao B. Natural killer cells in liver disease. Hepatology 2013; 57:1654-62. [PMID: 23111952 PMCID: PMC3573257 DOI: 10.1002/hep.26115] [Citation(s) in RCA: 227] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 10/01/2012] [Accepted: 10/12/2012] [Indexed: 12/12/2022]
Abstract
Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including tumor necrosis factor-related apoptosis-inducing ligand-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors through their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis, but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease, but has also revealed new therapeutic targets for managing this disease.
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Affiliation(s)
- Zhigang Tian
- Department of Microbiology and Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Yongyan Chen
- Department of Microbiology and Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
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41
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Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH. Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 2012; 56:1567-74. [PMID: 22378061 PMCID: PMC3381981 DOI: 10.1002/hep.25674] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 02/13/2012] [Indexed: 12/11/2022]
Abstract
Sustained hepatic inflammation, driven by alcohol consumption, nonalcoholic fatty liver disease, and/or chronic viral hepatitis (hepatitis B and C), results in damage to parenchyma, oxidative stress, and compensatory regeneration/proliferation. There is substantial evidence linking these inflammation-associated events with the increased incidence of hepatocellular carcinogenesis. Although acute liver inflammation can play a vital and beneficial role in response to liver damage or acute infection, the effects of chronic liver inflammation, including liver fibrosis and cirrhosis, are sufficient in a fraction of individuals to initiate the process of transformation and the development of hepatocellular carcinoma. This review highlights immune-dependent mechanisms that may be associated with hepatocellular oncogenesis, including critical transformative events/pathways in the context of chronic inflammation and subverted tolerogenesis.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/pathology
- Fatty Liver/immunology
- Fatty Liver/pathology
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/pathology
- Hepatitis, Chronic/immunology
- Hepatitis, Chronic/pathology
- Hepatitis, Viral, Human/immunology
- Hepatitis, Viral, Human/pathology
- Humans
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Non-alcoholic Fatty Liver Disease
- Oxidative Stress/immunology
- Oxidative Stress/physiology
- Precancerous Conditions/pathology
- Prognosis
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Affiliation(s)
| | | | | | - Robert H. Wiltrout
- Correspondence: Robert H. Wiltrout, NCI-Frederick, Bldg 428, Rm 48A, Frederick, MD 21702, Telephone:301-496-4345, Fax:301-496-0775,
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42
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Coulouarn C, Corlu A, Glaise D, Guenon I, Thorgeirsson SS, Clement B. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 2012; 72:2533-2542. [PMID: 22419664 PMCID: PMC3498759 DOI: 10.1158/0008-5472.can-11-3317] [Citation(s) in RCA: 170] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte-HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte-HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP)9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte-HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation.
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Affiliation(s)
- Cédric Coulouarn
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France
- University of Rennes 1, F-35043 Rennes, France
| | - Anne Corlu
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France
- University of Rennes 1, F-35043 Rennes, France
| | - Denise Glaise
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France
- University of Rennes 1, F-35043 Rennes, France
| | - Isabelle Guenon
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France
- University of Rennes 1, F-35043 Rennes, France
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Bruno Clement
- Inserm, UMR991, Liver Metabolisms and Cancer, F-35033 Rennes, France
- University of Rennes 1, F-35043 Rennes, France
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Huard J, Mueller S, Gilles ED, Klingmüller U, Klamt S. An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes. FEBS J 2012; 279:3290-313. [PMID: 22443451 PMCID: PMC3466406 DOI: 10.1111/j.1742-4658.2012.08572.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G1 phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels.
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Affiliation(s)
- Jérémy Huard
- Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg, Germany
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