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Rahdan F, Abedi F, Dianat-Moghadam H, Sani MZ, Taghizadeh M, Alizadeh E. Autophagy-based therapy for hepatocellular carcinoma: from standard treatments to combination therapy, oncolytic virotherapy, and targeted nanomedicines. Clin Exp Med 2024; 25:13. [PMID: 39621122 PMCID: PMC11611955 DOI: 10.1007/s10238-024-01527-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 11/22/2024] [Indexed: 12/06/2024]
Abstract
Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.
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Affiliation(s)
- Fereshteh Rahdan
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Abedi
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
- Pediatric Inherited Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, 8174673461, Iran.
| | - Maryam Zamani Sani
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Zhou Y, Li Y, Chenm J, Mei K, Kang M, Chen P, Li Q. Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma. Hum Gene Ther 2024; 35:838-854. [PMID: 39001830 PMCID: PMC11511779 DOI: 10.1089/hum.2024.002] [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: 01/08/2024] [Accepted: 07/09/2024] [Indexed: 07/15/2024] Open
Abstract
A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.
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Affiliation(s)
- Yi Zhou
- Department of Abdominal Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yongzhong Li
- Department of Oncology, LuXian People’s Hospital, Luzhou, China
| | - Jing Chenm
- Department of Abdominal Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Kai Mei
- Department of Abdominal Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Mingxiang Kang
- Department of Oncology, LuXian People’s Hospital, Luzhou, China
| | - Ping Chen
- Department of Abdominal Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Qiu Li
- Division of Abdominal Tumor Multimodality Treatment, Department of Medical Oncology, West China Hospital, Cancer Center, Sichuan University, Chengdu, China
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Al-Shammari AM, Salman MI. Antimetastatic and antitumor activities of oncolytic NDV AMHA1 in a 3D culture model of breast cancer. Front Mol Biosci 2024; 11:1331369. [PMID: 39281317 PMCID: PMC11392722 DOI: 10.3389/fmolb.2024.1331369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 07/29/2024] [Indexed: 09/18/2024] Open
Abstract
Introduction Newcastle disease virus (NDV) AMHA1 is capable of killing cancer cells by direct replication or induction of apoptosis alongside other pathways. In this study, we report the potent antimetastatic and anticancer activities of NDV AMHA1 in a 3D spheroid model of breast cancer metastasis. Methods we used two breast cancer cell lines AMJ13 and MCF7 in our metastasis model system. Results First, we showed that NDV AMHA1 can infect and kill breast cancer cells in proliferating adherent cells and tumor spheroids using different virus doses and studying virus replication kinetics. We showed that NDV can infect and spread within the spheroids that represent metastasis before and after reattachment. Furthermore, we evaluated the ability of NDV to induce apoptosis in cancer spheroids and by virus tracking showed that NDV infection is essential for the elimination of these metastasis spheroids. Discussion The mechanism by which NDV induces cell killing in the metastasis model is the induction of caspase-3 and P21 and inhibition of Ki67 in cancer cells, but not in normal cells. In conclusion, these results indicate that NDV AMHA1 has the ability to kill breast cancer metastases in suspension or attached, and this is a novel finding of NDV AMHA1 being a possibly efficient therapy against human metastatic breast cancer.
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Affiliation(s)
- Ahmed Majeed Al-Shammari
- Experimental Therapy Department, Iraqi Center for Cancer and Medical Genetic Research, Mustansiriyah University, Baghdad, Iraq
| | - Marwa Ibrahim Salman
- Department of Biotechnology, College of Science, University of Baghdad, Baghdad, Iraq
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Kiaheyrati N, Babaei A, Ranji R, Bahadoran E, Taheri S, Farokhpour Z. Cancer therapy with the viral and bacterial pathogens: The past enemies can be considered the present allies. Life Sci 2024; 349:122734. [PMID: 38788973 DOI: 10.1016/j.lfs.2024.122734] [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: 03/02/2024] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024]
Abstract
Cancer continues to be one of the leading causes of mortality worldwide despite significant advancements in cancer treatment. Many difficulties have arisen as a result of the detrimental consequences of chemotherapy and radiotherapy as a common cancer therapy, such as drug inability to penetrate deep tumor tissue, and also the drug resistance in tumor cells continues to be a major concern. These obstacles have increased the need for the development of new techniques that are more selective and effective against cancer cells. Bacterial-based therapies and the use of oncolytic viruses can suppress cancer in comparison to other cancer medications. The tumor microenvironment is susceptible to bacterial accumulation and proliferation, which can trigger immune responses against the tumor. Oncolytic viruses (OVs) have also gained considerable attention in recent years because of their potential capability to selectively target and induce apoptosis in cancer cells. This review aims to provide a comprehensive summary of the latest literature on the role of bacteria and viruses in cancer treatment, discusses the limitations and challenges, outlines various strategies, summarizes recent preclinical and clinical trials, and emphasizes the importance of optimizing current strategies for better clinical outcomes.
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Affiliation(s)
- Niloofar Kiaheyrati
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran; Department of Microbiology and Immunology, School of Medicine, Qazvin University of Medical Science, Qazvin, Iran.
| | - Reza Ranji
- Department of Genetics, Faculty of Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Zahra Farokhpour
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
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Xiao R, Jin H, Huang F, Huang B, Wang H, Wang YG. Oncolytic virotherapy for hepatocellular carcinoma: A potent immunotherapeutic landscape. World J Gastrointest Oncol 2024; 16:2867-2876. [PMID: 39072175 PMCID: PMC11271782 DOI: 10.4251/wjgo.v16.i7.2867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 04/24/2024] [Accepted: 05/13/2024] [Indexed: 07/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a systemic disease with augmented malignant degree, high mortality and poor prognosis. Since the establishment of the immune mechanism of tumor therapy, people have realized that immunotherapy is an effective means for improvement of HCC patient prognosis. Oncolytic virus is a novel immunotherapy drug, which kills tumor cells and exempts normal cells by directly lysing tumor and inducing anti-tumor immune response, and it has been extensively examined as an HCC therapy. This editorial discusses oncolytic viruses for the treatment of HCC, emphasizing viral immunotherapy strategies and clinical applications related to HCC.
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Affiliation(s)
- Rong Xiao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Hao Jin
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Fang Huang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Biao Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Hui Wang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
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Zhang J, Xiao Y, Zhang J, Yang Y, Zhang L, Liang F. Recent advances of engineered oncolytic viruses-based combination therapy for liver cancer. J Transl Med 2024; 22:3. [PMID: 38167076 PMCID: PMC10763442 DOI: 10.1186/s12967-023-04817-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 12/18/2023] [Indexed: 01/05/2024] Open
Abstract
Liver cancer is a major malignant tumor, which seriously threatens human health and increases the economic burden on patients. At present, gene therapy has been comprehensively studied as an excellent therapeutic measure in liver cancer treatment. Oncolytic virus (OV) is a kind of virus that can specifically infect and kill tumor cells. After being modified by genetic engineering, the specificity of OV infection to tumor cells is increased, and its influence on normal cells is reduced. To date, OV has shown its effectiveness and safety in experimental and clinical studies on a variety of tumors. Thus, this review primarily introduces the current status of different genetically engineered OVs used in gene therapy for liver cancer, focuses on the application of OVs and different target genes for current liver cancer therapy, and identifies the problems encountered in OVs-based combination therapy and the corresponding solutions, which will provide new insights into the treatment of liver cancer.
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Affiliation(s)
- Junhe Zhang
- Institutes of Health Central Plains, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan Province, China.
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China.
| | - Yunxi Xiao
- Institutes of Health Central Plains, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan Province, China
| | - Jie Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yun Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China
| | - Liao Zhang
- Institutes of Health Central Plains, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan Province, China
| | - Fan Liang
- Institutes of Health Central Plains, Xinxiang Medical University, No. 601 Jinsui Road, Xinxiang, 453003, Henan Province, China
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Norollahi SE, Babaei K, Vahidi S, Motaz SJH, Tarbeghan MK, Khaleghipour M, Gharakhyli EA, Mirhafez SR, Samadani AA. Evaluation of Fluctuations of BRAF Gene Expression and its Polymorphism at rs1267623 in Colorectal Cancer. Microrna 2024; 13:202-210. [PMID: 39005128 DOI: 10.2174/0122115366286360240625095932] [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: 12/20/2023] [Revised: 05/25/2024] [Accepted: 05/27/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND Molecular markers in Colorectal Cancer (CRC) are needed for more accurate classification and personalized treatment. In this way, we investigated the effects of the BRAF gene on clinical outcomes of its expression fluctuations and its polymorphism at rs1267623 in CRC. METHODS In this study, 36.36 percent of patients with CRC were women, and 63.63 percent were men. After the pathology department confirmed the tumor of the samples, the stage and grade of the tumor were determined according to the TNM system. Real-time PCR was used to check the expression of the BRAF gene in tumor and non-tumor tissues, and its polymorphism in rs1267623 was also checked using the Tetra-ARMs PCR technique. RESULTS The expression of BRAF in tumor tissues was significantly higher than in non-tumoral tissues (P = 0.001), indicating an upregulation of BRAF gene expression in tumoral tissues. The user's text is empty. Furthermore, there was a significant correlation between BRAF expression and tumor stage (P = 0.001), as well as tumor grade (P = 0.003). However, no significant link was found between lymph node metastasis and distant metastasis of BRAF gene expression (P = 0.3). Additionally, no mutation was detected in the investigation of rs1267623 polymorphism. CONCLUSION The BRAF gene was upregulated in tumoral tissues. Remarkably, no mutation was found in the rs1267623 polymorphism. As a result, this gene can be used as a biomarker in the diagnosis and treatment of CRC.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | | | - Mostafa Khaleghipour
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | | | - Seyed Reza Mirhafez
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Akbar Samadani
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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Xu B, Jia W, Feng Y, Wang J, Wang J, Zhu D, Xu C, Liang L, Ding W, Zhou Y, Kong L. Exosome-transported circHDAC1_004 Promotes Proliferation, Migration, and Angiogenesis of Hepatocellular Carcinoma by the miR-361-3p/NACC1 Axis. J Clin Transl Hepatol 2023; 11:1079-1093. [PMID: 37577235 PMCID: PMC10412708 DOI: 10.14218/jcth.2022.00097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/26/2023] [Accepted: 02/15/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims Hepatocellular carcinoma (HCC) is among the most common malignant tumors globally. Circular RNAs (circRNAs), as a type of noncoding RNAs, reportedly participate in various tumor biological processes. However, the role of circHDAC1_004 in HCC remains unclear. Thus, we aimed to explore the role and the underlying mechanisms of circHDAC1_004 in the development and progression of HCC. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect circHDAC1_004 expression (circ_0005339) in HCC. Sanger sequencing and agarose gel electrophoresis were used to determine the structure of circHDAC1_004. In vitro and in vivo experiments were used to determine the biological function of circHDAC1_004 in HCC. Herein, qRT-PCR, RNA immunoprecipitation, western blotting, and a luciferase reporter assay were used to explore the relationships among circHDAC1_004, miR-361-3p, and NACC1. Results circHDAC1_004 was upregulated in HCC and significantly associated with poor overall survival. circHDAC1_004 promoted HCC cell proliferation, stemness, migration, and invasion. In addition, circHDAC1_004 upregulated human umbilical vein endothelial cells (HUVECs) and promoted angiogenesis through exosomes. circHDAC1_004 promoted NACC1 expression and stimulated the epithelial-mesenchymal transition pathway by sponging miR-361-3p. Conclusions We found that circHDAC1_004 overexpression enhanced the proliferation, stemness, and metastasis of HCC via the miR-361-3p/NACC1 axis and promoted HCC angiogenesis through exosomes. Our findings may help develop a possible therapeutic strategy for HCC.
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Affiliation(s)
- Bin Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Wenbo Jia
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Yanzhi Feng
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Jinyi Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Jing Wang
- Department of health, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Deming Zhu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Chao Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Litao Liang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Wenzhou Ding
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
| | - Yongping Zhou
- Jiangnan University Medical Center, JUMC, Department of Hepatobiliary, Wuxi, Jiangsu, China
| | - Lianbao Kong
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, National Health Commission Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center, Nanjing, Jiangsu, China
- Jiangsu Provincial Medical Key Laboratory, Nanjing, Jiangsu, China
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Faghihkhorasani A, Dalvand A, Derafsh E, Tavakoli F, Younis NK, Yasamineh S, Gholizadeh O, Shokri P. The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells. Cancer Cell Int 2023; 23:250. [PMID: 37880659 PMCID: PMC10599042 DOI: 10.1186/s12935-023-03099-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/13/2023] [Indexed: 10/27/2023] Open
Abstract
Cancer Stem Cells (CSCs) are the main "seeds" for the initiation, growth, metastasis, and recurrence of tumors. According to many studies, several viral infections, including the human papillomaviruses, hepatitis B virus, Epstein-Barr virus, and hepatitis C virus, promote the aggressiveness of cancer by encouraging the development of CSC features. Therefore, a better method for the targeted elimination of CSCs and knowledge of their regulatory mechanisms in human carcinogenesis may lead to the development of a future tool for the management and treatment of cancer. Oncolytic viruses (OVs), which include the herpes virus, adenovirus, vaccinia, and reovirus, are also a new class of cancer therapeutics that have favorable properties such as selective replication in tumor cells, delivery of numerous eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumor immunity, as well as a tolerable safety profile that essentially differs from that of other cancer therapeutics. The effects of viral infection on the development of CSCs and the suppression of CSCs by OV therapy were examined in this paper. The purpose of this review is to investigate the dual role of viruses in CSCs (oncolytic virotherapy and viral oncogenes).
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Affiliation(s)
| | - Alaleh Dalvand
- Tehran Medical Branch, Islamic Azad University of Medical Sciences, Tehran, Iran
| | - Ehsan Derafsh
- Department of Basic Medical Science, Windsor University School of Medicine, Brighton's Estate, Cayton, St. Kitts And Nevis
| | - Farnaz Tavakoli
- Nephrology and Transplantation Ward, Shariati Hospital Tehran University of Medical Sciences, Tehran, Iran
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | | | - Pooria Shokri
- Department of Medical Science, Faculty of Medical Science, Arak University of Medical Sciences, Arak, Iran.
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Li D, Peng X, He G, Liu J, Li X, Lin W, Fang J, Li X, Yang S, Yang L, Li H. Crosstalk between autophagy and CSCs: molecular mechanisms and translational implications. Cell Death Dis 2023; 14:409. [PMID: 37422448 PMCID: PMC10329683 DOI: 10.1038/s41419-023-05929-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 06/07/2023] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Cancer stem cells(CSCs) play a key role in regulating tumorigenesis, progression, as well as recurrence, and possess typical metabolic characteristics. Autophagy is a catabolic process that can aid cells to survive under stressful conditions such as nutrient deficiency and hypoxia. Although the role of autophagy in cancer cells has been extensively studied, CSCs possess unique stemness, and their potential relationship with autophagy has not been fully analyzed. This study summarizes the possible role of autophagy in the renewal, proliferation, differentiation, survival, metastasis, invasion, and treatment resistance of CSCs. It has been found that autophagy can contribute to the maintenance of CSC stemness, facilitate the tumor cells adapt to changes in the microenvironment, and promote tumor survival, whereas in some other cases autophagy acts as an important process involved in the deprivation of CSC stemness thus leading to tumor death. Mitophagy, which has emerged as another popular research area in recent years, has a great scope when explored together with stem cells. In this study, we have aimed to elaborate on the mechanism of action of autophagy in regulating the functions of CSCs to provide deeper insights for future cancer treatment.
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Affiliation(s)
- Dai Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xian Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Weikai Lin
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Jianjun Fang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
- Shenyang Clinical Medical Research Center for Diagnosis, Treatment and Health Management of Early Digestive Cancer, Shenyang, 110032, China.
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11
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Wang S, Liang B, Wang W, Li L, Feng N, Zhao Y, Wang T, Yan F, Yang S, Xia X. Viral vectored vaccines: design, development, preventive and therapeutic applications in human diseases. Signal Transduct Target Ther 2023; 8:149. [PMID: 37029123 PMCID: PMC10081433 DOI: 10.1038/s41392-023-01408-5] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 04/09/2023] Open
Abstract
Human diseases, particularly infectious diseases and cancers, pose unprecedented challenges to public health security and the global economy. The development and distribution of novel prophylactic and therapeutic vaccines are the prioritized countermeasures of human disease. Among all vaccine platforms, viral vector vaccines offer distinguished advantages and represent prominent choices for pathogens that have hampered control efforts based on conventional vaccine approaches. Currently, viral vector vaccines remain one of the best strategies for induction of robust humoral and cellular immunity against human diseases. Numerous viruses of different families and origins, including vesicular stomatitis virus, rabies virus, parainfluenza virus, measles virus, Newcastle disease virus, influenza virus, adenovirus and poxvirus, are deemed to be prominent viral vectors that differ in structural characteristics, design strategy, antigen presentation capability, immunogenicity and protective efficacy. This review summarized the overall profile of the design strategies, progress in advance and steps taken to address barriers to the deployment of these viral vector vaccines, simultaneously highlighting their potential for mucosal delivery, therapeutic application in cancer as well as other key aspects concerning the rational application of these viral vector vaccines. Appropriate and accurate technological advances in viral vector vaccines would consolidate their position as a leading approach to accelerate breakthroughs in novel vaccines and facilitate a rapid response to public health emergencies.
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Affiliation(s)
- Shen Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Bo Liang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Weiqi Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ling Li
- China National Research Center for Exotic Animal Diseases, China Animal Health and Epidemiology Center, Qingdao, China
| | - Na Feng
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Yongkun Zhao
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Tiecheng Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Feihu Yan
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
| | - Songtao Yang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
| | - Xianzhu Xia
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.
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12
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Wu YY, Sun TK, Chen MS, Munir M, Liu HJ. Oncolytic viruses-modulated immunogenic cell death, apoptosis and autophagy linking to virotherapy and cancer immune response. Front Cell Infect Microbiol 2023; 13:1142172. [PMID: 37009515 PMCID: PMC10050605 DOI: 10.3389/fcimb.2023.1142172] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 02/28/2023] [Indexed: 03/17/2023] Open
Abstract
Recent reports have revealed that oncolytic viruses (OVs) play a significant role in cancer therapy. The infection of OVs such as oncolytic vaccinia virus (OVV), vesicular stomatitis virus (VSV), parvovirus, mammalian reovirus (MRV), human adenovirus, Newcastle disease virus (NDV), herpes simplex virus (HSV), avian reovirus (ARV), Orf virus (ORFV), inactivated Sendai virus (ISV), enterovirus, and coxsackievirus offer unique opportunities in immunotherapy through diverse and dynamic pathways. This mini-review focuses on the mechanisms of OVs-mediated virotherapy and their effects on immunogenic cell death (ICD), apoptosis, autophagy and regulation of the immune system.
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Affiliation(s)
- Yi-Ying Wu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
| | - Te-Kai Sun
- Tsairder Boitechnology Co. Ltd., Taichung, Taiwan
| | - Ming-Shan Chen
- Department of Anesthesiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
| | - Muhammad Munir
- Department of Biomedical and Life Sciences, Lancaster University, Lancashire, United Kingdom
| | - Hung-Jen Liu
- Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan
- The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Ph.D Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
- *Correspondence: Hung-Jen Liu,
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13
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Oladejo M, Paulishak W, Wood L. Synergistic potential of immune checkpoint inhibitors and therapeutic cancer vaccines. Semin Cancer Biol 2023; 88:81-95. [PMID: 36526110 DOI: 10.1016/j.semcancer.2022.12.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022]
Abstract
Cancer vaccines and immune checkpoint inhibitors (ICIs) function at different stages of the cancer immune cycle due to their distinct mechanisms of action. Therapeutic cancer vaccines enhance the activation and infiltration of cytotoxic immune cells into the tumor microenvironment (TME), while ICIs, prevent and/or reverse the dysfunction of these immune cells. The efficacy of both classes of immunotherapy has been evaluated in monotherapy, but they have been met with several challenges. Although therapeutic cancer vaccines can activate anti-tumor immune responses, these responses are susceptible to attenuation by immunoregulatory molecules. Similarly, ICIs are ineffective in the absence of tumor-infiltrating lymphocytes (TILs). Further, ICIs are often associated with immune-related adverse effects that may limit quality of life and compliance. However, the combination of the improved immunogenicity afforded by cancer vaccines and restrained immunosuppression provided by immune checkpoint inhibitors may provide a suitable platform for therapeutic synergism. In this review, we revisit the history and various classifications of therapeutic cancer vaccines. We also provide a summary of the currently approved ICIs. Finally, we provide mechanistic insights into the synergism between ICIs and cancer vaccines.
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Affiliation(s)
- Mariam Oladejo
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Wyatt Paulishak
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA
| | - Laurence Wood
- Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.
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14
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Nisar M, Paracha RZ, Adil S, Qureshi SN, Janjua HA. An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer. Front Oncol 2022; 12:875188. [PMID: 35686109 PMCID: PMC9171400 DOI: 10.3389/fonc.2022.875188] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy resistance and peculiar tumor microenvironment, which diminish or mitigate the effects of therapies, make pancreatic cancer one of the deadliest malignancies to manage and treat. Advanced immunotherapies are under consideration intending to ameliorate the overall patient survival rate in pancreatic cancer. Oncolytic viruses therapy is a new type of immunotherapy in which a virus after infecting and lysis the cancer cell induces/activates patients’ immune response by releasing tumor antigen in the blood. The current review covers the pathways and molecular ablation that take place in pancreatic cancer cells. It also unfolds the extensive preclinical and clinical trial studies of oncolytic viruses performed and/or undergoing to design an efficacious therapy against pancreatic cancer.
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Affiliation(s)
- Maryum Nisar
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Rehan Zafar Paracha
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | - Sidra Adil
- School of Interdisciplinary Engineering & Sciences (SINES), National University of Sciences and Technology (NUST), Islamabad, Pakistan
| | | | - Hussnain Ahmed Janjua
- Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Sector H-12, Islamabad, Pakistan
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15
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Mardi A, Shirokova AV, Mohammed RN, Keshavarz A, Zekiy AO, Thangavelu L, Mohamad TAM, Marofi F, Shomali N, Zamani A, Akbari M. Biological causes of immunogenic cancer cell death (ICD) and anti-tumor therapy; Combination of Oncolytic virus-based immunotherapy and CAR T-cell therapy for ICD induction. Cancer Cell Int 2022; 22:168. [PMID: 35488303 PMCID: PMC9052538 DOI: 10.1186/s12935-022-02585-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/11/2022] [Indexed: 12/22/2022] Open
Abstract
Chimeric antigen receptor (CAR) T-cell therapy is a promising and rapidly expanding therapeutic option for a wide range of human malignancies. Despite the ongoing progress of CAR T-cell therapy in hematologic malignancies, the application of this therapeutic strategy in solid tumors has encountered several challenges due to antigen heterogeneity, suboptimal CAR T-cell trafficking, and the immunosuppressive features of the tumor microenvironment (TME). Oncolytic virotherapy is a novel cancer therapy that employs competent or genetically modified oncolytic viruses (OVs) to preferentially proliferate in tumor cells. OVs in combination with CAR T-cells are promising candidates for overcoming the current drawbacks of CAR T-cell application in tumors through triggering immunogenic cell death (ICD) in cancer cells. ICD is a type of cellular death in which danger-associated molecular patterns (DAMPs) and tumor-specific antigens are released, leading to the stimulation of potent anti-cancer immunity. In the present review, we discuss the biological causes of ICD, different types of ICD, and the synergistic combination of OVs and CAR T-cells to reach potent tumor-specific immunity.
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Affiliation(s)
- Amirhossein Mardi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Anastasia V Shirokova
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Science, Cihan University of Sulaimaniya, Suleimanyah, Kurdistan region, Iraq.,College of. Veterinary Medicine, University of Sulaimani, Suleimanyah, Iraq
| | - Ali Keshavarz
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Talar Ahmad Merza Mohamad
- Department of Pharmacology and Toxicology, Clinical Pharmacy, Hawler Medical University, College of Pharmacy, Kurdistan Region-Erbil, Iraq
| | - Faroogh Marofi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. .,Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Swoboda J, Mittelsdorf P, Chen Y, Weiskirchen R, Stallhofer J, Schüle S, Gassler N. Intestinal Wnt in the transition from physiology to oncology. World J Clin Oncol 2022; 13:168-185. [PMID: 35433295 PMCID: PMC8966512 DOI: 10.5306/wjco.v13.i3.168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 09/07/2021] [Accepted: 02/19/2022] [Indexed: 02/06/2023] Open
Abstract
Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
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Affiliation(s)
- Julia Swoboda
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Patrick Mittelsdorf
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Johannes Stallhofer
- Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital, Jena 07747, Germany
| | - Silke Schüle
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Jena 07747, Germany
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17
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Wnt signaling pathway in cancer immunotherapy. Cancer Lett 2022; 525:84-96. [PMID: 34740608 DOI: 10.1016/j.canlet.2021.10.034] [Citation(s) in RCA: 120] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 10/06/2021] [Accepted: 10/20/2021] [Indexed: 12/11/2022]
Abstract
Wnt/β-catenin signaling is a highly conserved pathway that regulates cell proliferation, differentiation, apoptosis, stem cell self-renewal, tissue homeostasis, and wound healing. Dysregulation of the Wnt pathway is intricately involved in almost all stages of tumorigenesis in various cancers. Through direct and/or indirect effects on effector T cells, T-regulatory cells, T-helper cells, dendritic cells, and other cytokine-expressing immune cells, abnormal activation of Wnt/β-catenin signaling benefits immune exclusion and hinders T-cell-mediated antitumor immune responses. Activation of Wnt signaling results in increased resistance to immunotherapies. In this review, we summarize the process by which Wnt signaling affects cancer and immune surveillance, and the potential for targeting the Wnt-signaling pathway via cancer immunotherapy.
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18
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Cristi F, Gutiérrez T, Hitt MM, Shmulevitz M. Genetic Modifications That Expand Oncolytic Virus Potency. Front Mol Biosci 2022; 9:831091. [PMID: 35155581 PMCID: PMC8826539 DOI: 10.3389/fmolb.2022.831091] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/06/2022] [Indexed: 12/20/2022] Open
Abstract
Oncolytic viruses (OVs) are a promising type of cancer therapy since they selectively replicate in tumor cells without damaging healthy cells. Many oncolytic viruses have progressed to human clinical trials, however, their performance as monotherapy has not been as successful as expected. Importantly, recent literature suggests that the oncolytic potential of these viruses can be further increased by genetically modifying the viruses. In this review, we describe genetic modifications to OVs that improve their ability to kill tumor cells directly, to dismantle the tumor microenvironment, or to alter tumor cell signaling and enhance anti-tumor immunity. These advances are particularly important to increase virus spread and reduce metastasis, as demonstrated in animal models. Since metastasis is the principal cause of mortality in cancer patients, having OVs designed to target metastases could transform cancer therapy. The genetic alterations reported to date are only the beginning of all possible improvements to OVs. Modifications described here could be combined together, targeting multiple processes, or with other non-viral therapies with potential to provide a strong and lasting anti-tumor response in cancer patients.
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Affiliation(s)
- Francisca Cristi
- Shmulevitz Laboratory, Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Tomás Gutiérrez
- Goping Laboratory, Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Mary M. Hitt
- Hitt Laboratory, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Mary M. Hitt, ; Maya Shmulevitz,
| | - Maya Shmulevitz
- Shmulevitz Laboratory, Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
- *Correspondence: Mary M. Hitt, ; Maya Shmulevitz,
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19
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Rahman MM, McFadden G. Oncolytic Viruses: Newest Frontier for Cancer Immunotherapy. Cancers (Basel) 2021; 13:5452. [PMID: 34771615 PMCID: PMC8582515 DOI: 10.3390/cancers13215452] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer remains a leading cause of death worldwide. Despite many signs of progress, currently available cancer treatments often do not provide desired outcomes for too many cancers. Therefore, newer and more effective therapeutic approaches are needed. Oncolytic viruses (OVs) have emerged as a novel cancer treatment modality, which selectively targets and kills cancer cells while sparing normal ones. In the past several decades, many different OV candidates have been developed and tested in both laboratory settings as well as in cancer patient clinical trials. Many approaches have been taken to overcome the limitations of OVs, including engineering OVs to selectively activate anti-tumor immune responses. However, newer approaches like the combination of OVs with current immunotherapies to convert "immune-cold" tumors to "immune-hot" will almost certainly improve the potency of OVs. Here, we discuss strategies that are explored to further improve oncolytic virotherapy.
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Affiliation(s)
- Masmudur M. Rahman
- Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA;
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20
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Xu JQ, Tang N, Zhang LF, Tan C, Su Y, George DM, He GX, Huang TL. A bibliometric analysis of Wnt signaling pathway: from the top-100 cited articles to emerging trends. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1065. [PMID: 34422977 PMCID: PMC8339812 DOI: 10.21037/atm-21-174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/02/2021] [Indexed: 11/07/2022]
Abstract
Background Wnt signaling pathway plays a vital role in the regulation of development. An increasing number of articles about Wnt pathway components have been published. By analyzing these studies’ characteristics and qualities, we aim to reveal the current research focus and emerging trends in Wnt signaling. Methods The databases of Web of Science Core Collection, BIOSIS Citation Index, MEDLINE, etc. were utilized to identify articles on May 23rd, 2020. Wnt signaling pathway-related articles were identified, the 100 most cited articles and articles in the last decade were selected and calculated for citations without self-citation. The subsequent analysis included citation density (citations/article age), time-related flux, authorship, institution, journal, geographic distribution, and theme. Results These articles were published mainly from 2000 to 2009 (62%). Citations per article ranged from 599 to 3,780 with a median number of 880 times. Most studies (66%) came from the United States. Nusse Roel and Clevers Hans (15 and 13 papers) have contributed significantly to the field. The most highlighted study themes were cancer (15%), embryo development (14%), and cytoplasm signal transduction (11%). From 2011 to 2020, interest in emerging subtopics, including osteogenesis, immune, apoptosis, autophagy, microRNA, and cancer stem cell, are rising. Conclusions Cancer, embryo development, stem cell, and signal transduction process still play a major role in the field. With multiple emerging subtopics and investigation on an integrated view of the Wnt signal network, the association of Wnt with diseases was further revealed.
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Affiliation(s)
- Jia-Qi Xu
- Orthopaedic Department, The Second Xiangya Hospital of Central South University, Changsha, China.,Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Ning Tang
- Orthopaedic Department, The Second Xiangya Hospital of Central South University, Changsha, China
| | | | - Chen Tan
- Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Yang Su
- Orthopaedic Department, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Daniel M George
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Guang-Xu He
- Orthopaedic Department, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Tian-Long Huang
- Orthopaedic Department, The Second Xiangya Hospital of Central South University, Changsha, China
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21
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Kamynina M, Tskhovrebova S, Fares J, Timashev P, Laevskaya A, Ulasov I. Oncolytic Virus-Induced Autophagy in Glioblastoma. Cancers (Basel) 2021; 13:cancers13143482. [PMID: 34298694 PMCID: PMC8304501 DOI: 10.3390/cancers13143482] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 01/20/2023] Open
Abstract
Simple Summary Glioblastoma (GBM) is the most common and aggressive brain tumor with an incidence rate of nearly 3.19/100,000. Current therapeutic options fall short in improving the survival of patients with GBM. Various genetic and microenvironmental factors contribute to GBM progression and resistance to therapy. The development of gene therapies using self-replicating oncolytic viruses can advance GBM treatment. Due to GBM heterogeneity, oncolytic viruses have been genetically modified to improve the antiglioma effect in vitro and in vivo. Oncolytic viruses can activate autophagy signaling in GBM upon tumoral infection. Autophagy can be cytoprotective, whereby the GBM cells catabolize damaged organelles to accommodate to virus-induced stress, or cytotoxic, whereby it leads to the destruction of GBM cells. Understanding the molecular mechanisms that control oncolytic virus-induced autophagic signaling in GBM can fuel further development of novel and more effective genetic vectors. Abstract Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death.
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Affiliation(s)
- Margarita Kamynina
- Group of Experimental Biotherapy and Diagnostic, Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (M.K.); (S.T.); (A.L.)
| | - Salome Tskhovrebova
- Group of Experimental Biotherapy and Diagnostic, Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (M.K.); (S.T.); (A.L.)
| | - Jawad Fares
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia;
- Department of Polymers and Composites, N. N. Semenov Institute of Chemical Physics, 119991 Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia
| | - Anastasia Laevskaya
- Group of Experimental Biotherapy and Diagnostic, Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (M.K.); (S.T.); (A.L.)
| | - Ilya Ulasov
- Group of Experimental Biotherapy and Diagnostic, Institute for Regenerative Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (M.K.); (S.T.); (A.L.)
- Correspondence:
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Wang Y, Huang P, Hu Y, Guo K, Jia X, Huang B, Liu X, He X, Huang F. An oncolytic adenovirus delivering TSLC1 inhibits Wnt signaling pathway and tumor growth in SMMC-7721 xenograft mice model. Acta Biochim Biophys Sin (Shanghai) 2021; 53:766-774. [PMID: 33928346 DOI: 10.1093/abbs/gmab048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Indexed: 11/13/2022] Open
Abstract
Tumor suppressor in lung cancer-1 (TSLC1) was first identified as a tumor suppressor for lung cancer, and frequently downregulated in various types of cancers including hepatocellular carcinoma (HCC). The Wnt pathway plays a critical role in tumorigenesis, migration, and invasion in HCC. However, the function of TSLC1 in modulating Wnt signaling in HCC is unclear. In this study, we evaluated the effect of TSLC1-armed oncolytic adenovirus (S24-TSLC1) on the Wnt/β-catenin pathway, cell viability, invasion and migration abilities of HCC in vitro and the growth of SMMC-7721-xenografted tumor in mice model. We detected the expression of TSLC1 in tumor samples and HCC cell lines. The results showed that TSLC1 expression was low in HCC, but high in pericarcinomatous tissue and normal cells, which implied that TSLC1 is a tumor suppressor of liver cancer. S24-TSLC1 exhibited an antitumor effect on HCC cell growth in vitro, but did little damage to normal liver cells. Overexpression of TSLC1 downregulated the transcriptional activity of TCF4/β-catenin and inhibited the mRNA or protein expression of Wnt target genes cyclinD1 and c-myc. S24-TSLC1 also inhibited the invasion and migration of HCC cells. Animal experiments further confirmed that S24-TSLC1 significantly inhibited tumor growth of the SMMC-7721-xenografted tumor. In conclusion, TSLC1 could downregulate the Wnt signal pathway and suppress HCC cell growth, migration and invasion, suggesting that S24-TSLC1 may be a potent antitumor agent for future clinical trials in liver cancer treatment.
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Affiliation(s)
- Yigang Wang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Panpan Huang
- School of Basic Medicine, Gannan Medical University, Ganzhou 341000, China
| | - Yanping Hu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Keni Guo
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Xiaoyuan Jia
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Biao Huang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
| | - Xinyuan Liu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
- State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xianglei He
- Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou 311402, China
| | - Fang Huang
- Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou 311402, China
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23
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Zhang J, Song Q, Wu M, Zheng W. The Emerging Roles of Exosomes in the Chemoresistance of Hepatocellular Carcinoma. Curr Med Chem 2021; 28:93-109. [PMID: 32000636 DOI: 10.2174/0929867327666200130103206] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 10/08/2019] [Accepted: 10/23/2019] [Indexed: 11/22/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common gastrointestinal malignancy with a leading incidence of cancer-related mortality worldwide. Despite the progress of treatment options, there remains low efficacy for patients with intermediate-advanced HCC, due to tumor metastasis, recurrence and chemoresistance. Increasing evidence suggests that exosomes in the tumor microenvironment (TME), along with other extracellular vesicles (EVs) and cytokines, contribute to the drug chemosensitivity of cancer cells. Exosomes, the intercellular communicators in various biological activities, have shown to play important roles in HCC progression. This review summarizes the underlying associations between exosomes and chemoresistance of HCC cells. The exosomes derived from distinct cell types mediate the drug resistance by regulating drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) properties, autophagic phenotypes, as well as the immune response. In summary, TME-related exosomes can be a potential target to reverse chemoresistance and a candidate biomarker of drug efficacy in HCC patients.
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Affiliation(s)
- Jie Zhang
- Department of Chemotherapy, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Qianqian Song
- Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, Winston-Salem, 27157 NC, United States
| | - Mengna Wu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
| | - Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China
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24
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Yoshida H, Sato-Dahlman M, Hajeri P, Jacobsen K, Koodie L, Yanagiba C, Shanley R, Yamamoto M. Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells. Transl Oncol 2021; 14:100997. [PMID: 33338875 PMCID: PMC7749408 DOI: 10.1016/j.tranon.2020.100997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 12/09/2020] [Indexed: 11/20/2022] Open
Abstract
The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.
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Affiliation(s)
- Hideki Yoshida
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
| | - Mizuho Sato-Dahlman
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States
| | - Praveensingh Hajeri
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
| | - Kari Jacobsen
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
| | - Lisa Koodie
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
| | - Chikako Yanagiba
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
| | - Ryan Shanley
- Masonic Cancer Center, Biostatistics Core, University of Minnesota, Minneapolis, MN 55455, United States
| | - Masato Yamamoto
- Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, United States.
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25
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Jin KT, Tao XH, Fan YB, Wang SB. Crosstalk between oncolytic viruses and autophagy in cancer therapy. Biomed Pharmacother 2020; 134:110932. [PMID: 33370632 DOI: 10.1016/j.biopha.2020.110932] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/15/2020] [Accepted: 10/22/2020] [Indexed: 02/06/2023] Open
Abstract
Oncolytic viruses have attracted attention as a promising strategy in cancer therapy owing to their ability to selectively infect and kill tumor cells, without affecting healthy cells. They also exert their anti-tumor effects by releasing immunostimulatory molecules from dying cancer cells. Several regulatory mechanisms, such as autophagy, contribute to the anti-tumor properties of oncolytic viruses. Autophagy is a conserved catabolic process in responses to various stresses, such as nutrient deprivation, hypoxia, and infection that produces energy by lysosomal degradation of intracellular contents. Autophagy can support infectivity and replication of the oncolytic virus and enhance their anti-tumor effects via mediating oncolysis, autophagic cell death, and immunogenic cell death. On the other hand, autophagy can reduce the cytotoxicity of oncolytic viruses by providing survival nutrients for tumor cells. In his review, we summarize various types of oncolytic viruses in clinical trials, their mechanism of action, and autophagy machinery. Furthermore, we precisely discuss the interaction between oncolytic viruses and autophagy in cancer therapy and their combinational effects on tumor cells.
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Affiliation(s)
- Ke-Tao Jin
- Department of Colorectal Surgery, Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang Province, PR China
| | - Xiao-Hua Tao
- Department of Dermatology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, PR China
| | - Yi-Bin Fan
- Department of Dermatology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, PR China.
| | - Shi-Bing Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, PR China.
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26
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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27
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Praharaj PP, Panigrahi DP, Bhol CS, Patra S, Mishra SR, Mahapatra KK, Behera BP, Singh A, Patil S, Bhutia SK. Mitochondrial rewiring through mitophagy and mitochondrial biogenesis in cancer stem cells: A potential target for anti-CSC cancer therapy. Cancer Lett 2020; 498:217-228. [PMID: 33186655 DOI: 10.1016/j.canlet.2020.10.036] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/12/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Cancer stem cells (CSCs) are distinct subpopulations of cancer cells with stem cell-like abilities and are more resilient to chemotherapy, causing tumor relapse. Mitophagy, a selective form of autophagy, removes damaged unwanted mitochondria from cells through a lysosome-based degradation pathway to maintain cellular homeostasis. CSCs use mitophagy as a chief survival response mechanism for their growth, propagation, and tumorigenic ability. Mitochondrial biogenesis is a crucial cellular event replacing damaged mitochondria through the coordinated regulation of several transcription factors to achieve the bioenergetic demands of the cell. Because of the high mitochondrial content in CSCs, mitochondrial biogenesis is an interesting target to address the resistance mechanisms of anti-CSC therapy. However, to what extent both mitophagy and mitochondrial biogenesis are vital in promoting stemness, metabolic reprogramming, and drug resistance in CSCs has yet to be established. Therefore, in this review, we focus on understanding the interesting aspects of mitochondrial rewiring that involve mitophagy and mitochondrial biogenesis in CSCs. We also discuss their coordinated regulation in the elimination of CSCs, with respect to stemness and differentiation of the CSC phenotype, and the different aspects of tumorigenesis such as cancer initiation, progression, resistance, and tumor relapse. Finally, we address several other unanswered questions relating to targeted anti-CSC cancer therapy, which improves patient survival.
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Affiliation(s)
- Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Chandra Sekhar Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Soumya Ranjan Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Kewal Kumar Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Bishnu Prasad Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Amruta Singh
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
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28
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Zhong Y, Qi H, Li X, An M, Shi Q, Qi J. Tumor supernatant derived from hepatocellular carcinoma cells treated with vincristine sulfate have therapeutic activity. Eur J Pharm Sci 2020; 155:105557. [PMID: 32946955 DOI: 10.1016/j.ejps.2020.105557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/03/2020] [Accepted: 09/13/2020] [Indexed: 12/11/2022]
Abstract
Vincristine sulfate (VCR), a commonly used chemotherapeutic agent, kills cancer cells as well as the normal cells for its cytotoxicity. But it is still unclear whether it can exert therapeutic effect on untreated cancer cells by changing the supernatant of cancer cells. Here, we explored the subsequent cascade effects of the supernatant of cancer cells that were transiently treated with VCR on untreated tumor cells and its responsible mechanisms. VCR and three different hepatocellular carcinoma (HCC) cell lines were used for an experiment. The experiment was conducted in vitro to eliminate the body's internal factors and the effects of the immune system. The results suggested that drug-free tumor supernatant (TSN) could promote the differentiation, repress the transcription of liver cancer stem cell's markers and the proliferation in SMMC-7721, Bel-7402 and Huh7 cells. Furthermore, we found that the TSN could abolish YAP1 transcriptional activity to inhibit the proliferation and increase the transcriptional activity of HNF4α to promote the differentiation in SMMC-7721 and Bel-7402 cells. In conclusion, the TSN could inhibit the proliferation and induce differentiation in different HCC cells.
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Affiliation(s)
- Yan Zhong
- School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China
| | - Huanli Qi
- Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Xuejiao Li
- Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Mengyang An
- Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Qingwen Shi
- School of Pharmaceutical Sciences, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang 050017, China.
| | - Jinsheng Qi
- Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050017, China.
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29
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Mandhair HK, Arambasic M, Novak U, Radpour R. Molecular modulation of autophagy: New venture to target resistant cancer stem cells. World J Stem Cells 2020; 12:303-322. [PMID: 32547680 PMCID: PMC7280868 DOI: 10.4252/wjsc.v12.i5.303] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/19/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a highly regulated catabolic process in which superfluous, damaged organelles and other cytoplasmic constituents are delivered to the lysosome for clearance and the generation of macromolecule substrates during basal or stressed conditions. Autophagy is a bimodal process with a context dependent role in the initiation and the development of cancers. For instance, autophagy provides an adaptive response to cancer stem cells to survive metabolic stresses, by influencing disease propagation via modulation of essential signaling pathways or by promoting resistance to chemotherapeutics. Autophagy has been implicated in a cross talk with apoptosis. Understanding the complex interactions provides an opportunity to improve cancer therapy and the clinical outcome for the cancer patients. In this review, we provide a comprehensive view on the current knowledge on autophagy and its role in cancer cells with a particular focus on cancer stem cell homeostasis.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Miroslav Arambasic
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland.
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30
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Zeng Y, Guo Z, Hu Z, Liu M, Chen Y, Chen S, Peng B, Zhang P, Wu Z, Luo H, Zhong F, Jiang K, Lu Y, Yuan G, He S. FGD1 exhibits oncogenic properties in hepatocellular carcinoma through regulating cell morphology, autophagy and mitochondrial function. Biomed Pharmacother 2020; 125:110029. [PMID: 32106378 DOI: 10.1016/j.biopha.2020.110029] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 02/12/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022] Open
Abstract
Faciogenital Dysplasia 1 (FGD1) has been involved in a variety of biological processes, including cytoskeleton restructuring, cell morphology, cell cycle progression, and cell polarity. Abnormal expression of FGD1 was also identified in several types of cancers, indicating its critical role in the development of cancers. However, little is known about the role of FGD1 in hepatocellular carcinoma (HCC). In this study, the expression of FGD1 in HCC was mined with the RNA sequencing data from the cancer genome atlas. By over-expressing or knocking down of FGD1, the effects of FGD1 on the malignant behavior of HCC were evaluated both in vitro and in vivo. We find that FGD1 is up-regulated in HCC and correlated with the development and prognosis of HCC. By over-expressing or knocking down of FGD1, the effects of FGD1 on the malignant behavior of HCC were evaluated both in vitro and in vivo. Knockdown of FGD1 remarkably inhibits the malignant behaviors and causes morphological disorder of pseudopodia, autophagy inhibition and mitochondrial dyfunction in HCC cells. Further investigation shows that Cdc42, a Rho GTPase, plays a role in these processes. Overexpression of FGD1 significantly promotes the oncogenic properties of HCC cells. Collectively, these findings reveal that FGD1 exhibits oncogenic properties in HCC through regulating cell morphology, autophagy and mitochondrial function, suggesting that FGD1 may serve as a potential therapeutic target for HCC.
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Affiliation(s)
- Yonglian Zeng
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China; Basic Medical School of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhenya Guo
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhigao Hu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Mingjiang Liu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yubing Chen
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Shilian Chen
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Bo Peng
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Peng Zhang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhan Wu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Hongliang Luo
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Fudi Zhong
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Keqing Jiang
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yi Lu
- School of Medicine, Southern University of Science and Technology, 1088 Xili Xueyuan Avenue, Shenzhen, 518055, Guangdong, China.
| | - Guandou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Songqing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
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31
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Zhang YN, Wang SB, Song SS, Hu PY, Zhou YC, Mou YP, Mou XZ. Recent advances in targeting cancer stem cells using oncolytic viruses. Biotechnol Lett 2020; 42:865-874. [DOI: 10.1007/s10529-020-02857-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/27/2020] [Indexed: 12/22/2022]
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32
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Wu Y, Zhang J, Zhang X, Zhou H, Liu G, Li Q. Cancer Stem Cells: A Potential Breakthrough in HCC-Targeted Therapy. Front Pharmacol 2020; 11:198. [PMID: 32210805 PMCID: PMC7068598 DOI: 10.3389/fphar.2020.00198] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are subpopulations of cells with stem cell characteristics that produce both cancerous and non-tumorigenic cells in tumor tissues. The literature reports that CSCs are closely related to the development of hepatocellular carcinoma (HCC) and promote the malignant features of HCC such as high invasion, drug resistance, easy recurrence, easy metastasis, and poor prognosis. This review discusses the origin, molecular, and biological features, functions, and applications of CSCs in HCC in recent years; the goal is to clarify the importance of CSCs in treatment and explore their potential value in HCC-targeted therapy.
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33
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Abudoureyimu M, Lai Y, Tian C, Wang T, Wang R, Chu X. Oncolytic Adenovirus-A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC. Front Oncol 2019; 9:1182. [PMID: 31781493 PMCID: PMC6857090 DOI: 10.3389/fonc.2019.01182] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/21/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, particularly in China. Despite the development of HCC treatment strategies, the survival rate remains unpleasant. Gene-targeted oncolytic viral therapy (GTOVT) is an emerging treatment modality-a kind of cancer-targeted therapy-which creates viral vectors armed with anti-cancer genes. The adenovirus is a promising agent for GAOVT due to its many advantages. In spite of the oncolytic adenovirus itself, the host immune response is the determining factor for the anti-cancer efficacy. In this review, we have summarized recent developments in oncolytic adenovirus engineering and the development of novel therapeutic genes utilized in HCC treatment. Furthermore, the diversified roles the immune response plays in oncolytic adenovirus therapy and recent attempts to modulate immune responses to enhance the anti-cancer efficacy of oncolytic adenovirus have been discussed.
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Affiliation(s)
- Mubalake Abudoureyimu
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Yongting Lai
- Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing, China
| | - Chuan Tian
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Ting Wang
- Department of Medical Oncology, Jinling Hospital, Nanjing, China
| | - Rui Wang
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Xiaoyuan Chu
- Department of Medical Oncology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
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Feng L, Huang S, An G, Wang G, Gu S, Zhao X. Identification of new cancer stem cell markers and signaling pathways in HER‑2‑positive breast cancer by transcriptome sequencing. Int J Oncol 2019; 55:1003-1018. [PMID: 31545416 PMCID: PMC6776190 DOI: 10.3892/ijo.2019.4876] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/06/2019] [Indexed: 12/17/2022] Open
Abstract
Human epidermal growth factor receptor (HER)‑2‑positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER‑2‑positive breast cancer. CD44+/CD24‑/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24‑/low cells was almost zero in SK‑BR‑3 cells; however, it was >90% in MDA‑MB‑231 cells, as determined by flow cytometry. Since SK‑BR‑3 and MDA‑MB‑231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK‑BR‑3 cells. Therefore, transcriptome sequencing was performed for SK‑BR‑3 and MDA‑MB‑231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK‑BR‑3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK‑BR‑3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription‑polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER‑2‑positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of β‑catenin in the Wnt signaling pathway was lower in SK‑BR‑3 cells compared with in MDA‑MB‑231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER‑2‑positive breast cancer.
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Affiliation(s)
- Lu Feng
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Gaili An
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Guanying Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shanzhi Gu
- College of Forensic Medicine, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
| | - Xinhan Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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35
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Luo T, Chen M, Zhao Y, Wang D, Liu J, Chen J, Luo H, Li L. Macrophage-associated lncRNA ELMO1-AS1: a novel therapeutic target and prognostic biomarker for hepatocellular carcinoma. Onco Targets Ther 2019; 12:6203-6216. [PMID: 31498334 PMCID: PMC6689543 DOI: 10.2147/ott.s213833] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/22/2019] [Indexed: 12/11/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is a prevalent malignant tumor. Long non-coding RNAs (lncRNAs) have been demonstrated to be abnormally expressed in many tumors and act as crucial regulators in various biological processes. However, the expression and function of the recently identified macrophage-associated lncRNA ELMO1 antisense RNA 1 (ELMO1-AS1) in HCC are unclear. Methods The expression of ELMO1-AS1 was determined in HCC tissues and adjacent nontumorous tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The Kaplan-Meier survival analysis and Cox regression analysis were performed to establish the correlation between the expression level and survival of HCC patients in a training set and a validation set, respectively. The overexpression experiments were also conducted to investigate the biological role of ELMO1-AS1 in HCC cells. Results We uncovered that ELMO1-AS1 was significantly downregulated in HCC tissues, and high expression of ELMO1-AS1 is correlated with optimistic treatment outcome suggesting its potential as an independent prognostic biomarker for HCC. It was also found that overexpression of ELMO1-AS1 in HCC cells suppressed cell proliferation, migration and invasion and engulfment and cell motility 1 (ELMO1) may be a target of ELMO1-AS1. Conclusion Our results suggested that macrophage-associated lncRNA ELMO1-AS1 could be a crucial regulator involved in HCC progression and considered as a potential prognostic biomarker and therapeutic target for HCC.
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Affiliation(s)
- Tao Luo
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, People's Republic of China
| | - Miao Chen
- Department of Ultrasound, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province 530021, People's Republic of China
| | - Yuan Zhao
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, People's Republic of China
| | - Duo Wang
- Department of Ultrasound, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province 530021, People's Republic of China
| | - Junjie Liu
- Department of Ultrasound, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province 530021, People's Republic of China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, People's Republic of China
| | - Honglin Luo
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, People's Republic of China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, People's Republic of China
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Abstract
Gene therapy is emerging as a viable option for clinical therapy of monogenic disorders and other genetically defined diseases, with approved gene therapies available in Europe and newly approved gene therapies in the United States. In the past 10 years, gene therapy has moved from a distant possibility, even in the minds of much of the scientific community, to being widely realized as a valuable therapeutic tool with wide-ranging potential. The U.S. Food and Drug Administration has recently approved Luxturna (Spark Therapeutics Inc, Philadelphia, PA, USA), a recombinant adeno-associated virus (rAAV) 2 gene therapy for one type of Leber congenital amaurosis 2 ( 1 , 2 ). The European Medicines Agency (EMA) has approved 3 recombinant viral vector products: Glybera (UniQure, Amsterdam, The Netherlands), an rAAV vector for lipoprotein lipase deficiency; Strimvelis (Glaxo Smith-Kline, Brentford, United Kingdom), an ex vivo gammaretrovirus-based therapy for patients with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID); and Kymriah (Novartis, Basel, Switzerland), an ex vivo lentivirus-based therapy to engineer autologous chimeric antigen-receptor T (CAR-T) cells targeting CD19-positive cells in acute lymphoblastic leukemia. These examples will be followed by the clinical approval of other gene therapy products as this field matures. In this review we provide an overview of the state of gene therapy by discussing where the field stands with respect to the different gene therapy vector platforms and the types of therapies that are available.-Gruntman, A. M., Flotte, T. R. The rapidly evolving state of gene therapy.
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Affiliation(s)
- Alisha M Gruntman
- Horae Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA.,Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA
| | - Terence R Flotte
- Horae Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Harrington K, Freeman DJ, Kelly B, Harper J, Soria JC. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov 2019; 18:689-706. [PMID: 31292532 DOI: 10.1038/s41573-019-0029-0] [Citation(s) in RCA: 337] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2019] [Indexed: 02/07/2023]
Abstract
In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
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Affiliation(s)
- Kevin Harrington
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
| | | | - Beth Kelly
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
| | | | - Jean-Charles Soria
- Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.,Department of Medicine and Medical Oncology, Université Paris-Sud, Orsay, France
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Zhu L, Li T, Shen Y, Yu X, Xiao B, Guo J. Using tRNA halves as novel biomarkers for the diagnosis of gastric cancer. Cancer Biomark 2019; 25:169-176. [DOI: 10.3233/cbm-182184] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Linwen Zhu
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
| | - Tianwen Li
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yijing Shen
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
| | - Xiuchong Yu
- Department of Gastrointestinal Surgery, Ningbo No. 1 Hospital and the Affiliated Hospital of Medical School of Ningbo University, Ningbo, Zhejiang 315010, China
| | - Bingxiu Xiao
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
| | - Junming Guo
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, Zhejiang 315211, China
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Espelt MV, Bacigalupo ML, Carabias P, Troncoso MF. MicroRNAs contribute to ATP-binding cassette transporter- and autophagy-mediated chemoresistance in hepatocellular carcinoma. World J Hepatol 2019; 11:344-358. [PMID: 31114639 PMCID: PMC6504855 DOI: 10.4254/wjh.v11.i4.344] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has an elevated mortality rate, largely because of high recurrence and metastasis. Additionally, the main obstacle during treatment of HCC is that patients usually develop resistance to chemotherapy. Cancer drug resistance involves many different mechanisms, including alterations in drug metabolism and processing, impairment of the apoptotic machine, activation of cell survival signaling, decreased drug sensitivity and autophagy, among others. Nowadays, miRNAs are emerging as master regulators of normal physiology- and tumor-related gene expression. In HCC, aberrant expression of many miRNAs leads to chemoresistance. Herein, we particularly analyzed miRNA impact on HCC resistance to drug therapy. Certain miRNAs target ABC (ATP-binding cassette) transporter genes. As most of these miRNAs are downregulated in HCC, transporter levels increase and intracellular drug accumulation decrease, turning cells less sensitive to death. Others miRNAs target autophagy-related gene expression, inhibiting autophagy and acting as tumor suppressors. Nevertheless, due to its downregulation in HCC, these miRNAs do not inhibit autophagy or tumor growth and, resistance is favored. Concluding, modulation of ABC transporter and/or autophagy-related gene expression or function by miRNAs could be determinant for HCC cell survival under chemotherapeutic drug treatment. Undoubtedly, more insights on the biological processes, signaling pathways and/or molecular mechanisms regulated by miRNAs are needed. Anyway, miRNA-based therapy together with conventional chemotherapeutic drugs has a great future in cancer therapy.
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Affiliation(s)
- María V Espelt
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - María L Bacigalupo
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - Pablo Carabias
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina
| | - María F Troncoso
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires C1113AAD, Argentina.
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Hartsough EJ, Weiss MB, Heilman SA, Purwin TJ, Kugel CH, Rosenbaum SR, Erkes DA, Tiago M, HooKim K, Chervoneva I, Aplin AE. CADM1 is a TWIST1-regulated suppressor of invasion and survival. Cell Death Dis 2019; 10:281. [PMID: 30911007 PMCID: PMC6433918 DOI: 10.1038/s41419-019-1515-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 03/05/2019] [Accepted: 03/07/2019] [Indexed: 12/11/2022]
Abstract
Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Increased expression of CADM1 resulted in significant inhibition of motility and invasiveness of melanoma cells. In addition, elevated CADM1 elicited caspase-independent cell death in non-adherent conditions. Expression array analysis suggests that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Importantly, tissue microarray analysis and clinical data from TCGA indicate that CADM1 expression is inversely associated with melanoma progression and positively correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be considered a biomarker for favorable prognosis.
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Affiliation(s)
- Edward J Hartsough
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.,Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, 19107, USA.,Department of Pharmacology and Physiology at Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Michele B Weiss
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Shea A Heilman
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Timothy J Purwin
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Curtis H Kugel
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Sheera R Rosenbaum
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Dan A Erkes
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Manoela Tiago
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Kim HooKim
- Departments of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Inna Chervoneva
- Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, 19107, USA.,Division of Biostatistics in Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Andrew E Aplin
- Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA. .,Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, 19107, USA.
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Zhu L, Yang N, Du G, Li C, Liu G, Liu S, Xu Y, Di Y, Pan W, Li X. LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β-catenin signaling pathway. J Cell Biochem 2019; 120:1156-1164. [PMID: 30430650 PMCID: PMC6587876 DOI: 10.1002/jcb.26762] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 01/31/2018] [Indexed: 01/24/2023]
Abstract
Colorectal neoplasia differentially expressed (CRNDE) is a significantly upregulated long noncoding RNA in hepatocellular carcinoma (HCC). CRNDE could promote cell proliferation, migration, and invasion, while its molecular mechanisms were still largely unclear. In this study, we investigated the expression and function of CRNDE. CRNDE was significantly upregulated in tumor tissues compared with adjacent normal tissues. In vitro, we revealed that knockdown of CRNDE inhibited cell proliferation, migration, and cell invasion capacities in HCC. Animal studies indicated that CRNDE knockdown represses both growth and metastasis of HCC tumors in vivo. Moreover, knockdown of CRNDE suppressed the cell epithelial-mesenchymal transition (EMT) process by increasing the expression of E-cadherin and ZO-1, whereas, decreasing the expression of N-cadherin, slug, twist, and vimentin in HCC cells. We also revealed that knockdown of CRNDE suppressed the Wnt/β-catenin signaling in HCC. Thus, CRNDE could modulate EMT of HCC cells and knockdown of CRNDE impaired the mesenchymal properties. CRNDE increased invasion of HCC cells might be through activating the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Liying Zhu
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Nenghong Yang
- Department of Hepatobiliary SurgerySurgery, Affiliated Hospital of Guizhou Medical UniversityGuiyangChina
| | - Guiqin Du
- The First People's Hospital of GuiyangGuiyangGuizhouChina
| | - Chengcheng Li
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Guoqi Liu
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Shengju Liu
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Yongjie Xu
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Yanan Di
- Department of Clinical Laboratory MedicineBeifang Hospital of China North Industries Group CorporationBeijingChina
| | - Wei Pan
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
| | - Xing Li
- Department of Medical LaboratoryAffiliated Hospital of Guizhou Medical UniversityGuiyangGuizhouChina
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42
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Li N, Zhu Y. Targeting liver cancer stem cells for the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol 2019; 12:1756284818821560. [PMID: 30719075 PMCID: PMC6348509 DOI: 10.1177/1756284818821560] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 11/15/2018] [Indexed: 02/04/2023] Open
Abstract
Liver cancer is one of the most common malignant tumors and prognosis remains poor. It has been increasingly recognized that liver cancer stem cells (LCSCs) are responsible for the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). Targeting LCSCs is promising to be a new direction for the treatment of HCC. Herein, we summarize the potentially therapeutic targets in LCSCs at the level of genes, molecules and cells, such as knockout of oncogenes or oncoproteins, restoring the silent tumor suppressor genes, inhibition of the transcription factors and regulation of noncoding RNAs (including microRNAs and long noncoding RNAs) in LCSCs at the genetic level; inhibition of markers and blockade of the key signaling pathways of LCSCs at the molecular level; and inhibiting autophagy and application of oncolytic adenoviruses in LCSCs at the cellular level. Moreover, we analyze the potential targets in LCSCs to eliminate chemoresistance of HCC. Thereinto, the suppression of autophagy and Nanog by chloroquine and shRNA respectively may be the most promising targeting approaches. These targets may provide novel therapeutic strategies for the treatment of HCC by targeting LCSCs.
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Affiliation(s)
- Na Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
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43
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Huang F, Wang BR, Wang YG. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol 2018; 24:4643-4651. [PMID: 30416312 PMCID: PMC6224467 DOI: 10.3748/wjg.v24.i41.4643] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/04/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a “self-degradative” process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.
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Affiliation(s)
- Fang Huang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Bing-Rong Wang
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
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44
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Kloker LD, Yurttas C, Lauer UM. Three-dimensional tumor cell cultures employed in virotherapy research. Oncolytic Virother 2018; 7:79-93. [PMID: 30234074 PMCID: PMC6130269 DOI: 10.2147/ov.s165479] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Oncolytic virotherapy constitutes an upcoming alternative treatment option for a broad spectrum of cancer entities. However, despite great research efforts, there is still only a single US Food and Drug Administration/European Medicines Agency-approved oncolytic virus available for clinical use. One reason for that is the gap between promising preclinical data and limited clinical success. Since oncolytic viruses are biological agents, they might require more realistic in vitro tumor models than common monolayer tumor cell cultures to provide meaningful predictive preclinical evaluation results. For more realistic invitro tumor models, three-dimensional tumor cell-culture systems can be employed in preclinical virotherapy research. This review provides an overview of spheroid and hydrogel tumor cell cultures, organotypic tumor-tissue slices, organotypic raft cultures, and tumor organoids utilized in the context of oncolytic virotherapy. Furthermore, we also discuss advantages, disadvantages, techniques, and difficulties of these three-dimensional tumor cell-culture systems when applied specifically in virotherapy research.
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Affiliation(s)
- Linus D Kloker
- Department of Clinical Tumor Biology, University Hospital, University of Tübingen, Tübingen, Germany,
| | - Can Yurttas
- Department of General, Visceral and Transplant Surgery, University Hospital, University of Tübingen, Tübingen, Germany
| | - Ulrich M Lauer
- Department of Clinical Tumor Biology, University Hospital, University of Tübingen, Tübingen, Germany, .,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Tübingen, Germany,
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Xie W, Hao J, Zhang K, Fang X, Liu X. Adenovirus armed with VGLL4 selectively kills hepatocellular carcinoma with G2/M phase arrest and apoptosis promotion. Biochem Biophys Res Commun 2018; 503:2758-2763. [PMID: 30119884 DOI: 10.1016/j.bbrc.2018.08.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 08/04/2018] [Indexed: 01/08/2023]
Abstract
The Vestigial-Like Family Member 4 (VGLL4) functions as a native inhibitor of cell proliferation and tumor growth through multiple signaling pathways. We first discovered that VGLL4 causes G2/M phase arrest in hepatocellular carcinoma (HCC) cells. Then, we designed a novel survivin-regulated oncolytic adenovirus Ad-sp-VGLL4 carrying the VGLL4 gene. Ad-sp-VGLL4 exerted high HCC-targeting-selectivity but is less harmful to normal cells. This adenovirus construction enhanced antitumor activity due to G2/M phase arrest and enhanced apoptosis. It's also indicated that Ad-sp-VGLL4 could suppress the growth of transplanted tumor of HCC in vivo experiment. Taken together, our results suggest that Ad-sp-VGLL4 possesses strong antitumor capacity and has great potential use for HCC therapy.
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Affiliation(s)
- Wenjie Xie
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, PR China.
| | - Jiali Hao
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, PR China.
| | - Kangjian Zhang
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China; Shanghai YuanSong Biological Technology Co., Ltd, No. 1588, Shanghai and Hangzhou Highway, Fengxian District, Shanghai, 201401, PR China.
| | - Xianlong Fang
- Shanghai YuanSong Biological Technology Co., Ltd, No. 1588, Shanghai and Hangzhou Highway, Fengxian District, Shanghai, 201401, PR China.
| | - Xinyuan Liu
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310018, PR China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, PR China; Shanghai YuanSong Biological Technology Co., Ltd, No. 1588, Shanghai and Hangzhou Highway, Fengxian District, Shanghai, 201401, PR China.
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Di Fazio P, Matrood S. Targeting autophagy in liver cancer. Transl Gastroenterol Hepatol 2018; 3:39. [PMID: 30148224 PMCID: PMC6088143 DOI: 10.21037/tgh.2018.06.09] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Autophagy is a catabolic cellular process conserved in animals. It is characterized by the main role of recycling all the non-functional products of the cells. Once, autophagy players detect non-functioning sub-cellular organelles and proteins, they start the so-called nucleation process. The organelles will be surrounded by a double membrane vesicle mainly constituted by endoplasmic reticulum (ER) membrane and autophagy proteins, e.g., MAP1LC3B, Beclin-1, VPS34, Unc-51 like autophagy activating kinase (ULK1) and ubiquitination-related proteins. Then the autophagic membrane will go through an elongation phase involving additional autophagy players. Once the autophagic vesicle is complete, the sub-cellular organelles will be isolated from the rest of the cytosol and driven to the final fusion with lysosomes. Here, the digestion process will end. Alteration and or impairment of autophagy have been shown to be correlated with development of diseases affecting the central nervous system, e.g., Alzheimer and other neurodegenerative diseases. Nonetheless, autophagy defect is responsible for tumorigenesis in blood and solid malignancies, in particular liver cancer. Malignancies of the liver are determined by several genetics and epigenetics mechanisms triggering the up-regulation of survival mechanisms and resistance to cell death. Furthermore, liver cancer could result from pathologic conditions like cirrhosis and fibrosis related to virus infection, aflatoxin, alcohol consumption and high fat diet together with insulin resistance. The role exerted by autophagy in the pathogenesis of the liver and tumor development has been evidenced in recent years. The alteration of autophagy assumes a fundamental role for liver tumorigenesis determining an accumulation of non-functional proteins and organelles that trigger oxidative stress leading to genotoxic stress and gene alterations. Furthermore, the absence of this degradation mechanism could prompt the cells to alter their metabolic status and turn into malignant cells. Interestingly, the heterozygous loss of function of Beclin-1 is able to trigger liver tumorigenesis or even the simple accumulation of proteins caused by the block of the final autolysosome fusion and degradation process is responsible for liver cancer development. This review highlights the importance of targeting the autophagy process in liver cancer in order to restore its function and to promote autophagy-mediated cell demise.
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Affiliation(s)
- Pietro Di Fazio
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany
| | - Sami Matrood
- Department of Visceral Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany
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Yao T, Chen Q, Shao Z, Song Z, Fu L, Xiao B. Circular RNA 0068669 as a new biomarker for hepatocellular carcinoma metastasis. J Clin Lab Anal 2018; 32:e22572. [PMID: 29785842 DOI: 10.1002/jcla.22572] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 04/20/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) play important roles in disease occurrence. However, the roles of circRNAs in the diagnosis of hepatocellular carcinoma (HCC) are largely unknown. The aim of this study is to investigate the clinical diagnostic values of hsa_circ_0068669 (Alias: hsa_circ_103561), one of the representative HCC-associated circRNAs. METHODS Hsa_circ_0068669 expression levels in HCC tissues, HCC cell lines, and chronic hepatitis tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Its expression levels between HCC tissues and adjacent non-tumorous tissues were analyzed using paired t test. Independent t test and one-way analysis of variance (ANOVA) were performed to analyze the relationships between hsa_circ_0068669 expression levels and clinicopathological factors of patients with HCC. A receiver operating characteristic (ROC) curve was established to estimate the value of hsa_circ_0068669 as a biomarker in HCC. RESULTS Hsa_circ_0068669 expression was significantly downregulated in HCC tissues and HCC cell lines compared with paired non-tumorous tissues and normal hepatic cell line, respectively. Moreover, hsa_circ_0068669 expression in HCC tissues was decreased comparing with chronic hepatitis tissues. Furthermore, hsa_circ_0068669 expression was correlated with microvascular invasion and TNM stages. CONCLUSIONS Our findings indicate that hsa_circ_0068669 might be served as a novel potential biomarker for HCC metastasis.
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Affiliation(s)
- Ting Yao
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
| | - Qingqing Chen
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
| | - Zhouwei Shao
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
| | - Zhihua Song
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
| | - Liyun Fu
- Ningbo No. 2 Hospital and the Affiliated Hospital, Medical School of Ningbo University, Ningbo, China
| | - Bingxiu Xiao
- Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo, China
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Katoh M. Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review). Int J Mol Med 2018; 42:713-725. [PMID: 29786110 PMCID: PMC6034925 DOI: 10.3892/ijmm.2018.3689] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/16/2018] [Indexed: 12/13/2022] Open
Abstract
β-catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E-cadherin/CDH1, N-cadherin/CDH2, VE-cadherin/CDH5 and α-catenins), transmembrane-type mucins (MUC1/CD227 and MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 and NHERF1/EBP50) and epigenetic or transcriptional regulators (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 and TCF/LEF). Gain-of-function CTTNB1 mutations are detected in bladder cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, pancreatic cancer, prostate cancer and uterine cancer, whereas loss-of-function CTNNB1 mutations are also detected in human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA and ZNRF3 are representative β-catenin target genes. β-catenin signaling is involved in myofibroblast activation and subsequent pulmonary fibrosis, in addition to other types of fibrosis. β-catenin and NF-κB signaling activation are involved in field cancerization in the stomach associated with Helicobacter pylori (H. pylori) infection and in the liver associated with hepatitis C virus (HCV) infection and other etiologies. β-catenin-targeted therapeutics are functionally classified into β-catenin inhibitors targeting upstream regulators (AZ1366, ETC-159, G007-LK, GNF6231, ipafricept, NVP-TNKS656, rosmantuzumab, vantictumab, WNT-C59, WNT974 and XAV939), β-catenin inhibitors targeting protein-protein interactions (CGP049090, CWP232228, E7386, ICG-001, LF3 and PRI-724), β-catenin inhibitors targeting epigenetic regulators (PKF118-310), β-catenin inhibitors targeting mediator complexes (CCT251545 and cortistatin A) and β-catenin inhibitors targeting transmembrane-type transcriptional outputs, including CD44v6, FZD7 and LGR5. Eradicating H. pylori and HCV is the optimal approach for the first-line prevention of gastric cancer and hepatocellular carcinoma (HCC), respectively. However, β-catenin inhibitors may be applicable for the prevention of organ fibrosis, second-line HCC prevention and treating β-catenin-driven cancer. The multi-layered prevention and treatment strategy of β-catenin-related human diseases is necessary for the practice of personalized medicine and implementation of precision medicine.
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Affiliation(s)
- Masaru Katoh
- Department of Omics Network, National Cancer Center, Chuo Ward, Tokyo 104‑0045, Japan
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Zhang Y, Mo WJ, Wang X, Zhang TT, Qin Y, Wang HL, Chen G, Wei DM, Dang YW. Microarray‑based bioinformatics analysis of the prospective target gene network of key miRNAs influenced by long non‑coding RNA PVT1 in HCC. Oncol Rep 2018; 40:226-240. [PMID: 29749550 PMCID: PMC6059745 DOI: 10.3892/or.2018.6410] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 04/17/2018] [Indexed: 12/12/2022] Open
Abstract
The long non-coding RNA (lncRNA) PVT1 plays vital roles in the tumorigenesis and development of various types of cancer. However, the potential expression profiling, functions and pathways of PVT1 in HCC remain unknown. PVT1 was knocked down in SMMC-7721 cells, and a miRNA microarray analysis was performed to detect the differentially expressed miRNAs. Twelve target prediction algorithms were used to predict the underlying targets of these differentially expressed miRNAs. Bioinformatics analysis was performed to explore the underlying functions, pathways and networks of the targeted genes. Furthermore, the relationship between PVT1 and the clinical parameters in HCC was confirmed based on the original data in the TCGA database. Among the differentially expressed miRNAs, the top two upregulated and downregulated miRNAs were selected for further analysis based on the false discovery rate (FDR), fold-change (FC) and P-values. Based on the TCGA database, PVT1 was obviously highly expressed in HCC, and a statistically higher PVT1 expression was found for sex (male), ethnicity (Asian) and pathological grade (G3+G4) compared to the control groups (P<0.05). Furthermore, Gene Ontology (GO) analysis revealed that the target genes were involved in complex cellular pathways, such as the macromolecule biosynthetic process, compound metabolic process, and transcription. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the MAPK and Wnt signaling pathways may be correlated with the regulation of the four candidate miRNAs. The results therefore provide significant information on the differentially expressed miRNAs associated with PVT1 in HCC, and we hypothesized that PVT1 may play vital roles in HCC by regulating different miRNAs or target gene expression (particularly MAPK8) via the MAPK or Wnt signaling pathways. Thus, further investigation of the molecular mechanism of PVT1 in HCC is needed.
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Affiliation(s)
- Yu Zhang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Wei-Jia Mo
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiao Wang
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China
| | - Tong-Tong Zhang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yuan Qin
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Han-Lin Wang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Gang Chen
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Dan-Ming Wei
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yi-Wu Dang
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Chen Y, Meng L, Shang H, Dou Q, Lu Z, Liu L, Wang Z, He X, Song Y. β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin. Cell Death Dis 2018; 9:424. [PMID: 29555987 PMCID: PMC5859291 DOI: 10.1038/s41419-018-0456-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 01/01/2018] [Accepted: 02/27/2018] [Indexed: 12/23/2022]
Abstract
βII-Spectrin (β2SP), a Smad3/4 adaptor protein during transforming growth factor (TGF) β/Smad signal pathway, plays a critical role in suppressing hepatocarcinogenesis. Dedifferentiation is a distinctive feature of cancer progression. Therefore, we investigated whether the disruption of β2SP contributed to tumorigenesis of hepatocellular carcinoma (HCC) through the dedifferentiation. Down-regulation of β2SP in hepatocytes was observed in cirrhotic liver and HCC. The level of β2SP expression was closely associated with the differentiation status of hepatocytes in rat model of hepatocarcinogenesis and clinical specimens. Transgenic expression of β2SP in HCC cells promoted the differentiation of HCC cells and suppressed the growth of HCC cells in vitro. Efficient transduction of β2SP into liver CSCs resulted in a reduction in colony formation ability, spheroid formation capacity, invasive activity, chemo-resistance properties, tumorigenicity in vivo. In addition, β2 spectrin exerted its effect through β catenin in liver CSCs. In conclusion, β2 spectrin repressed the properties of liver CSCs through inducing differentiation; thus, strategies to restore its levels and activities would be a novel strategy for HCC prevention and differentiation therapy.
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Affiliation(s)
- Yuhua Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lingling Meng
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Haitao Shang
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qian Dou
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhiwen Lu
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Liping Liu
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhijun Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xingxing He
- Institute of Liver Diseases, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yuhu Song
- Division of Gastroenterology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology, Wuhan, 430022, China.
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