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Alzahrani MS, Almutairy B, Althobaiti YS, Alsaab HO. Recent Advances in RNA Interference-Based Therapy for Hepatocellular Carcinoma: Emphasis on siRNA. Cell Biochem Biophys 2024; 82:1947-1964. [PMID: 38987439 DOI: 10.1007/s12013-024-01395-6] [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] [Accepted: 06/30/2024] [Indexed: 07/12/2024]
Abstract
Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.
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Affiliation(s)
- Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
| | - Yusuf S Althobaiti
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
- Addiction and Neuroscience Research Unit, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia.
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Ding Y, Chen QB, Xu H, Adi D, Ding YW, Luo WJ, Zhu WZ, Xu JC, Zhao X, Shi XJ, Luo J, Yin H, Lu XY. siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice. J Lipid Res 2024; 65:100626. [PMID: 39173829 PMCID: PMC11418111 DOI: 10.1016/j.jlr.2024.100626] [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: 06/30/2023] [Revised: 08/07/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open
Abstract
Atherosclerotic cardiovascular disease is closely correlated with elevated low density lipoprotein-cholesterol. In feeding state, glucose and insulin activate mammalian target of rapamycin 1 that phosphorylates the deubiquitylase ubiquitin-specific peptidase 20 (USP20). USP20 then stabilizes HMG-CoA reductase, thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity, and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.
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Affiliation(s)
- Yi Ding
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Qiu-Bing Chen
- Department of Urology, Frontier Science Center for Immunology and Metabolism Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Hui Xu
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Dilare Adi
- Heart Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yi-Wen Ding
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Wen-Jun Luo
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Wen-Zhuo Zhu
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Jia-Chen Xu
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Xiaolu Zhao
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Xiong-Jie Shi
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Jie Luo
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China
| | - Hao Yin
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China; Department of Urology, Frontier Science Center for Immunology and Metabolism Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Xiao-Yi Lu
- College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Taikang Center for Life and Medical Sciences, Taikang Medical School, Wuhan University, Wuhan, China.
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Zhang Q, Wu S, Chen Q, Zhang Y, Zhang C, Yin R, Ouyang Z, Wei Y. Reducing Oxidative Stress-Mediated Alcoholic Liver Injury by Multiplexed RNAi of Cyp2e1, Cyp4a10, and Cyp4a14. Biomedicines 2024; 12:1505. [PMID: 39062078 PMCID: PMC11274525 DOI: 10.3390/biomedicines12071505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/24/2024] [Accepted: 07/02/2024] [Indexed: 07/28/2024] Open
Abstract
The prevalence of excessive drinking-related alcoholic liver disease (ALD) is rising, yet therapeutic options remain limited. High alcohol consumption and consequent oxidative metabolism by cytochrome P450 (CYP) can lead to extremely high levels of reactive oxygen species, which overwhelm cellular defenses and harm hepatocytes. Our previous investigations showed that inhibiting Cyp2e1 using RNA interference reduced the incidence of ALD. However, compensatory mechanisms other than CYP2E1 contribute to oxidative stress in the liver. Therefore, we coupled triple siRNA lipid nanoparticles (LNPs) targeting Cyp2e1 with two isoenzymes Cyp4a10 and Cyp4a14 to treat ALD mouse models fed with Lieber-Decarli ethanol liquid diet for 12 weeks at the early (1st week), middle (5th week), and late (9th week) stages. The administration of triple siRNA LNPs significantly ameliorated chronic alcoholic liver injury in mice, and early treatment achieved the most profound effects. These effects can be attributed to a reduction in oxidative stress and increased expression of antioxidant genes, including Gsh-Px, Gsh-Rd, and Sod1. Moreover, we observed the alleviation of inflammation, evidenced by the downregulation of Il-1β, Il-6, Tnf-α, and Tgf-β, and the prevention of excessive lipid synthesis, evidenced by the restoration of the expression of Srebp1c, Acc, and Fas. Finally, triple siRNA treatment maintained normal metabolism in lipid oxidation. In brief, our research examined the possible targets for clinical intervention in ALD by examining the therapeutic effects of triple siRNA LNPs targeting Cyp2e1, Cyp4a10, and Cyp4a14. The in vivo knockdown of the three genes in this study is suggested as a promising siRNA therapeutic approach for ALD.
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Affiliation(s)
- Qi Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Shuang Wu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Qiubing Chen
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yahong Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Cai Zhang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China; (Q.Z.); (S.W.)
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Arjunan P, Kathirvelu D, Mahalingam G, Goel AK, Zacharaiah UG, Srivastava A, Marepally S. Lipid-nanoparticle-enabled nucleic acid therapeutics for liver disorders. Acta Pharm Sin B 2024; 14:2885-2900. [PMID: 39027251 PMCID: PMC11252464 DOI: 10.1016/j.apsb.2024.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 02/08/2024] [Accepted: 03/19/2024] [Indexed: 07/20/2024] Open
Abstract
Inherited genetic disorders of the liver pose a significant public health burden. Liver transplantation is often limited by the availability of donor livers and the exorbitant costs of immunosuppressive therapy. To overcome these limitations, nucleic acid therapy provides a hopeful alternative that enables gene repair, gene supplementation, and gene silencing with suitable vectors. Though viral vectors are the most efficient and preferred for gene therapy, pre-existing immunity debilitating immune responses limit their use. As a potential alternative, lipid nanoparticle-mediated vectors are being explored to deliver multiple nucleic acid forms, including pDNA, mRNA, siRNA, and proteins. Herein, we discuss the broader applications of lipid nanoparticles, from protein replacement therapy to restoring the disease mechanism through nucleic acid delivery and gene editing, as well as multiple preclinical and clinical studies as a potential alternative to liver transplantation.
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Affiliation(s)
- Porkizhi Arjunan
- Center for Stem Cell Research (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, Tamil Nadu, India
- Manipal academy for higher education, Mangalore 576104, Karnataka, India
| | - Durga Kathirvelu
- Center for Stem Cell Research (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, Tamil Nadu, India
| | - Gokulnath Mahalingam
- Center for Stem Cell Research (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, Tamil Nadu, India
| | - Ashish Kumar Goel
- Department of Hepatology, Christian Medical College & Hospital, Vellore 632004, Tamil Nadu, India
| | - Uday George Zacharaiah
- Department of Hepatology, Christian Medical College & Hospital, Vellore 632004, Tamil Nadu, India
| | - Alok Srivastava
- Center for Stem Cell Research (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, Tamil Nadu, India
- Department of Hematology, Christian Medical College & Hospital, Vellore 632004, Tamil Nadu, India
| | - Srujan Marepally
- Center for Stem Cell Research (A Unit of inStem, Bengaluru), Christian Medical College Campus, Bagayam, Vellore 632002, Tamil Nadu, India
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Yu X, Zhang H, Li J, Gu L, Cao L, Gong J, Xie P, Xu J. Construction of a prognostic prediction model in liver cancer based on genes involved in integrin cell surface interactions pathway by multi-omics screening. Front Cell Dev Biol 2024; 12:1237445. [PMID: 38374893 PMCID: PMC10875080 DOI: 10.3389/fcell.2024.1237445] [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: 06/22/2023] [Accepted: 01/23/2024] [Indexed: 02/21/2024] Open
Abstract
Background: Liver cancer is a common malignant tumor with an increasing incidence in recent years. We aimed to develop a model by integrating clinical information and multi-omics profiles of genes to predict survival of patients with liver cancer. Methods: The multi-omics data were integrated to identify liver cancer survival-associated signal pathways. Then, a prognostic risk score model was established based on key genes in a specific pathway, followed by the analysis of the relationship between the risk score and clinical features as well as molecular and immunologic characterization of the key genes included in the prediction model. The function experiments were performed to further elucidate the undergoing molecular mechanism. Results: Totally, 4 pathways associated with liver cancer patients' survival were identified. In the pathway of integrin cell surface interactions, low expression of COMP and SPP1, and low CNVs level of COL4A2 and ITGAV were significantly related to prognosis. Based on above 4 genes, the risk score model for prognosis was established. Risk score, ITGAV and SPP1 were the most significantly positively related to activated dendritic cell. COL4A2 and COMP were the most significantly positively associated with Type 1 T helper cell and regulatory T cell, respectively. The nomogram (involved T stage and risk score) may better predict short-term survival. The cell assay showed that overexpression of ITGAV promoted tumorigenesis. Conclusion: The risk score model constructed with four genes (COMP, SPP1, COL4A2, and ITGAV) may be used to predict survival in liver cancer patients.
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Affiliation(s)
- Xiang Yu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Hao Zhang
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jinze Li
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lu Gu
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Lei Cao
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jun Gong
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ping Xie
- Department of Radiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Radiology, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jian Xu
- Department of Hepatobiliary Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Department of Hepatobiliary Surgery, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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Romeo M, Dallio M, Scognamiglio F, Ventriglia L, Cipullo M, Coppola A, Tammaro C, Scafuro G, Iodice P, Federico A. Role of Non-Coding RNAs in Hepatocellular Carcinoma Progression: From Classic to Novel Clinicopathogenetic Implications. Cancers (Basel) 2023; 15:5178. [PMID: 37958352 PMCID: PMC10647270 DOI: 10.3390/cancers15215178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as "small ncRNAs" (sncRNAs) and "long ncRNAs" (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. In this review, we describe the main dysregulated ncRNAs and the relative molecular pathways involved in HCC progression, analyzing their implications in certain etiologically related contexts, and their applicability in clinical practice as novel diagnostic, prognostic, and therapeutic tools. Finally, given the growing evidence supporting the immune system response, the oxidative stress-regulated mechanisms, and the gut microbiota composition as relevant emerging elements mutually influencing liver-cancerogenesis processes, we investigate the relationship of ncRNAs with this triad, shedding light on novel pathogenetic frontiers of HCC progression.
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Affiliation(s)
- Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marcello Dallio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Flavia Scognamiglio
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Lorenzo Ventriglia
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Annachiara Coppola
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
| | - Chiara Tammaro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Giuseppe Scafuro
- Biochemistry Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (C.T.); (G.S.)
| | - Patrizia Iodice
- Division of Medical Oncology, AORN Azienda dei Colli, Monaldi Hospital, Via Leonardo Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, 80138 Naples, Italy; (M.R.); (F.S.); (L.V.); (M.C.); (A.C.); (A.F.)
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Wang Y, Chen Q, Wu S, Sun X, Yin R, Ouyang Z, Yin H, Wei Y. Amelioration of ethanol-induced oxidative stress and alcoholic liver disease by in vivo RNAi targeting Cyp2e1. Acta Pharm Sin B 2023; 13:3906-3918. [PMID: 37719371 PMCID: PMC10502278 DOI: 10.1016/j.apsb.2023.01.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/16/2022] [Accepted: 12/10/2022] [Indexed: 09/19/2023] Open
Abstract
Alcoholic liver disease (ALD) results from continuous and heavy alcohol consumption. The current treatment strategy for ALD is based on alcohol withdrawal coupled with antioxidant drug intervention, which is a long process with poor efficacy and low patient compliance. Alcohol-induced CYP2E1 upregulation has been demonstrated as a key regulator of ALD, but CYP2E1 knockdown in humans was impractical, and pharmacological inhibition of CYP2E1 by a clinically relevant approach for treating ALD was not shown. In this study, we developed a RNAi therapeutics delivered by lipid nanoparticle, and treated mice fed on Lieber-DeCarli ethanol liquid diet weekly for up to 12 weeks. This RNAi-based inhibition of Cyp2e1 expression reduced reactive oxygen species and oxidative stress in mouse livers, and contributed to improved ALD symptoms in mice. The liver fat accumulation, hepatocyte inflammation, and fibrosis were reduced in ALD models. Therefore, this study suggested the feasibility of RNAi targeting to CYP2E1 as a potential therapeutic tool to the development of ALD.
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Affiliation(s)
- Yalan Wang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Qiubing Chen
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Shuang Wu
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Xinyu Sun
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Runting Yin
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Zhen Ouyang
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
| | - Hao Yin
- Department of Urology, Frontier Science Centre for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Department of Pulmonary and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
- RNA Institute, Wuhan University, Wuhan 430072, China
- Wuhan Research Centre for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430010, China
| | - Yuan Wei
- School of Pharmacy, Jiangsu University, Zhenjiang 212013, China
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Bakrania A, To J, Zheng G, Bhat M. Targeting Wnt-β-Catenin Signaling Pathway for Hepatocellular Carcinoma Nanomedicine. GASTRO HEP ADVANCES 2023; 2:948-963. [PMID: 39130774 PMCID: PMC11307499 DOI: 10.1016/j.gastha.2023.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 07/17/2023] [Indexed: 08/13/2024]
Abstract
Hepatocellular carcinoma (HCC) represents a high-fatality cancer with a 5-year survival of 22%. The Wnt/β-catenin signaling pathway presents as one of the most upregulated pathways in HCC. However, it has so far not been targetable in the clinical setting. Therefore, studying new targets of this signaling cascade from a therapeutic aspect could enable reversal, delay, or prevention of hepatocarcinogenesis. Although enormous advancement has been achieved in HCC research and its therapeutic management, since HCC often occurs in the context of other liver diseases such as cirrhosis leading to liver dysfunction and/or impaired drug metabolism, the current therapies face the challenge of safely and effectively delivering drugs to the HCC tumor site. In this review, we discuss how a targeted nano drug delivery system could help minimize the off-target toxicities of conventional HCC therapies as well as enhance treatment efficacy. We also put forward the current challenges in HCC nanomedicine along with some potential therapeutic targets from the Wnt/β-catenin signaling pathway that could be used for HCC therapy. Overall, this review will provide an insight to the current advances, limitations and how HCC nanomedicine could change the landscape of some of the undruggable targets in the Wnt/β-catenin pathway.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey To
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network and University of Toronto, Toronto, Ontario, Canada
- Department of Medical Sciences, University Health Network, Toronto, Ontario, Canada
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Improved anti-hepatocellular carcinoma effect by enhanced Co-delivery of Tim-3 siRNA and sorafenib via multiple pH triggered drug-eluting nanoparticles. Mater Today Bio 2022; 16:100350. [PMID: 35856043 PMCID: PMC9287642 DOI: 10.1016/j.mtbio.2022.100350] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/15/2022] [Accepted: 07/01/2022] [Indexed: 11/23/2022] Open
Abstract
Effective systemic treatment for hepatocellular carcinoma (HCC) remains urgently needed. Sorafenib is the first FDA-approved systemic treatment for HCC. However, individual HCC patents’ response to sorafenib varies greatly. How to enhance the anti-HCC effect of sorafenib is still a significant challenge. T cell immunoglobulin mucin-3 (Tim-3) is a newly identified immune checkpoint molecule and a promising target for HCC treatment. Herein, we developed a novel pH-triggered drug-eluting nanoparticle (CC@SR&SF@PP) for simultaneously delivery of Tim-3 siRNA and sorafenib to HCC in situ. By a single emulsification method, a representative HCC targeted-therapeutic drug sorafenib (SF) was encapsulated into the pH-triggered positive-charged mPEG5K-PAE10K (PP) nanoparticles, followed by condensing of negative-charged Tim-3 siRNA. Then, carboxymethyl chitosan (CMCS), an amphoteric polysaccharide with negative charge in the physiological pH and positive charge in the acidic environment of the tumor, was eventually adsorbed onto the surface of nanoparticles. This co-delivery nanoparticle rapidly and specifically accumulated in the tumor site of the liver and enhanced the targeted, specific and multiple release of siRNA and sorafenib. Enhanced Tim-3 siRNA transfected into tumor cells can not only directly inhibit the growth of tumor cells by knock down the expression Tim-3, but also induce the immune response and enhance the recruitment of cytotoxic T cells to kill tumor cells. The following pH-triggered sorafenib release from SF@PP NPs greatly inhibited the tumor proliferation and angiogenesis, resulting in remarkable tumor growth inhibition in a mouse hepatoma 22 (H22) orthotopic tumor model. Thus, co-delivery of Tim-3 siRNA and sorafenib via this novel pH triggered drug-eluting nanoparticle enhances their anti-tumor efficacy. We expect that such combination treatment strategy will have great potential in future clinical applications.
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10
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Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes. Cell Metab 2022; 34:1824-1842.e9. [PMID: 36243006 DOI: 10.1016/j.cmet.2022.09.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 08/04/2022] [Accepted: 09/21/2022] [Indexed: 01/11/2023]
Abstract
During mammalian energy homeostasis, the glucagon receptor (Gcgr) plays a key role in regulating both glucose and lipid metabolisms. However, the mechanisms by which these distinct signaling arms are differentially regulated remain poorly understood. Using a Cy5-glucagon agonist, we show that the endosomal protein Vps37a uncouples glucose production from lipid usage downstream of Gcgr signaling by altering intracellular receptor localization. Hepatocyte-specific knockdown of Vps37a causes an accumulation of Gcgr in endosomes, resulting in overactivation of the cAMP/PKA/p-Creb signaling pathway to gluconeogenesis without affecting β-oxidation. Shifting the receptor back to the plasma membrane rescues the differential signaling and highlights the importance of the spatiotemporal localization of Gcgr for its metabolic effects. Importantly, since Vps37a knockdown in animals fed with a high-fat diet leads to hyperglycemia, although its overexpression reduces blood glucose levels, these data reveal a contribution of endosomal signaling to metabolic diseases that could be exploited for treatments of type 2 diabetes.
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11
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Xu M, Yang L, Lin Y, Lu Y, Bi X, Jiang T, Deng W, Zhang L, Yi W, Xie Y, Li M. Emerging nanobiotechnology for precise theranostics of hepatocellular carcinoma. J Nanobiotechnology 2022; 20:427. [PMID: 36175957 PMCID: PMC9524074 DOI: 10.1186/s12951-022-01615-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 08/31/2022] [Indexed: 11/18/2022] Open
Abstract
Primary liver cancer has become the second most fatal cancer in the world, and its five-year survival rate is only 10%. Most patients are in the middle and advanced stages at the time of diagnosis, losing the opportunity for radical treatment. Liver cancer is not sensitive to chemotherapy or radiotherapy. At present, conventional molecularly targeted drugs for liver cancer show some problems, such as short residence time, poor drug enrichment, and drug resistance. Therefore, developing new diagnosis and treatment methods to effectively improve the diagnosis, treatment, and long-term prognosis of liver cancer is urgent. As an emerging discipline, nanobiotechnology, based on safe, stable, and efficient nanomaterials, constructs highly targeted nanocarriers according to the unique characteristics of tumors and further derives a variety of efficient diagnosis and treatment methods based on this transport system, providing a new method for the accurate diagnosis and treatment of liver cancer. This paper aims to summarize the latest progress in this field according to existing research and the latest clinical diagnosis and treatment guidelines in hepatocellular carcinoma (HCC), as well as clarify the role, application limitations, and prospects of research on nanomaterials and the development and application of nanotechnology in the diagnosis and treatment of HCC.
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Affiliation(s)
- Mengjiao Xu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Tingting Jiang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China. .,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China. .,Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, 8 Jingshun East Street, Chaoyang District, Beijing, 100015, China.
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12
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Wang T, Yao Y, Hu X, Zhao Y. Message in hand: the application of CRISPRi, RNAi, and LncRNA in adenocarcinoma. Med Oncol 2022; 39:148. [PMID: 35834017 DOI: 10.1007/s12032-022-01727-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 04/05/2022] [Indexed: 06/15/2023]
Abstract
Gene editing interference technology has been flourishing for more than 30 years. It has always been a common means to interfere with the expression of particular genes. Today it has shown a broad application prospect in clinical treatment, especially in adenocarcinoma treatment. In just a few years, the CRISPRi technology has attracted much z attention with its precise targeting and convenient operability significantly promoted the transformation from bench to bedside, and won the Nobel Prize in Chemistry 2020. In recent years, the importance of non-coding RNA has led LncRNA research to the center. At the same time, it also recalls the surprises obtained in laboratory and clinic research by RNAi technologies such as microRNA, siRNA, and shRNA at the beginning of the century. Therefore, this article focuses on CRISPRi, RNAi, and LncRNA to review their gene interference mechanisms currently expected to be translational research. Their applications and differences in adenocarcinoma research will also be described powerfully. It will provide a helpful reference for scientists to understand better and apply several RNA interference technologies.
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Affiliation(s)
- Ting Wang
- Cancer Research Institute, Guangdong Medical University, Dongguan, 523808, China
- Pathology Department, Guangdong Medical University, Dongguan, 523808, China
| | - Yunhong Yao
- Pathology Department, Guangdong Medical University, Dongguan, 523808, China
| | - Xinrong Hu
- Cancer Research Institute, Guangdong Medical University, Dongguan, 523808, China.
- Pathology Department, Guangdong Medical University, Dongguan, 523808, China.
| | - Yi Zhao
- Cancer Research Institute, Guangdong Medical University, Dongguan, 523808, China.
- Microbiology and Immunology Department, Guangdong Medical University, Dongguan, 523808, China.
- Department of Traditional Chinese Medicine, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, 523713, China.
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13
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Deciphering signal transduction networks in the liver by mechanistic mathematical modelling. Biochem J 2022; 479:1361-1374. [PMID: 35748700 PMCID: PMC9246346 DOI: 10.1042/bcj20210548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/10/2022] [Accepted: 06/10/2022] [Indexed: 11/17/2022]
Abstract
In health and disease, liver cells are continuously exposed to cytokines and growth factors. While individual signal transduction pathways induced by these factors were studied in great detail, the cellular responses induced by repeated or combined stimulations are complex and less understood. Growth factor receptors on the cell surface of hepatocytes were shown to be regulated by receptor interactions, receptor trafficking and feedback regulation. Here, we exemplify how mechanistic mathematical modelling based on quantitative data can be employed to disentangle these interactions at the molecular level. Crucial is the analysis at a mechanistic level based on quantitative longitudinal data within a mathematical framework. In such multi-layered information, step-wise mathematical modelling using submodules is of advantage, which is fostered by sharing of standardized experimental data and mathematical models. Integration of signal transduction with metabolic regulation in the liver and mechanistic links to translational approaches promise to provide predictive tools for biology and personalized medicine.
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14
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Murine Falcor/LL35 lncRNA Contributes to Glucose and Lipid Metabolism In Vitro and In Vivo. Biomedicines 2022; 10:biomedicines10061397. [PMID: 35740417 PMCID: PMC9220108 DOI: 10.3390/biomedicines10061397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Glucose and lipid metabolism are crucial functional systems in eukaryotes. A large number of experimental studies both in animal models and humans have shown that long non-coding RNAs (lncRNAs) play an important role in glucose and lipid metabolism. Previously, human lncRNA DEANR1/linc00261 was described as a tumor suppressor that regulates a variety of biological processes such as cell proliferation, apoptosis, glucose metabolism and tumorigenesis. Here we report that murine lncRNA Falcor/LL35, a proposed functional analog of human DEANR1/linc00261, is predominantly expressed in murine normal hepatocytes and downregulated in HCC and after partial hepatectomy. The application of high-throughput approaches such as RNA-seq, LC-MS proteomics, lipidomics and metabolomics analysis allowed changes to be found in the transcriptome, proteome, lipidome and metabolome of hepatocytes after LL35 depletion. We revealed that LL35 is involved in the regulation of glycolysis and lipid biosynthesis in vitro and in vivo. Moreover, LL35 affects Notch and NF-κB signaling pathways in normal hepatocytes. All observed changes result in the decrease in the proliferation and migration of hepatocytes. We demonstrated similar phenotype changes between murine LL35 and human linc00261 depletion in vitro and in vivo that opens the opportunity to translate results for LL35 from a liver murine model to possible functions of human lncRNA linc00261.
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15
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Chakraborty E, Sarkar D. Emerging Therapies for Hepatocellular Carcinoma (HCC). Cancers (Basel) 2022; 14:2798. [PMID: 35681776 PMCID: PMC9179883 DOI: 10.3390/cancers14112798] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 01/30/2023] Open
Abstract
Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.
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Affiliation(s)
- Eesha Chakraborty
- C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
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16
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Sartorius K, Antwi SO, Chuturgoon A, Roberts LR, Kramvis A. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality? Front Oncol 2022; 12:891812. [PMID: 35600358 PMCID: PMC9115561 DOI: 10.3389/fonc.2022.891812] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa.,The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Department of Surgery, KZN Kwazulu-Natal (UKZN) Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Samuel O Antwi
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Lewis R Roberts
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States.,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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17
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Stanislovas J, Kermorgant S. c-Met-integrin cooperation: Mechanisms, tumorigenic effects, and therapeutic relevance. Front Cell Dev Biol 2022; 10:994528. [PMID: 36330337 PMCID: PMC9624249 DOI: 10.3389/fcell.2022.994528] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
c-Met is a receptor tyrosine kinase which upon activation by its ligand, the hepatocyte growth factor, mediates many important signalling pathways that regulate cellular functions such as survival, proliferation, and migration. Its oncogenic and tumorigenic signalling mechanisms, greatly contributing to cancer development and progression, are well documented. Integrins, heterogeneous adhesion receptors which facilitate cell-extracellular matrix interactions, are important in biomechanically sensitive cell adhesion and motility but also modulate diverse cell behaviour. Here we review the studies which reported cooperation between c-Met and several integrins, particularly β1 and β4, in various cell models including many tumour cell types. From the various experimental models and results analysed, we propose that c-Met-integrin cooperation occurs via inside-out or outside-in signalling. Thus, either c-Met activation triggers integrin activation and cell adhesion or integrin adhesion to its extracellular ligand triggers c-Met activation. These two modes of cooperation require the adhesive function of integrins and mostly lead to cell migration and invasion. In a third, less conventional, mode of cooperation, the integrin plays the role of a signalling adaptor for c-Met, independently from its adhesive property, leading to anchorage independent survival. Recent studies have revealed the influence of endocytic trafficking in c-Met-integrin cooperation including the adaptor function of integrin occurring on endomembranes, triggering an inside-in signalling, believed to promote survival of metastatic cells. We present the evidence of the cooperation in vivo and in human tissues and highlight its therapeutic relevance. A better understanding of the mechanisms regulating c-Met-integrin cooperation in cancer progression could lead to the design of new therapies targeting this cooperation, providing more effective therapeutic approaches than c-Met or integrin inhibitors as monotherapies used in the clinic.
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Affiliation(s)
- Justas Stanislovas
- Spatial Signalling Group, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stéphanie Kermorgant
- Spatial Signalling Group, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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18
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Bakrania A, Zheng G, Bhat M. Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment. Pharmaceutics 2021; 14:41. [PMID: 35056937 PMCID: PMC8779722 DOI: 10.3390/pharmaceutics14010041] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2-9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.
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Affiliation(s)
- Anita Bakrania
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada;
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mamatha Bhat
- Toronto General Hospital Research Institute, Toronto, ON M5G 2C4, Canada;
- Ajmera Transplant Program, University Health Network, Toronto, ON M5G 2N2, Canada
- Division of Gastroenterology, Department of Medicine, University Health Network, Toronto, ON M5G 2C4, Canada
- Department of Medical Sciences, University of Toronto, Toronto, ON M5S 1A1, Canada
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19
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Xiong J, Yan L, Zou C, Wang K, Chen M, Xu B, Zhou Z, Zhang D. Integrins regulate stemness in solid tumor: an emerging therapeutic target. J Hematol Oncol 2021; 14:177. [PMID: 34715893 PMCID: PMC8555177 DOI: 10.1186/s13045-021-01192-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023] Open
Abstract
Integrins are the adhesion molecules and transmembrane receptors that consist of α and β subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.
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Affiliation(s)
- Jiangling Xiong
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Lianlian Yan
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Cheng Zou
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Kai Wang
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Mengjie Chen
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China.,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China
| | - Bin Xu
- Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Zhipeng Zhou
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, 430070, Hubei Province, China.
| | - Dingxiao Zhang
- School of Biomedical Sciences, Hunan University, Changsha, 410082, Hunan Province, China. .,College of Biology, Hunan University, Changsha, 410082, Hunan Province, China.
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20
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Sun Y, Yang J, Yang T, Li Y, Zhu R, Hou Y, Liu Y. Co-delivery of IL-12 cytokine gene and cisplatin prodrug by a polymetformin-conjugated nanosystem for lung cancer chemo-gene treatment through chemotherapy sensitization and tumor microenvironment modulation. Acta Biomater 2021; 128:447-461. [PMID: 33894351 DOI: 10.1016/j.actbio.2021.04.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/27/2022]
Abstract
The combination of chemotherapy and gene therapy has been indicated as a promising approach for cancer therapy. However, this combination strategy is still faced a challenge by the lack of suitable carriers to co-loaded chemotherapeutic drug and gene into one single nanoplatform. In this study, a tumor-targeted HC/pIL-12/polyMET micelleplexes were developed for the co-loading and co-delivery of cisplatin (CDDP) and plasmid encoding interleukin-12 gene (pIL-12), which would be utilized to generate synergistic actions through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, effective intracellular CDDP release and pIL-12 transfection efficiency. More important, the HC/pIL-12/polyMET generated the enhanced LLC cell proliferation inhibition and apoptosis induction efficiency. The long-circulating HC/pIL-12/polyMET micelleplexes promoted the accumulation of CDDP and pIL-12 in tumor site, which resulted in significantly inhibiting the growth of lung cancer, and prolonging the overall survival of tumor-bearing mice. The underlying immune mechanism demonstrated the combination of CDDP and pIL-12 activated immune effector cells to release IFN-γ and induced M1-type differentiation of tumor-related macrophages, thereby generating synergistic chemoimmunotherapy effect. Taken together, this study may provide an effective strategy for drug/gene co-delivery and cancer chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Chemoimmunotherapy has been indicated as an approach to improve efficacy of cancer therapy. Herein, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of cisplatin (CDDP) and plasmid encoding IL-12 gene (pIL-12), which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, high gene transfection efficiency and antitumor activity on tumor cell proliferation inhibition and apoptosis induction. More importantly, the long-circulating HC/pIL-12/polyMET micelleplexes could effectively accumulate in tumor sites and then rapidly release the CDDP and pIL-12, significantly inhibit the growth of lung cancer. This strategy provides a new concept for chemo-gene combination with a strengthened overall therapeutic efficacy of chemoimmunotherapy.
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Affiliation(s)
- Yue Sun
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Jiayu Yang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Tong Yang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yifan Li
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Rongyue Zhu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yanhui Hou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan, 750004, China.
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21
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Sergeeva O, Abakumova T, Kurochkin I, Ialchina R, Kosyreva A, Prikazchikova T, Varlamova V, Shcherbinina E, Zatsepin T. Level of Murine DDX3 RNA Helicase Determines Phenotype Changes of Hepatocytes In Vitro and In Vivo. Int J Mol Sci 2021; 22:ijms22136958. [PMID: 34203429 PMCID: PMC8269429 DOI: 10.3390/ijms22136958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 11/26/2022] Open
Abstract
DDX3 RNA helicase is intensively studied as a therapeutic target due to participation in the replication of some viruses and involvement in cancer progression. Here we used transcriptome analysis to estimate the primary response of hepatocytes to different levels of RNAi-mediated knockdown of DDX3 RNA helicase both in vitro and in vivo. We found that a strong reduction of DDX3 protein (>85%) led to similar changes in vitro and in vivo—deregulation of the cell cycle and Wnt and cadherin pathways. Also, we observed the appearance of dead hepatocytes in the healthy liver and a decrease of cell viability in vitro after prolonged treatment. However, more modest downregulation of the DDX3 protein (60–65%) showed discordant results in vitro and in vivo—similar changes in vitro as in the case of strong knockdown and a different phenotype in vivo. These results demonstrate that the level of DDX3 protein can dramatically influence the cell phenotype in vivo and the decrease of DDX3, for more than 85% leads to cell death in normal tissues, which should be taken into account during the drug development of DDX3 inhibitors.
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Affiliation(s)
- Olga Sergeeva
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
- Correspondence: ; Tel.: +7-926-388-0865
| | - Tatiana Abakumova
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Ilia Kurochkin
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Renata Ialchina
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Anna Kosyreva
- Research Institute of Human Morphology, 117418 Moscow, Russia;
| | - Tatiana Prikazchikova
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Varvara Varlamova
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Evgeniya Shcherbinina
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
| | - Timofei Zatsepin
- Skolkovo Institute of Science and Technology, Skolkovo, 121205 Moscow, Russia; (T.A.); (I.K.); (R.I.); (T.P.); (V.V.); (E.S.); (T.Z.)
- Department of Chemistry, Lomonosov Moscow State University, 119992 Moscow, Russia
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22
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Banerjee I, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC). Adv Cancer Res 2021; 152:329-381. [PMID: 34353442 DOI: 10.1016/bs.acr.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.
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Affiliation(s)
- Indranil Banerjee
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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23
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Reker D, Rybakova Y, Kirtane AR, Cao R, Yang JW, Navamajiti N, Gardner A, Zhang RM, Esfandiary T, L'Heureux J, von Erlach T, Smekalova EM, Leboeuf D, Hess K, Lopes A, Rogner J, Collins J, Tamang SM, Ishida K, Chamberlain P, Yun D, Lytton-Jean A, Soule CK, Cheah JH, Hayward AM, Langer R, Traverso G. Computationally guided high-throughput design of self-assembling drug nanoparticles. NATURE NANOTECHNOLOGY 2021; 16:725-733. [PMID: 33767382 PMCID: PMC8197729 DOI: 10.1038/s41565-021-00870-y] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/28/2021] [Indexed: 05/22/2023]
Abstract
Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug-loading capacities of up to 95%. There is currently no understanding of which of the millions of small-molecule combinations can result in the formation of these nanoparticles. Here we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2,686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug-loading capacities for a wide range of therapeutics.
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Affiliation(s)
- Daniel Reker
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Yulia Rybakova
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ameya R Kirtane
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ruonan Cao
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Engineering Science, University of Toronto, Toronto, Ontario, Canada
| | - Jee Won Yang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA
| | - Natsuda Navamajiti
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Biomedical Engineering Program, Faculty of Engineering, Chulalongkorn University, Bangkok, Thailand
| | - Apolonia Gardner
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Rosanna M Zhang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Tina Esfandiary
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Johanna L'Heureux
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Thomas von Erlach
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Elena M Smekalova
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Kaitlyn Hess
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Aaron Lopes
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jaimie Rogner
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Joy Collins
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Siddartha M Tamang
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Keiko Ishida
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Paul Chamberlain
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - DongSoo Yun
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Abigail Lytton-Jean
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Christian K Soule
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jaime H Cheah
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alison M Hayward
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Robert Langer
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Giovanni Traverso
- Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
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24
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Manna D, Sarkar D. Multifunctional Role of Astrocyte Elevated Gene-1 (AEG-1) in Cancer: Focus on Drug Resistance. Cancers (Basel) 2021; 13:cancers13081792. [PMID: 33918653 PMCID: PMC8069505 DOI: 10.3390/cancers13081792] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/31/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Chemotherapy is a major mode of treatment for cancers. However, cancer cells adapt to survive in stressful conditions and in many cases, they are inherently resistant to chemotherapy. Additionally, after initial response to chemotherapy, the surviving cancer cells acquire new alterations making them chemoresistant. Genes that help adapt the cancer cells to cope with stress often contribute to chemoresistance and one such gene is Astrocyte elevated gene-1 (AEG-1). AEG-1 levels are increased in all cancers studied to date and AEG-1 contributes to the development of highly aggressive, metastatic cancers. In this review, we provide a comprehensive description of the mechanism by which AEG-1 augments tumor development with special focus on its ability to regulate chemoresistance. We also discuss potential ways to inhibit AEG-1 to overcome chemoresistance. Abstract Cancer development results from the acquisition of numerous genetic and epigenetic alterations in cancer cells themselves, as well as continuous changes in their microenvironment. The plasticity of cancer cells allows them to continuously adapt to selective pressures brought forth by exogenous environmental stresses, the internal milieu of the tumor and cancer treatment itself. Resistance to treatment, either inherent or acquired after the commencement of treatment, is a major obstacle an oncologist confronts in an endeavor to efficiently manage the disease. Resistance to chemotherapy, chemoresistance, is an important hallmark of aggressive cancers, and driver oncogene-induced signaling pathways and molecular abnormalities create the platform for chemoresistance. The oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) is overexpressed in a diverse array of cancers, and its overexpression promotes all the hallmarks of cancer, such as proliferation, invasion, metastasis, angiogenesis and chemoresistance. The present review provides a comprehensive description of the molecular mechanism by which AEG-1 promotes tumorigenesis, with a special emphasis on its ability to regulate chemoresistance.
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25
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Shi L, Liu B, Shen DD, Yan P, Zhang Y, Tian Y, Hou L, Jiang G, Zhu Y, Liang Y, Liang X, Shen B, Yu H, Zhang Y, Wang Y, Guo X, Cai X. A tumor-suppressive circular RNA mediates uncanonical integrin degradation by the proteasome in liver cancer. SCIENCE ADVANCES 2021; 7:7/13/eabe5043. [PMID: 33762338 PMCID: PMC7990343 DOI: 10.1126/sciadv.abe5043] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 02/04/2021] [Indexed: 05/03/2023]
Abstract
Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β1 integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.
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Affiliation(s)
- Liang Shi
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
| | - Boqiang Liu
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
| | - Dan-Dan Shen
- Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Peijian Yan
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
- Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Yanan Zhang
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Yuanshi Tian
- Department of Diagnostic Ultrasound and Echocardiography, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Lidan Hou
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
| | - Guangyi Jiang
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou 310016, China
| | - Yinxin Zhu
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Yuelong Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Xiao Liang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Bo Shen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Hong Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China
| | - Yan Zhang
- Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Yifan Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
| | - Xing Guo
- Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
| | - Xiujun Cai
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
- Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China
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26
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Xie J, Guo T, Zhong Z, Wang N, Liang Y, Zeng W, Liu S, Chen Q, Tang X, Wu H, Zhang S, Ma K, Wang B, Ou Y, Gu W, Chen H, Qiu Y, Duan Y. ITGB1 Drives Hepatocellular Carcinoma Progression by Modulating Cell Cycle Process Through PXN/YWHAZ/AKT Pathways. Front Cell Dev Biol 2021; 9:711149. [PMID: 34977001 PMCID: PMC8718767 DOI: 10.3389/fcell.2021.711149] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/09/2021] [Indexed: 12/24/2022] Open
Abstract
Integrin β1 (ITGB1), which acts as an extracellular matrix (ECM) receptor, has gained increasing attention as a therapeutic target for the treatment of hepatocellular carcinoma (HCC). However, the underpinning mechanism of how ITGB1 drives HCC progression remains elusive. In this study, we first found that ITGB1 expression was significantly higher in HCC tissues than in normal controls by bioinformatics analysis. Furthermore, bioinformatics analysis revealed that paxillin (PXN) and 14-3-3 protein zeta (YWHAZ) are the molecules participating in ITGB1-regulated HCC tumor cell cycle progression. Indeed, immunohistochemistry (IHC) revealed that ITGB1, paxillin, and YWHAZ were strongly upregulated in paired HCC tissue compared with adjacent normal tissues. Notably, the inhibition of ITGB1 expression by small interfering RNA (siRNA) resulted in the downregulated expression of PXN and YWHAZ in primary HCC cells, as assessed by western blot and immunostaining. In addition, ITGB1 knockdown markedly impaired the aggressive behavior of HCC tumor cells and delayed cell cycle progression as determined by cell migration assay, drug-resistance analysis, colony formation assay, quantitative real-time polymerase chain reaction (qRT-PCR), and cell cycle analysis as well as cell viability measurements. More importantly, we proved that xenograft ITGB1high tumors grew more rapidly than ITGB1low tumors. Altogether, our study showed that the ITGB1/PXN/YWHAZ/protein kinase B (AKT) axis enhances HCC progression by accelerating the cell cycle process, which offers a promising approach to halt HCC tumor growth.
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Affiliation(s)
- Jinghe Xie
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, China
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Tingting Guo
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Zhiyong Zhong
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, China
| | - Ning Wang
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, China
| | - Yan Liang
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Weiping Zeng
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Shoupei Liu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Qicong Chen
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Xianglian Tang
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, China
| | - Haibin Wu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
| | - Shuai Zhang
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Keqiang Ma
- Department of Hepatobiliary Pancreatic Surgery, Huadu District People’s Hospital of Guangzhou, Guangzhou, China
| | - Bailin Wang
- Department of General Surgery, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China
| | - Yimeng Ou
- Department of General Surgery, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Weili Gu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
- *Correspondence: Yuyou Duan, ; Yaqi Qiu, ; Honglin Chen, ; Weili Gu,
| | - Honglin Chen
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China
- Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education of China, South China University of Technology, Guangzhou, China
- Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China
- *Correspondence: Yuyou Duan, ; Yaqi Qiu, ; Honglin Chen, ; Weili Gu,
| | - Yaqi Qiu
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
- *Correspondence: Yuyou Duan, ; Yaqi Qiu, ; Honglin Chen, ; Weili Gu,
| | - Yuyou Duan
- Laboratory of Stem Cells and Translational Medicine, Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China
- Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education of China, South China University of Technology, Guangzhou, China
- Innovation Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, China
- *Correspondence: Yuyou Duan, ; Yaqi Qiu, ; Honglin Chen, ; Weili Gu,
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27
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Weng Y, Lieberthal TJ, Zhou VX, Lopez-Ichikawa M, Armas-Phan M, Bond TK, Yoshida MC, Choi WT, Chang TT. Liver epithelial focal adhesion kinase modulates fibrogenesis and hedgehog signaling. JCI Insight 2020; 5:141217. [PMID: 32910808 PMCID: PMC7605528 DOI: 10.1172/jci.insight.141217] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022] Open
Abstract
Focal adhesion kinase (FAK) is an important mediator of extracellular matrix-integrin mechano-signal transduction that regulates cell motility, survival, and proliferation. As such, FAK is being investigated as a potential therapeutic target for malignant and fibrotic diseases, and numerous clinical trials of FAK inhibitors are underway. The function of FAK in nonmalignant, nonmotile epithelial cells is not well understood. We previously showed that hepatocytes demonstrated activated FAK near stiff collagen tracts in fibrotic livers. In this study, we examined the role of liver epithelial FAK by inducing fibrotic liver disease in mice with liver epithelial FAK deficiency. We found that mice that lacked FAK in liver epithelial cells developed more severe liver injury and worse fibrosis as compared with controls. Increased fibrosis in liver epithelial FAK-deficient mice was linked to the activation of several profibrotic pathways, including the hedgehog/smoothened pathway. FAK-deficient hepatocytes produced increased Indian hedgehog in a manner dependent on matrix stiffness. Furthermore, expression of the hedgehog receptor, smoothened, was increased in macrophages and biliary cells of hepatocyte-specific FAK-deficient fibrotic livers. These results indicate that liver epithelial FAK has important regulatory roles in the response to liver injury and progression of fibrosis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Tammy T Chang
- Department of Surgery.,Liver Center, University of California, San Francisco, California, USA
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28
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Cao P, Jin Q, Feng L, Li H, Qin G, Zhou G. Emerging roles and potential clinical applications of noncoding RNAs in hepatocellular carcinoma. Semin Cancer Biol 2020; 75:136-152. [PMID: 32931952 DOI: 10.1016/j.semcancer.2020.09.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma(HCC) is one of the most common forms of cancer, and accounts for a high proportion of cancer-associated deaths. Growing evidences have demonstrated that non- protein-coding regions of the genome could give rise to transcripts, termed noncoding RNA (ncRNA), that form novel functional layers of the cellular activity. ncRNAs are implicated in different molecular mechanisms and functions at transcriptional, translational and post-translational levels. An increasing number of studies have demonstrated a complex array of molecular and cellular functions of ncRNAs in different stages of the HCC tumorigenesis, either in an oncogenic or tumor-suppressive manner. As a result, several pre-clinical studies have highlighted the great potentials of ncRNAs as novel biomarkers for cancer diagnosis or therapeutics in targeting HCC progression. In this review, we briefly described the characteristics of several representative ncRNAs and summarized the latest findings of their roles and mechanisms in the development of HCC, in order to better understand the cancer biology and their potential clinical applications in this malignancy.
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Affiliation(s)
- Pengbo Cao
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China
| | - Qian Jin
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China
| | - Lan Feng
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China
| | - Haibei Li
- Key Laboratory of Risk Assessment and Control for Environment & Food Safety, Tianjin Institute of Environmental & Operational Medicine, Tianjin City, China
| | - Geng Qin
- State Key Laboratory of Rare Earth Resources Utilization and Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun City, China
| | - Gangqiao Zhou
- State Key Laboratory of Proteomics, National Center for Protein Sciences at Beijing, Beijing Institute of Radiation Medicine, Beijing, China; Collaborative Innovation Center for Personalized Cancer Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing City, China; Medical College, Guizhou University, Guiyang City, China.
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29
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Mroweh M, Decaens T, Marche PN, Macek Jilkova Z, Clément F. Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma. Int J Mol Sci 2020; 21:E5250. [PMID: 32722054 PMCID: PMC7432232 DOI: 10.3390/ijms21155250] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with one of the highest mortality rates among solid cancers. It develops almost exclusively in the background of chronic liver inflammation, which can be caused by viral hepatitis, chronic alcohol consumption or an unhealthy diet. Chronic inflammation deregulates the innate and adaptive immune responses that contribute to the proliferation, survival and migration of tumor cells. The continuous communication between the tumor and its microenvironment components serves as the overriding force of the tumor against the body's defenses. The importance of this crosstalk between the tumor microenvironment and immune cells in the process of hepatocarcinogenesis has been shown, and therapeutic strategies modulating this communication have improved the outcomes of patients with liver cancer. To target this communication, an RNA interference (RNAi)-based approach can be used, an innovative and promising strategy that can disrupt the crosstalk at the transcriptomic level. Moreover, RNAi offers the advantage of specificity in comparison to the treatments currently used for HCC in clinics. In this review, we will provide the recent data pertaining to the modulation of a tumor and its microenvironment by using RNAi and its potential for therapeutic intervention in HCC.
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Affiliation(s)
- Mariam Mroweh
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath Beirut 6573-14, Lebanon
| | - Thomas Decaens
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Service d’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Patrice N Marche
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
| | - Zuzana Macek Jilkova
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
- Service d’hépato-Gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, 38700 La Tronche, France
| | - Flora Clément
- Institute for Advanced Biosciences, Research Center Inserm U 1209/CNRS 5309, 38700 La Tronche, France; (M.M.); (T.D.); (P.N.M.)
- Université Grenoble Alpes, 38000 Grenoble, France
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Lau CH, Tin C. The Synergy between CRISPR and Chemical Engineering. Curr Gene Ther 2020; 19:147-171. [PMID: 31267870 DOI: 10.2174/1566523219666190701100556] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/18/2019] [Accepted: 06/21/2019] [Indexed: 02/06/2023]
Abstract
Gene therapy and transgenic research have advanced quickly in recent years due to the development of CRISPR technology. The rapid development of CRISPR technology has been largely benefited by chemical engineering. Firstly, chemical or synthetic substance enables spatiotemporal and conditional control of Cas9 or dCas9 activities. It prevents the leaky expression of CRISPR components, as well as minimizes toxicity and off-target effects. Multi-input logic operations and complex genetic circuits can also be implemented via multiplexed and orthogonal regulation of target genes. Secondly, rational chemical modifications to the sgRNA enhance gene editing efficiency and specificity by improving sgRNA stability and binding affinity to on-target genomic loci, and hence reducing off-target mismatches and systemic immunogenicity. Chemically-modified Cas9 mRNA is also more active and less immunogenic than the native mRNA. Thirdly, nonviral vehicles can circumvent the challenges associated with viral packaging and production through the delivery of Cas9-sgRNA ribonucleoprotein complex or large Cas9 expression plasmids. Multi-functional nanovectors enhance genome editing in vivo by overcoming multiple physiological barriers, enabling ligand-targeted cellular uptake, and blood-brain barrier crossing. Chemical engineering can also facilitate viral-based delivery by improving vector internalization, allowing tissue-specific transgene expression, and preventing inactivation of the viral vectors in vivo. This review aims to discuss how chemical engineering has helped improve existing CRISPR applications and enable new technologies for biomedical research. The usefulness, advantages, and molecular action for each chemical engineering approach are also highlighted.
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Affiliation(s)
- Cia-Hin Lau
- Department of Biomedical Engineering, City University of Hong Kong, Kowloon Tong, Hong Kong
| | - Chung Tin
- Department of Biomedical Engineering, City University of Hong Kong, Kowloon Tong, Hong Kong
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31
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Cabriales L, Hautefeuille M, Vázquez‐Victorio G, Martinez‐Pastor D, Carretero‐Ortega J, Jiménez‐Escobar A, Macias‐Silva M. Hepatic C9 cells switch their behaviour in short or long exposure to soft substrates. Biol Cell 2020; 112:265-279. [DOI: 10.1111/boc.201900115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/13/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022]
Affiliation(s)
- Lucia Cabriales
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
- Departamento de Física Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - Mathieu Hautefeuille
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
- Departamento de Física Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - Genaro Vázquez‐Victorio
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
- Departamento de Física Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - David Martinez‐Pastor
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
- Instituto de Fisiología Celular Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - Jorge Carretero‐Ortega
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - Alejandra Jiménez‐Escobar
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
| | - Marina Macias‐Silva
- LaNSBioDyT, Facultad de Ciencias Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
- Instituto de Fisiología Celular Universidad Nacional Autónoma de México Ciudad Universitaria Circuito Exterior S/N Ciudad de México CP 04510 México
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Subhan MA, Torchilin VP. siRNA based drug design, quality, delivery and clinical translation. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 29:102239. [PMID: 32544449 DOI: 10.1016/j.nano.2020.102239] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/01/2020] [Accepted: 06/02/2020] [Indexed: 01/20/2023]
Abstract
Gene silencing by RNA interference represents a promising therapeutic approach. The development of carriers, e.g., polymers, lipids, peptides, antibodies, aptamers, small molecules, exosome and red blood cells, is crucial for the systemic delivery of siRNA. Cell-specific targeting ligands in the nano-carriers can improve the pharmacokinetics, biodistribution, and selectivity of siRNA therapeutics. The safety, effectiveness, quality and prosperity of production and manufacturing are important considerations for selecting the appropriate siRNA carriers. Efficacy of systemic delivery of siRNA requires considerations of trafficking through the blood, off-target effects, innate immune response and endosomal escape avoiding lysosomal degradation for entering into RNAi process. Multifunctional nanocarriers with stimuli-responsive properties such as pH, magnetic and photo-sensitive segments can enhance the efficacy of siRNA delivery. The improved preclinical characterization of suitable siRNA drugs, good laboratory practice, that reduce the differences between in vitro and in vivo results may increase the success of siRNA drugs in clinical settings.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, ShahJalal University of Science and Technology, Sylhet, Bangladesh.
| | - V P Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA; Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
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Sharma G, Jagtap JM, Parchur AK, Gogineni VR, Ran S, Bergom C, White SB, Flister MJ, Joshi A. Heritable modifiers of the tumor microenvironment influence nanoparticle uptake, distribution and response to photothermal therapy. Theranostics 2020; 10:5368-5383. [PMID: 32373218 PMCID: PMC7196309 DOI: 10.7150/thno.41171] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 03/16/2020] [Indexed: 12/14/2022] Open
Abstract
We report the impact of notch-DLL4-based hereditary vascular heterogeneities on the enhanced permeation and retention (EPR) effect and plasmonic photothermal therapy response in tumors. Methods: We generated two consomic rat strains with differing DLL4 expression on 3rd chromosome. These strains were based on immunocompromised Salt-sensitive or SSIL2Rγ- (DLL4-high) and SS.BN3IL2Rγ- (DLL4-low) rats with 3rd chromosome substituted from Brown Norway rat. We further constructed three novel SS.BN3IL2Rγ- congenic strains by introgressing varying segments of BN chromosome 3 into the parental SSIL2Rγ- strain to localize the role of SSIL2Rγ- DLL4 on tumor EPR effect with precision. We synthesized multimodal theranostic nanoparticles (TNPs) based on Au-nanorods which provide magnetic resonance imaging (MRI), X-ray, and optical contrasts to assess image guided PTT response and quantify host specific therapy response differences in tumors orthotopically xenografted in DLL4-high and -low strains. We tested recovery of therapy sensitivity of PTT resistant strains by employing anti-DLL4 conjugated TNPs in two triple negative breast cancer tumor xenografts. Results: Host strains with high DLL4 allele demonstrated slightly increased tumor nanoparticle uptake but consistently developed photothermal therapy resistance compared to tumors in host strains with low DLL4 allele. Tumor micro-environment with low DLL4 expression altered the geographic distribution of nanoparticles towards closer proximity with vasculature which improved efficacy of PTT in spite of lower overall TNP uptake. Targeting TNPs to tumor endothelium via anti-DLL4 antibody conjugation improved therapy sensitivity in high DLL4 allele hosts for two triple negative human breast cancer xenografts. Conclusions: Inherited DLL4 expression modulates EPR effects in tumors, and molecular targeting of endothelial DLL4 via nanoparticles is an effective personalized nanomedicine strategy.
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Affiliation(s)
- Gayatri Sharma
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Jaidip M. Jagtap
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Abdul K. Parchur
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
| | | | - Sophia Ran
- Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL, USA
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA
| | - Carmen Bergom
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Sarah B. White
- Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Michael J. Flister
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Amit Joshi
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA
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Smekalova EM, Gerashchenko MV, O'Connor PBF, Whittaker CA, Kauffman KJ, Fefilova AS, Zatsepin TS, Bogorad RL, Baranov PV, Langer R, Gladyshev VN, Anderson DG, Koteliansky V. In Vivo RNAi-Mediated eIF3m Knockdown Affects Ribosome Biogenesis and Transcription but Has Limited Impact on mRNA-Specific Translation. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 19:252-266. [PMID: 31855834 PMCID: PMC6926209 DOI: 10.1016/j.omtn.2019.11.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 10/20/2019] [Accepted: 11/05/2019] [Indexed: 12/19/2022]
Abstract
Translation is an essential biological process, and dysregulation is associated with a range of diseases including ribosomopathies, diabetes, and cancer. Here, we examine translation dysregulation in vivo using RNAi to knock down the m-subunit of the translation initiation factor eIF3 in the mouse liver. Transcriptome sequencing, ribosome profiling, whole proteome, and phosphoproteome analyses show that eIF3m deficiency leads to the transcriptional response and changes in cellular translation that yield few detectable differences in the translation of particular mRNAs. The transcriptional response fell into two main categories: ribosome biogenesis (increased transcription of ribosomal proteins) and cell metabolism (alterations in lipid, amino acid, nucleic acid, and drug metabolism). Analysis of ribosome biogenesis reveals inhibition of rRNA processing, highlighting decoupling of rRNA synthesis and ribosomal protein gene transcription in response to eIF3m knockdown. Interestingly, a similar reduction in eIF3m protein levels is associated with induction of the mTOR pathway in vitro but not in vivo. Overall, this work highlights the utility of a RNAi-based in vivo approach for studying the regulation of mammalian translation in vivo.
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Affiliation(s)
- Elena M Smekalova
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Maxim V Gerashchenko
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Patrick B F O'Connor
- School of Biochemistry and Cell Biology, University College Cork, Cork T12 YN60, Ireland
| | - Charles A Whittaker
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Kevin J Kauffman
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Anna S Fefilova
- Skolkovo Institute of Science and Technology, Skolkovo, Moscow, 121205, Russia
| | - Timofei S Zatsepin
- Skolkovo Institute of Science and Technology, Skolkovo, Moscow, 121205, Russia; Department of Chemistry and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia
| | - Roman L Bogorad
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Pavel V Baranov
- School of Biochemistry and Cell Biology, University College Cork, Cork T12 YN60, Ireland; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, RAS, Moscow 117997, Russia
| | - Robert Langer
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Vadim N Gladyshev
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Daniel G Anderson
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA; Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
| | - Victor Koteliansky
- Skolkovo Institute of Science and Technology, Skolkovo, Moscow, 121205, Russia.
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Leboeuf D, Abakumova T, Prikazchikova T, Rhym L, Anderson DG, Zatsepin TS, Piatkov KI. Downregulation of the Arg/N-degron Pathway Sensitizes Cancer Cells to Chemotherapy In Vivo. Mol Ther 2020; 28:1092-1104. [PMID: 32087767 DOI: 10.1016/j.ymthe.2020.01.021] [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: 09/19/2019] [Accepted: 01/16/2020] [Indexed: 02/07/2023] Open
Abstract
The N-degron pathway is an emerging target for anti-tumor therapies, because of its capacity to positively regulate many hallmarks of cancer, including angiogenesis, cell proliferation, motility, and survival. Thus, inhibition of the N-degron pathway offers the potential to be a highly effective anti-cancer treatment. With the use of a small interfering RNA (siRNA)-mediated approach for selective downregulation of the four Arg/N-degron-dependent ubiquitin ligases, UBR1, UBR2, UBR4, and UBR5, we demonstrated decreased cell migration and proliferation and increased spontaneous apoptosis in cancer cells. Chronic treatment with lipid nanoparticles (LNPs) loaded with siRNA in mice efficiently downregulates the expression of UBR-ubiquitin ligases in the liver without any significant toxic effects but engages the immune system and causes inflammation. However, when used in a lower dose, in combination with a chemotherapeutic drug, downregulation of the Arg/N-degron pathway E3 ligases successfully reduced tumor load by decreasing proliferation and increasing apoptosis in a mouse model of hepatocellular carcinoma, while avoiding the inflammatory response. Our study demonstrates that UBR-ubiquitin ligases of the Arg/N-degron pathway are promising targets for the development of improved therapies for many cancer types.
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Affiliation(s)
| | | | | | - Luke Rhym
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Daniel G Anderson
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
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Liver Cancer: Current and Future Trends Using Biomaterials. Cancers (Basel) 2019; 11:cancers11122026. [PMID: 31888198 PMCID: PMC6966667 DOI: 10.3390/cancers11122026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/11/2019] [Accepted: 12/13/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches-e.g., cell capture-as promising future trends in the application of biomaterials to treat HCC.
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Integrin β 1-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol 2019; 71:1193-1205. [PMID: 31433301 PMCID: PMC6864271 DOI: 10.1016/j.jhep.2019.07.019] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/08/2019] [Accepted: 07/15/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatic recruitment of monocyte-derived macrophages (MoMFs) contributes to the inflammatory response in non-alcoholic steatohepatitis (NASH). However, how hepatocyte lipotoxicity promotes MoMF inflammation is unclear. Here we demonstrate that lipotoxic hepatocyte-derived extracellular vesicles (LPC-EVs) are enriched with active integrin β1 (ITGβ1), which promotes monocyte adhesion and liver inflammation in murine NASH. METHODS Hepatocytes were treated with either vehicle or the toxic lipid mediator lysophosphatidylcholine (LPC); EVs were isolated from the conditioned media and subjected to proteomic analysis. C57BL/6J mice were fed a diet rich in fat, fructose, and cholesterol (FFC) to induce NASH. Mice were treated with anti-ITGβ1 neutralizing antibody (ITGβ1Ab) or control IgG isotype. RESULTS Ingenuity® Pathway Analysis of the LPC-EV proteome indicated that ITG signaling is an overrepresented canonical pathway. Immunogold electron microscopy and nanoscale flow cytometry confirmed that LPC-EVs were enriched with activated ITGβ1. Furthermore, we showed that LPC treatment in hepatocytes activates ITGβ1 and mediates its endocytic trafficking and sorting into EVs. LPC-EVs enhanced monocyte adhesion to liver sinusoidal cells, as observed by shear stress adhesion assay. This adhesion was attenuated in the presence of ITGβ1Ab. FFC-fed, ITGβ1Ab-treated mice displayed reduced inflammation, defined by decreased hepatic infiltration and activation of proinflammatory MoMFs, as assessed by immunohistochemistry, mRNA expression, and flow cytometry. Likewise, mass cytometry by time-of-flight on intrahepatic leukocytes showed that ITGβ1Ab reduced levels of infiltrating proinflammatory monocytes. Furthermore, ITGβ1Ab treatment significantly ameliorated liver injury and fibrosis. CONCLUSIONS Lipotoxic EVs mediate monocyte adhesion to LSECs mainly through an ITGβ1-dependent mechanism. ITGβ1Ab ameliorates diet-induced NASH in mice by reducing MoMF-driven inflammation, suggesting that blocking ITGβ1 is a potential anti-inflammatory therapeutic strategy in human NASH. LAY SUMMARY Herein, we report that a cell adhesion molecule termed integrin β1 (ITGβ1) plays a key role in the progression of non-alcoholic steatohepatitis (NASH). ITGβ1 is released from hepatocytes under lipotoxic stress as a cargo of extracellular vesicles, and mediates monocyte adhesion to liver sinusoidal endothelial cells, which is an essential step in hepatic inflammation. In a mouse model of NASH, blocking ITGβ1 reduces liver inflammation, injury and fibrosis. Hence, ITGβ1 inhibition may serve as a new therapeutic strategy for NASH.
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Efficient nanocarriers of siRNA therapeutics for cancer treatment. Transl Res 2019; 214:62-91. [PMID: 31369717 DOI: 10.1016/j.trsl.2019.07.006] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/01/2019] [Accepted: 07/15/2019] [Indexed: 02/02/2023]
Abstract
Nanocarriers as drug delivery systems are promising and becoming popular, especially for cancer treatment. In addition to improving the pharmacokinetics of poorly soluble hydrophobic drugs by solubilizing them in a hydrophobic core, nanocarriers allow cancer-specific combination drug deliveries by inherent passive targeting phenomena and adoption of active targeting strategies. Nanoparticle-drug formulations can enhance the safety, pharmacokinetic profiles, and bioavailability of locally or systemically administered drugs, leading to improved therapeutic efficacy. Gene silencing by RNA interference (RNAi) is rapidly developing as a personalized field of cancer treatment. Small interfering RNAs (siRNAs) can be used to switch off specific cancer genes, in effect, "silence the gene, silence the cancer." siRNA can be used to silence specific genes that produce harmful or abnormal proteins. The activity of siRNA can be used to harness cellular machinery to destroy a corresponding sequence of mRNA that encodes a disease-causing protein. At present, the main barrier to implementing siRNA therapies in clinical practice is the lack of an effective delivery system that protects the siRNA from nuclease degradation, delivers to it to cancer cells, and releases it into the cytoplasm of targeted cancer cells, without creating adverse effects. This review provides an overview of various nanocarrier formulations in both research and clinical applications with a focus on combinations of siRNA and chemotherapeutic drug delivery systems for the treatment of multidrug resistant cancer. The use of various nanoparticles for siRNA-drug delivery, including liposomes, polymeric nanoparticles, dendrimers, inorganic nanoparticles, exosomes, and red blood cells for targeted drug delivery in cancer is discussed.
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Reghupaty SC, Sarkar D. Current Status of Gene Therapy in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:cancers11091265. [PMID: 31466358 PMCID: PMC6770843 DOI: 10.3390/cancers11091265] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/21/2019] [Accepted: 08/27/2019] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer related deaths world-wide. Liver transplantation, surgical resection, trans-arterial chemoembolization, and radio frequency ablation are effective strategies to treat early stage HCC. Unfortunately, HCC is usually diagnosed at an advanced stage and there are not many treatment options for late stage HCC. First-line therapy for late stage HCC includes sorafenib and lenvatinib. However, these treatments provide only an approximate three month increase in survival. Besides, they cannot specifically target cancer cells that lead to a wide array of side effects. Patients on these drugs develop resistance within a few months and have to rely on second-line therapy that includes regorafenib, pembrolizumab, nivolumab, and cabometyx. These disadvantages make gene therapy approach to treat HCC an attractive option. The two important questions that researchers have been trying to answer in the last 2-3 decades are what genes should be targeted and what delivery systems should be used. The objective of this review is to analyze the changing landscape of HCC gene therapy, with a focus on these two questions.
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Affiliation(s)
- Saranya Chidambaranathan Reghupaty
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Cancer Center, VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA.
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Jafarnejad M, Sové RJ, Danilova L, Mirando AC, Zhang Y, Yarchoan M, Tran PT, Pandey NB, Fertig EJ, Popel AS. Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma. NPJ Syst Biol Appl 2019; 5:29. [PMID: 31452933 PMCID: PMC6697704 DOI: 10.1038/s41540-019-0107-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte growth factor (HGF) signaling through its receptor Met has been implicated in hepatocellular carcinoma tumorigenesis and progression. Met interaction with integrins is shown to modulate the downstream signaling to Akt and ERK (extracellular-regulated kinase). In this study, we developed a mechanistically detailed systems biology model of HGF/Met signaling pathway that incorporated specific interactions with integrins to investigate the efficacy of integrin-binding peptide, AXT050, as monotherapy and in combination with other therapeutics targeting this pathway. Here we report that the modeled dynamics of the response to AXT050 revealed that receptor trafficking is sufficient to explain the effect of Met-integrin interactions on HGF signaling. Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for the patients.
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Affiliation(s)
- Mohammad Jafarnejad
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Richard J. Sové
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Ludmila Danilova
- Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA
| | - Adam C. Mirando
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Yu Zhang
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Phuoc T. Tran
- Department of Radiation Oncology and Molecular and Radiation Sciences, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Centre and Department of Urology, The Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Niranjan B. Pandey
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
| | - Elana J. Fertig
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
- Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD USA
| | - Aleksander S. Popel
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD USA
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Morales-Navarrete H, Nonaka H, Scholich A, Segovia-Miranda F, de Back W, Meyer K, Bogorad RL, Koteliansky V, Brusch L, Kalaidzidis Y, Jülicher F, Friedrich BM, Zerial M. Liquid-crystal organization of liver tissue. eLife 2019; 8:e44860. [PMID: 31204997 PMCID: PMC6598764 DOI: 10.7554/elife.44860] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 06/14/2019] [Indexed: 12/13/2022] Open
Abstract
Functional tissue architecture originates by self-assembly of distinct cell types, following tissue-specific rules of cell-cell interactions. In the liver, a structural model of the lobule was pioneered by Elias in 1949. This model, however, is in contrast with the apparent random 3D arrangement of hepatocytes. Since then, no significant progress has been made to derive the organizing principles of liver tissue. To solve this outstanding problem, we computationally reconstructed 3D tissue geometry from microscopy images of mouse liver tissue and analyzed it applying soft-condensed-matter-physics concepts. Surprisingly, analysis of the spatial organization of cell polarity revealed that hepatocytes are not randomly oriented but follow a long-range liquid-crystal order. This does not depend exclusively on hepatocytes receiving instructive signals by endothelial cells, since silencing Integrin-β1 disrupted both liquid-crystal order and organization of the sinusoidal network. Our results suggest that bi-directional communication between hepatocytes and sinusoids underlies the self-organization of liver tissue.
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Affiliation(s)
| | - Hidenori Nonaka
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - André Scholich
- Max Planck Institute for the Physics of Complex SystemsDresdenGermany
| | | | - Walter de Back
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav CarusTechnische Universität DresdenDresdenGermany
- Centre for Information Services and High Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Kirstin Meyer
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Roman L Bogorad
- David H. Koch Institute for Integrative Cancer ResearchMassachusetts Institute of TechnologyCambridgeUnited States
| | - Victor Koteliansky
- Skolkovo Institute of Science and TechnologySkolkovoRussia
- Department of ChemistryMV Lomonosov Moscow State UniversityMoscowRussia
| | - Lutz Brusch
- Centre for Information Services and High Performance ComputingTechnische Universität DresdenDresdenGermany
| | - Yannis Kalaidzidis
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
| | - Frank Jülicher
- Max Planck Institute for the Physics of Complex SystemsDresdenGermany
- Cluster of Excellence Physics of LifeTU DresdenDresdenGermany
| | - Benjamin M Friedrich
- Cluster of Excellence Physics of LifeTU DresdenDresdenGermany
- Center for Advancing Electronics DresdenTechnische Universität DresdenDresdenGermany
| | - Marino Zerial
- Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
- Cluster of Excellence Physics of LifeTU DresdenDresdenGermany
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42
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Hong Y, Rao Y. Current status of nanoscale drug delivery systems for colorectal cancer liver metastasis. Biomed Pharmacother 2019; 114:108764. [DOI: 10.1016/j.biopha.2019.108764] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 02/25/2019] [Accepted: 03/06/2019] [Indexed: 12/24/2022] Open
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43
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Ge L, Zhang X, Hu S, Song Y, Kong J, Zhang B, Yang X. H19 suppresses the growth of hepatoblastoma cells by promoting their apoptosis via the signaling pathways of miR-675/FADD and miR-138/PTK2. J Cell Biochem 2019; 120:5218-5231. [PMID: 30367502 DOI: 10.1002/jcb.27797] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 09/10/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The objective of this study was to clarify the molecular pathways involved in hepatitis B virus (HBV)-induced hepatoblastoma. METHOD The expression of factors in different signaling pathways (H19, miR-675, miR-138, protein tyrosine kinase 2 [PTK2], fas-associated death domain [FADD], hypoxia-inducible factor 1-alpha [HIFIA], focal adhesion kinase [FAK], caspase-8, and caspase-3) was compared between HBV (+) and HBV (-) groups using quantitative real-time polymerase chain reaction and Western blot analysis. Subsequently, immunohistochemistry (IHC) and TdT-mediated dUTP Nick-End Labeling (TUNEL) assays were used to verify the expression of above proteins in HBV (+) and HBV (-) groups. Computational analysis was conducted to predict the target genes of miR-675 and miR-138, whose regulatory relationships were then clarified using luciferase assays and cell transfection studies. RESULT The expression of H19, miR-675, PTK2, HIFIA, and FAK was increased in the HBV (+) group, while the expression of miR-138, FADD, caspase-8, and caspase-3 was decreased in the HBV (+) group. FADD and PTK2 were identified as target genes of miR-675 and miR-138, respectively. In addition, miR-675 was upregulated while miR-138 was downregulated by X protein (HBx). CONCLUSION In summary, the results of this study revealed the molecular pathways involved in HBV-induced hepatoblastoma. In the presence of HBV, HBX upregulated the expression of H19 through HIFIA. Consecutively, overexpressed H19 upregulated the expression of PTK2 via targeting miR-138 and downregulated the expression of FADD via targeting miR-675. Finally, increased expression of PTK2 and reduced expression of FADD both led to the inhibition of cell apoptosis, thus promoting the tumorigenesis of hepatoblastoma.
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Affiliation(s)
- Lili Ge
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University (Henan Children's Hospital, Zhengzhou Children's Hospital), Zhengzhou, Henan, China
| | - Xianwei Zhang
- Department of Pediatric Oncologic Surgery, Children's Hospital Affiliated to Zhengzhou University (Henan Children's Hospital, Zhengzhou Children's Hospital), Zhengzhou, Henan, China
| | - Shengnan Hu
- Department of Liver Disease, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Yinsen Song
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University (Henan Children's Hospital, Zhengzhou Children's Hospital), Zhengzhou, Henan, China
| | - Jinghui Kong
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University (Henan Children's Hospital, Zhengzhou Children's Hospital), Zhengzhou, Henan, China
| | - Bo Zhang
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University (Henan Children's Hospital, Zhengzhou Children's Hospital), Zhengzhou, Henan, China
| | - Xiaoang Yang
- Department of Liver Disease, Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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44
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Cooper J, Giancotti FG. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell 2019; 35:347-367. [PMID: 30889378 PMCID: PMC6684107 DOI: 10.1016/j.ccell.2019.01.007] [Citation(s) in RCA: 581] [Impact Index Per Article: 96.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 10/10/2018] [Accepted: 01/14/2019] [Indexed: 12/16/2022]
Abstract
Integrins mediate cell adhesion and transmit mechanical and chemical signals to the cell interior. Various mechanisms deregulate integrin signaling in cancer, empowering tumor cells with the ability to proliferate without restraint, to invade through tissue boundaries, and to survive in foreign microenvironments. Recent studies have revealed that integrin signaling drives multiple stem cell functions, including tumor initiation, epithelial plasticity, metastatic reactivation, and resistance to oncogene- and immune-targeted therapies. Here, we discuss the mechanisms leading to the deregulation of integrin signaling in cancer and its various consequences. We place emphasis on novel functions, determinants of context dependency, and mechanism-based therapeutic opportunities.
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Affiliation(s)
- Jonathan Cooper
- Department of Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Filippo G Giancotti
- Department of Cancer Biology and David H. Koch Center for Applied Research of Genitourinary Cancers, UT MD Anderson Cancer Center, Houston, TX 77054, USA.
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45
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Hajiasgharzadeh K, Somi MH, Shanehbandi D, Mokhtarzadeh A, Baradaran B. Small interfering RNA-mediated gene suppression as a therapeutic intervention in hepatocellular carcinoma. J Cell Physiol 2018; 234:3263-3276. [PMID: 30362510 DOI: 10.1002/jcp.27015] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 06/25/2018] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the lethal and difficult-to-cure cancers worldwide. Owing to the late diagnosis and drug resistance of malignant hepatocytes, treatment of this cancer by conventional chemotherapy agents is challenging, and researchers are seeking new alternative treatment options to overcome therapy resistance in this neoplasm. RNA interference (RNAi) is a potent and specific approach in targeting gene expression and has emerged as a novel therapeutic tool for many diseases, including cancers. Small interfering RNA (siRNA) is a type of RNAi that is produced intracellularly from exogenous synthetic oligonucleotides and can selectively knock down target gene expression in a sequence-specific manner. Various factors play roles in the initiation and progression of HCC and provide multiple candidate targets for siRNA intervention. In addition, due to the liver's unique architecture and availability of some hepatic siRNA delivery methods, this organ has received much more attention as a target tissue for such oligonucleotide action. Recent advances in designing nanoparticle systems for the in vivo delivery of siRNAs have markedly enhanced the potency of siRNA-mediated gene silencing under clinical development for HCC therapy. The utility of siRNAs as anti-HCC agents is the subject of the current review. siRNA-based gene therapies could be one of the main feasible approaches for HCC therapy in the future.
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Affiliation(s)
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Liu XY, Zhou CB, Fang C. Nanomaterial-involved neural stem cell research: Disease treatment, cell labeling, and growth regulation. Biomed Pharmacother 2018; 107:583-597. [PMID: 30114642 DOI: 10.1016/j.biopha.2018.08.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 07/19/2018] [Accepted: 08/06/2018] [Indexed: 12/21/2022] Open
Abstract
Neural stem cells (NSCs) have been widely investigated for their potential in the treatment of various diseases and transplantation therapy. However, NSC growth regulation, labeling, and its application to disease diagnosis and treatment are outstanding challenges. Recently, nanomaterials have shown promise for various applications including genetic modification, imaging, and controlled drug release. Here we summarize the recent progress in the use of nanomaterials in combination with NSCs for disease treatment and diagnosis, cell labeling, and NSC growth regulation. The toxicity of nanomaterials to NSCs is also discussed.
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Affiliation(s)
- Xiang-Yu Liu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China
| | - Cheng-Bin Zhou
- Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders (Ministry of Education), Shanghai Key Laboratory of Psychotic Disorders, and Brain Science and Technology Research Center, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240 China
| | - Chao Fang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
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47
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Tian T, Li CL, Fu X, Wang SH, Lu J, Guo H, Yao Y, Nan KJ, Yang YJ. β1 integrin-mediated multicellular resistance in hepatocellular carcinoma through activation of the FAK/Akt pathway. J Int Med Res 2018; 46:1311-1325. [PMID: 29332411 PMCID: PMC6091828 DOI: 10.1177/0300060517740807] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Objective To explore the role and mechanism of β1 integrin in the regulation of multicellular drug resistance in hepatocellular carcinoma (HCC). Methods This in vitro study used a liquid overlay technique to obtain multicellular spheroids of two human HCC cell lines, HepG2 and Bel-7402. The morphology of the spheroids was observed by optical and electron microscopy. The effects of exposure to 5-fluorouracil (5-FU) and cisplatin (CDDP) on cell proliferation and the induction of apoptosis were assessed in monolayer cells and multicellular spheroids. The levels of β1 integrin and the effects on the focal adhesion kinase (FAK)/protein kinase B (Akt) pathway were evaluated using Western blot analysis, immunofluorescence and flow cytometry. The role of β1 integrin was confirmed by using an inhibitory antibody. Results Cell proliferation inhibition and cell apoptosis induced by 5-FUl and CDDP were abrogated in multicellular spheroids compared with monolayer cells. There were high levels of β1 integrin in multicellular spheroids. β1 integrin inhibitory antibody prevented the formation of multicellular spheroids, coupled with a significant increase in proliferation inhibition and apoptosis induction. β1 integrin inhibitory antibody effectively suppressed activation of both FAK and Akt in multicellular spheroids. Conclusions β1 integrin mediated multicellular drug resistance through the FAK/Akt pathway in HCC spheroids.
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Affiliation(s)
- Tao Tian
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Chun-Li Li
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Xiao Fu
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Shu-Hong Wang
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Jun Lu
- 2 Clinical Research Centre, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Hui Guo
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Yu Yao
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Ke-Jun Nan
- 1 Department of Oncology, 162799 First Affiliated Hospital of Xi'an Jiaotong University , Xi'an, Shaanxi Province, China
| | - Yu-Juan Yang
- 3 Third Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, China
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Recent advances in smart biotechnology: Hydrogels and nanocarriers for tailored bioactive molecules depot. Adv Colloid Interface Sci 2017; 249:163-180. [PMID: 28527520 DOI: 10.1016/j.cis.2017.05.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 05/06/2017] [Accepted: 05/08/2017] [Indexed: 12/18/2022]
Abstract
Over the past ten years, the global biopharmaceutical market has remarkably grown, with ten over the top twenty worldwide high performance medical treatment sales being biologics. Thus, biotech R&D (research and development) sector is becoming a key leading branch, with expanding revenues. Biotechnology offers considerable advantages compared to traditional therapeutic approaches, such as reducing side effects, specific treatments, higher patient compliance and therefore more effective treatments leading to lower healthcare costs. Within this sector, smart nanotechnology and colloidal self-assembling systems represent pivotal tools able to modulate the delivery of therapeutics. A comprehensive understanding of the processes involved in the self-assembly of the colloidal structures discussed therein is essential for the development of relevant biomedical applications. In this review we report the most promising and best performing platforms for specific classes of bioactive molecules and related target, spanning from siRNAs, gene/plasmids, proteins/growth factors, small synthetic therapeutics and bioimaging probes.
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Ofek P, Tiram G, Satchi-Fainaro R. Angiogenesis regulation by nanocarriers bearing RNA interference. Adv Drug Deliv Rev 2017; 119:3-19. [PMID: 28163106 DOI: 10.1016/j.addr.2017.01.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 01/25/2017] [Accepted: 01/31/2017] [Indexed: 12/22/2022]
Abstract
Since the approval of bevacizumab as anti-angiogenic therapy in 2004 by the FDA, an array of angiogenesis inhibitors have been developed and approved. However, results were disappointing with regard to their therapeutic efficacy. RNA interference approaches offer the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer. However, in vivo delivery issues still represent a significant obstacle for widespread clinical applications. In the current review, we summarize the advances in the last decade in the field of angiogenesis-targeted RNA interference approaches, with special emphasis on oncology applications. We present pro-angiogenic and anti-angiogenic factors as potential targets, experimental evidence and clinical trials data on angiogenesis regulation by RNA interference. Consequent challenges and opportunities are discussed.
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Affiliation(s)
- Paula Ofek
- Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Galia Tiram
- Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Ronit Satchi-Fainaro
- Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
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50
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Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 2017; 547:350-354. [PMID: 28700576 PMCID: PMC5522613 DOI: 10.1038/nature23015] [Citation(s) in RCA: 388] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 05/24/2017] [Indexed: 12/19/2022]
Abstract
Following liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired, a feature of human chronic liver disease1,2. It is contested whether other liver cell types can regenerate hepatocytes3–5. Here, we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. Firstly, loss of β1-Integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, and ~25% of hepatocytes being derived from a non-hepatocyte origin. Secondly cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-Integrin knockdown or p21 over-expression, resulting in the significant emergence of cholangiocyte derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.
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