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1
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Jin B, Miao Z, Pan J, Zhang Z, Yang Y, Zhou Y, Jin Y, Niu Z, Xu Q. The emerging role of glycolysis and immune evasion in ovarian cancer. Cancer Cell Int 2025; 25:78. [PMID: 40045411 PMCID: PMC11881340 DOI: 10.1186/s12935-025-03698-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 02/17/2025] [Indexed: 03/09/2025] Open
Abstract
Ovarian cancer (OC) is one of the three most common malignant tumors of the female reproductive system, with the highest mortality rate among gynecologic malignancies. Like other tumors, OC cells undergo metabolic reprogramming phenomenon and convert glucose metabolism into "aerobic glycolysis" and generate a high concentration of lactate, i.e., the "Warburg effect", which provides a large amount of energy and corresponding intermediary metabolites for their survival, reproduction and metastasis. Numerous studies have shown that targeted inhibition of aerobic glycolysis and lactate metabolism is a promising strategy to enhance the sensitivity of cancer cells to immunotherapy. Therefore, this review summarizes the metabolic features of glycolysis in OC cells and highlights how abnormal lactate concentration affects the differentiation, metabolism, and function of infiltrating immune cells, which contributes to immunosuppression, and how targeted inhibition of this phenomenon may be a potential strategy to enhance the therapeutic efficacy of OC.
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Affiliation(s)
- Bowen Jin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zehua Miao
- Dalian Medical University, Dalian, China
| | - Junjie Pan
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhen Zhang
- Department of Oncology, Hangzhou Cancer Hospital, Zhejiang, Hangzhou, 310002, China
| | - Yibei Yang
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yidong Zhou
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuanxiang Jin
- Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Zheng Niu
- Department of Gynecology, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China.
| | - Qiaoping Xu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Westlake University School of Medicine, Hangzhou, 310006, China.
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China.
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2
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Chuang YT, Yen CY, Tang JY, Chang FR, Tsai YH, Wu KC, Chien TM, Chang HW. The modulation of immune cell death in connection to microRNAs and natural products. Front Immunol 2024; 15:1425602. [PMID: 39759512 PMCID: PMC11695430 DOI: 10.3389/fimmu.2024.1425602] [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: 04/30/2024] [Accepted: 11/27/2024] [Indexed: 01/07/2025] Open
Abstract
Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs.
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Affiliation(s)
- Ya-Ting Chuang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Yu Yen
- School of Dentistry, Taipei Medical University, Taipei, Taiwan
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hong Tsai
- Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan
| | - Kuo-Chuan Wu
- Department of Computer Science and Information Engineering, National Pingtung University, Pingtung, Taiwan
| | - Tsu-Ming Chien
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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3
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Hsu CY, Ahmed AT, Bansal P, Hjazi A, Al-Hetty HRAK, Qasim MT, Sapaev I, Deorari M, Mustafa YF, Elawady A. MicroRNA-enriched exosome as dazzling dancer between cancer and immune cells. J Physiol Biochem 2024; 80:811-829. [PMID: 39316240 DOI: 10.1007/s13105-024-01050-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 09/11/2024] [Indexed: 09/25/2024]
Abstract
Exosomes are widely recognized for their roles in numerous biological processes and as intercellular communication mediators. Human cancerous and normal cells can both produce massive amounts of exosomes. They are extensively dispersed in tumor-modeling animals' pleural effusions, ascites, and plasma from people with cancer. Tumor cells interact with host cells by releasing exosomes, which allow them to interchange various biological components. Tumor growth, invasion, metastasis, and even tumorigenesis can all be facilitated by this delicate and complex system by modifying the nearby and remote surroundings. Due to the existence of significant levels of biomolecules like microRNA, exosomes can modulate the immune system's stimulation or repression, which in turn controls tumor growth. However, the role of microRNA in exosome-mediated communication between immunological and cancer cells is still poorly understood. This study aims to get the most recent information on the "yin and yang" of exosomal microRNA in the regulation of tumor immunity and immunotherapy, which will aid current cancer treatment and diagnostic techniques.
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Affiliation(s)
- Chou-Yi Hsu
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, Arizona 85004, USA
| | - Abdulrahman T Ahmed
- Department of Nursing, Al-Maarif University College, Ramadi, AL-Anbar Governorate, Iraq
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, 560069, Karnataka, India
- Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | | | - Maytham T Qasim
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, 64001, Iraq
| | - Ibrokhim Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers" National Research University, Tashkent, Uzbekistan
- School of Engineering, Central Asian University, Tashkent, 111221, Uzbekistan
- Western Caspian University, Scientific researcher, Baku, Azerbaijan
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Ahmed Elawady
- College of Technical Engineering, the Islamic University, Najaf, Iraq
- College of Technical Engineering, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, the Islamic University of Babylon, Babylon, Iraq
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4
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Wilczyński M, Wilczyński J, Nowak M. MiRNAs as Regulators of Immune Cells in the Tumor Microenvironment of Ovarian Cancer. Cells 2024; 13:1343. [PMID: 39195233 PMCID: PMC11352322 DOI: 10.3390/cells13161343] [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: 06/24/2024] [Revised: 07/25/2024] [Accepted: 08/06/2024] [Indexed: 08/29/2024] Open
Abstract
Ovarian cancer is one of the leading causes of cancer deaths among women. There is an ongoing need to develop new biomarkers and targeted therapies to improve patient outcomes. One of the most critical research areas in ovarian cancer is identifying tumor microenvironment (TME) functions. TME consists of tumor-infiltrating immune cells, matrix, endothelial cells, pericytes, fibroblasts, and other stromal cells. Tumor invasion and growth depend on the multifactorial crosstalk between tumor cells and immune cells belonging to the TME. MiRNAs, which belong to non-coding RNAs that post-transcriptionally control the expression of target genes, regulate immune responses within the TME, shaping the landscape of the intrinsic environment of tumor cells. Aberrant expression of miRNAs may lead to the pathological dysfunction of signaling pathways or cancer cell-regulatory factors. Cell-to-cell communication between infiltrating immune cells and the tumor may depend on exosomes containing multiple miRNAs. MiRNAs may exert both immunosuppressive and immunoreactive responses, which may cause cancer cell elimination or survival. In this review, we highlighted recent advances in the field of miRNAs shaping the landscape of immune cells in the TME.
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Affiliation(s)
- Miłosz Wilczyński
- Department of Operative Gynecology, Endoscopy and Gynecologic Oncology, Polish Mother’s Health Center-Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland
| | - Jacek Wilczyński
- Department of Gynecological Surgery and Gynecological Oncology, Medical University of Lodz, 4 Kosciuszki Str., 90-419 Lodz, Poland;
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother’s Health Center-Research Institute, 281/289 Rzgowska Str., 93-338 Lodz, Poland;
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5
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Shah NN, Dave BP, Shah KC, Shah DD, Maheshwari KG, Chorawala MR, Parekh PS, Jani M. Disabled-2, a versatile tissue matrix multifunctional scaffold protein with multifaceted signaling: Unveiling its potential in the cancer battle. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:5533-5557. [PMID: 38502243 DOI: 10.1007/s00210-024-03037-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 03/01/2024] [Indexed: 03/21/2024]
Abstract
A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/β-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-β) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.
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Affiliation(s)
- Nidhi N Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Bhavarth P Dave
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Kashvi C Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Disha D Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Kunal G Maheshwari
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India.
| | - Priyajeet S Parekh
- AV Pharma LLC, 1545 University Blvd N Ste A, Jacksonville, FL, 32211, USA
| | - Maharsh Jani
- Anand Niketan Shilaj, Ahmedabad, 380059, Gujarat, India
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6
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Tavares V, Savva-Bordalo J, Rei M, Liz-Pimenta J, Assis J, Pereira D, Medeiros R. Plasma microRNA Environment Linked to Tissue Factor Pathway and Cancer-Associated Thrombosis: Prognostic Significance in Ovarian Cancer. Biomolecules 2024; 14:928. [PMID: 39199316 PMCID: PMC11352941 DOI: 10.3390/biom14080928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 07/27/2024] [Accepted: 07/30/2024] [Indexed: 09/01/2024] Open
Abstract
Ovarian cancer (OC) is a leading cause of death among gynaecological malignancies. The haemostatic system, which controls blood flow and prevents clotting disorders, paradoxically drives OC progression while increasing the risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) have emerged as crucial in understanding VTE pathogenesis. Exploring the connection between cancer and thrombosis through these RNAs could lead to novel biomarkers of cancer-associated thrombosis (CAT) and OC, as well as potential therapeutic targets for tumour management. Thus, this study examined the impact of eight plasma miRNAs targeting the tissue factor (TF) coagulation pathway-miR-18a-5p, -19a-3p, -20a-5p, -23a-3p, -27a-3p, -103a-3p, -126-5p and -616-3p-in 55 OC patients. Briefly, VTE occurrence post-OC diagnosis was linked to shorter disease progression time (log-rank test, p = 0.024) and poorer overall survival (OS) (log-rank test, p < 0.001). High pre-chemotherapy levels of miR-20a-5p (targeting coagulation factor 3 (F3) and tissue factor pathway inhibitor 2 (TFPI2)) and miR-616-3p (targeting TFPI2) predicted VTE after OC diagnosis (χ2, p < 0.05). Regarding patients' prognosis regardless of VTE, miR-20a-5p independently predicted OC progression (adjusted hazard ratio (aHR) = 6.13, p = 0.005), while miR-616-3p significantly impacted patients' survival (aHR = 3.72, p = 0.020). Further investigation is warranted for their translation into clinical practice.
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Affiliation(s)
- Valéria Tavares
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal;
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- Faculty of Medicine, University of Porto (FMUP), 4200-072 Porto, Portugal;
| | - Joana Savva-Bordalo
- Department of Medical Oncology, Portuguese Institute of Oncology of Porto (IPO Porto), 4200-072 Porto, Portugal; (J.S.-B.); (D.P.)
| | - Mariana Rei
- Department of Gynaecology, Portuguese Institute of Oncology of Porto (IPO Porto), 4200-072 Porto, Portugal;
| | - Joana Liz-Pimenta
- Faculty of Medicine, University of Porto (FMUP), 4200-072 Porto, Portugal;
- Department of Medical Oncology, Centro Hospitalar de Trás-os-Montes e Alto Douro (CHTMAD), 5000-508 Vila Real, Portugal
| | - Joana Assis
- Clinical Research Unit, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto. CCC), 4200-072 Porto, Portugal;
| | - Deolinda Pereira
- Department of Medical Oncology, Portuguese Institute of Oncology of Porto (IPO Porto), 4200-072 Porto, Portugal; (J.S.-B.); (D.P.)
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/Pathology and Laboratory Medicine Dep., Clinical Pathology SV/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Centre (Porto. CCC), 4200-072 Porto, Portugal;
- ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- Faculty of Medicine, University of Porto (FMUP), 4200-072 Porto, Portugal;
- Faculty of Health Sciences, Fernando Pessoa University, 4200-150 Porto, Portugal
- Research Department, Portuguese League Against Cancer (NRNorte), 4200-172 Porto, Portugal
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Cantoni C, Falco M, Vitale M, Pietra G, Munari E, Pende D, Mingari MC, Sivori S, Moretta L. Human NK cells and cancer. Oncoimmunology 2024; 13:2378520. [PMID: 39022338 PMCID: PMC11253890 DOI: 10.1080/2162402x.2024.2378520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 07/05/2024] [Indexed: 07/20/2024] Open
Abstract
The long story of NK cells started about 50 y ago with the first demonstration of a natural cytotoxic activity within an undefined subset of circulating leukocytes, has involved an ever-growing number of researchers, fascinated by the apparently easy-to-reach aim of getting a "universal anti-tumor immune tool". In fact, in spite of the impressive progress obtained in the first decades, these cells proved far more complex than expected and, paradoxically, the accumulating findings have continuously moved forward the attainment of a complete control of their function for immunotherapy. The refined studies of these latter years have indicated that NK cells can epigenetically calibrate their functional potential, in response to specific environmental contexts, giving rise to extraordinarily variegated subpopulations, comprehensive of memory-like cells, tissue-resident cells, or cells in various differentiation stages, or distinct functional states. In addition, NK cells can adapt their activity in response to a complex body of signals, spanning from the interaction with either suppressive or stimulating cells (myeloid-derived suppressor cells or dendritic cells, respectively) to the engagement of various receptors (specific for immune checkpoints, cytokines, tumor/viral ligands, or mediating antibody-dependent cell-mediated cytotoxicity). According to this picture, the idea of an easy and generalized exploitation of NK cells is changing, and the way is opening toward new carefully designed, combined and personalized therapeutic strategies, also based on the use of genetically modified NK cells and stimuli capable of strengthening and redirecting their effector functions against cancer.
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Affiliation(s)
- Claudia Cantoni
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
- Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Michela Falco
- Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Massimo Vitale
- UO Pathology and Experimental Immunology, IRCCS Ospedale Policlinico, San Martino, Genova, Italy
| | - Gabriella Pietra
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
- UO Pathology and Experimental Immunology, IRCCS Ospedale Policlinico, San Martino, Genova, Italy
| | - Enrico Munari
- Pathology Unit, Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Daniela Pende
- UO Pathology and Experimental Immunology, IRCCS Ospedale Policlinico, San Martino, Genova, Italy
| | - Maria Cristina Mingari
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
- UO Pathology and Experimental Immunology, IRCCS Ospedale Policlinico, San Martino, Genova, Italy
| | - Simona Sivori
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico, San Martino, Genova, Italy
| | - Lorenzo Moretta
- Tumor Immunology Unit, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
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Leng X, Zhang M, Xu Y, Wang J, Ding N, Yu Y, Sun S, Dai W, Xue X, Li N, Yang Y, Shi Z. Non-coding RNAs as therapeutic targets in cancer and its clinical application. J Pharm Anal 2024; 14:100947. [PMID: 39149142 PMCID: PMC11325817 DOI: 10.1016/j.jpha.2024.02.001] [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: 10/27/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 08/17/2024] Open
Abstract
Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression. Oncogenes promote cell growth and proliferation, whereas tumor suppressor genes inhibit cell growth and division. The dysregulation of these genes can lead to the development of cancer. Recent studies have focused on non-coding RNAs (ncRNAs), including circular RNA (circRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), as therapeutic targets for cancer. In this article, we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets. Here, we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment. Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.
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Affiliation(s)
- Xuejiao Leng
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Mengyuan Zhang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujing Xu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jingjing Wang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ning Ding
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yancheng Yu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shanliang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Weichen Dai
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xin Xue
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nianguang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ye Yang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhihao Shi
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China
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9
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Shah NN, Dave BP, Shah KC, Shah DD, Maheshwari KG, Chorawala MR. Disable 2, A Versatile Tissue Matrix Multifunctional Scaffold Protein with Multifaceted Signaling: Unveiling Role in Breast Cancer for Therapeutic Revolution. Cell Biochem Biophys 2024; 82:501-520. [PMID: 38594547 DOI: 10.1007/s12013-024-01261-5] [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: 03/22/2024] [Indexed: 04/11/2024]
Abstract
The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- β (TGF-β) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.
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Affiliation(s)
- Nidhi N Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Bhavarth P Dave
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Kashvi C Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Disha D Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Kunal G Maheshwari
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad, 380009, Gujarat, India.
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10
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Afra F, Eftekhar SP, Farid AS, Ala M. Non-coding RNAs in cancer immunotherapy: A solution to overcome immune resistance? PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 209:215-240. [PMID: 39461753 DOI: 10.1016/bs.pmbts.2024.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
With the rapid advancement in immunotherapy, cancer immune resistance has become more evident, which demands new treatment approaches to achieve greater efficacy. Non-coding RNAs (ncRNAs) are a heterogeneous group of RNAs that are not translated to proteins but instead regulate different stages of gene expression. Recent studies have increasingly supported the critical role of ncRNAs in immune cell-cancer cell cross-talk, and numerous ncRNAs have been implicated in the immune evasion of cancer cells. Cancer cells take advantage of ncRNAs to modulate several signaling pathways and upregulate the expression of immune checkpoints and anti-inflammatory mediators, thereby dampening the anti-tumor response of M1 macrophages, dendritic cells, cytotoxic T cells, and natural killer cells or potentiating the immunosuppressive properties of M2 macrophages, regulatory T cells, and myeloid-derived suppressive cells. Upregulation of immunosuppressive ncRNAs or downregulation of immunogenic ncNRAs is a major driver of resistance to immune checkpoint inhibitors, cancer vaccines, and other means of cancer immunotherapy, making ncRNAs ideal targets for treatment. In addition, ncRNAs released by cancer cells have been demonstrated to possess prognostic values for patients who undergo cancer immunotherapy. Future clinical trials are urged to consider the potential of ncRNAs in cancer immunotherapy.
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Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Parsa Eftekhar
- Student Research Committee, Health Research Center, Babol University of Medical Sciences, Babol, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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11
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Wilkinson AN, Chen R, Coleborn E, Neilson T, Le K, Bhavsar C, Wang Y, Atluri S, Irgam G, Wong K, Yang D, Steptoe R, Wu SY. Let-7i enhances anti-tumour immunity and suppresses ovarian tumour growth. Cancer Immunol Immunother 2024; 73:80. [PMID: 38554167 PMCID: PMC10981620 DOI: 10.1007/s00262-024-03674-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/08/2024] [Indexed: 04/01/2024]
Abstract
Cancer immunotherapy has seen significant success in the last decade for cancer management by enhancing endogenous cancer immunity. However, immunotherapies developed thus far have seen limited success in the majority of high-grade serous carcinoma (HGSC) ovarian cancer patients. This is largely due to the highly immunosuppressive tumour microenvironment of HGSC and late-stage identification. Thus, novel treatment interventions are needed to overcome this immunosuppression and complement existing immunotherapies. Here, we have identified through analysis of > 600 human HGSC tumours a critical role for Let-7i in modulating the tumoural immune network. Tumoural expression of Let-7i had high positive correlation with anti-cancer immune signatures in HGSC patients. Confirming this role, enforced Let-7i expression in murine HGSC tumours resulted in a significant decrease in tumour burden with a significant increase in tumour T cell numbers in tumours. In concert with the improved tumoural immunity, Let-7i treatment also significantly increased CD86 expression in antigen presenting cells (APCs) in the draining lymph nodes, indicating enhanced APC activity. Collectively, our findings highlight an important role of Let-7i in anti-tumour immunity and its potential use for inducing an anti-tumour effect in HGSC.
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Affiliation(s)
- Andrew N Wilkinson
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Rui Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Elaina Coleborn
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Trent Neilson
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Khang Le
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Chintan Bhavsar
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Yue Wang
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Sharat Atluri
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Gowri Irgam
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Kiefer Wong
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
| | - Da Yang
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Raymond Steptoe
- Frazer Institute, University of Queensland, Brisbane, QLD, 4102, Australia
| | - Sherry Y Wu
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
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12
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Chen R, Coleborn E, Bhavsar C, Wang Y, Alim L, Wilkinson AN, Tran MA, Irgam G, Atluri S, Wong K, Shim JJ, Adityan S, Lee JS, Overwijk WW, Steptoe R, Yang D, Wu SY. miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8 + T cell infiltration. Mol Ther Oncolytics 2023; 31:100725. [PMID: 37781339 PMCID: PMC10539880 DOI: 10.1016/j.omto.2023.09.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 09/08/2023] [Indexed: 10/03/2023] Open
Abstract
Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53-/- and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53-/- cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors.
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Affiliation(s)
- Rui Chen
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Elaina Coleborn
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Chintan Bhavsar
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Yue Wang
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Louisa Alim
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Andrew N. Wilkinson
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | | | - Gowri Irgam
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Sharat Atluri
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Kiefer Wong
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Jae-Jun Shim
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Siddharth Adityan
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Willem W. Overwijk
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Raymond Steptoe
- Frazer Institute, University of Queensland, Brisbane, QLD 4102, Australia
| | - Da Yang
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Sherry Y. Wu
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
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13
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Toledo-Stuardo K, Ribeiro CH, Campos I, Tello S, Latorre Y, Altamirano C, Dubois-Camacho K, Molina MC. Impact of MICA 3'UTR allelic variability on miRNA binding prediction, a bioinformatic approach. Front Genet 2023; 14:1273296. [PMID: 38146340 PMCID: PMC10749337 DOI: 10.3389/fgene.2023.1273296] [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: 08/05/2023] [Accepted: 11/13/2023] [Indexed: 12/27/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that participate as powerful genetic regulators. MiRNAs can interfere with cellular processes by interacting with a broad spectrum of target genes under physiological and pathological states, including cancer development and progression. Major histocompatibility complex major histocompatibility complex class I-related chain A (MICA) belongs to a family of proteins that bind the natural-killer group 2, member D (NKG2D) receptor on Natural Killer cells and other cytotoxic lymphocytes. MICA plays a crucial role in the host's innate immune response to several disease settings, including cancer. MICA harbors various single nucleotide polymorphisms (SNPs) located in its 3'-untranslated region (3'UTR), a characteristic that increases the complexity of MICA regulation, favoring its post-transcriptional modulation by miRNAs under physiological and pathological conditions. Here, we conducted an in-depth analysis of MICA 3'UTR sequences according to each MICA allele described to date using NCBI database. We also systematically evaluated interactions between miRNAs and their putative targets on MICA 3'UTR containing SNPs using in silico analysis. Our in silico results showed that MICA SNPs rs9266829, rs 1880, and rs9266825, located in the target sequence of miRNAs hsa-miR-106a-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-93, hsa-miR-1207.5p, and hsa-miR-711 could modify the binding free energy between -8.62 and -18.14 kcal/mol, which may affect the regulation of MICA expression. We believe that our results may provide a starting point for further exploration of miRNA regulatory effects depending on MICA allelic variability; they may also be a guide to conduct miRNA in silico analysis for other highly polymorphic genes.
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Affiliation(s)
- Karen Toledo-Stuardo
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Carolina H. Ribeiro
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Ivo Campos
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Samantha Tello
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Yesenia Latorre
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Claudia Altamirano
- School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Karen Dubois-Camacho
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- Faculty of Medicine, Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- Gastroenterology and Hepatology Department, University Medical Center Groningen, Groningen, Netherlands
| | - Maria Carmen Molina
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
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14
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Abou Khouzam R, Janji B, Thiery J, Zaarour RF, Chamseddine AN, Mayr H, Savagner P, Kieda C, Gad S, Buart S, Lehn JM, Limani P, Chouaib S. Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy. Semin Cancer Biol 2023; 97:104-123. [PMID: 38029865 DOI: 10.1016/j.semcancer.2023.11.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/04/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023]
Abstract
In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.
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Affiliation(s)
- Raefa Abou Khouzam
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
| | - Bassam Janji
- Department of Cancer Research, Luxembourg Institute of Health, Tumor Immunotherapy and Microenvironment (TIME) Group, 6A, rue Nicolas-Ernest Barblé, L-1210 Luxembourg city, Luxembourg.
| | - Jerome Thiery
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Rania Faouzi Zaarour
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates.
| | - Ali N Chamseddine
- Gastroenterology Department, Cochin University Hospital, Université de Paris, APHP, Paris, France; Ambroise Paré - Hartmann Private Hospital Group, Oncology Unit, Neuilly-sur-Seine, France.
| | - Hemma Mayr
- Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland; Department of Surgery & Transplantation, University and University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland.
| | - Pierre Savagner
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Claudine Kieda
- Laboratory of Molecular Oncology and Innovative Therapies, Military Institute of Medicine-National Research Institute, 04-141 Warsaw, Poland; Centre for Molecular Biophysics, UPR 4301 CNRS, 45071 Orleans, France; Centre of Postgraduate Medical Education, 01-004 Warsaw, Poland.
| | - Sophie Gad
- Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences Lettres University (PSL), 75014 Paris, France; UMR CNRS 9019, Genome Integrity and Cancers, Gustave Roussy, Paris-Saclay University, 94800 Villejuif, France.
| | - Stéphanie Buart
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
| | - Jean-Marie Lehn
- Institut de Science et d'Ingénierie Supramoléculaires (ISIS), Université de Strasbourg, 8 allée Gaspard Monge, Strasbourg, France.
| | - Perparim Limani
- Swiss Hepato-Pancreato-Biliary (HPB) and Transplantation Center, University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland; Department of Surgery & Transplantation, University and University Hospital Zurich, Raemistrasse 100, Zurich, Switzerland.
| | - Salem Chouaib
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates; INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
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15
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Zhang J, Luo Q, Li X, Guo J, Zhu Q, Lu X, Wei L, Xiang Z, Peng M, Ou C, Zou Y. Novel role of immune-related non-coding RNAs as potential biomarkers regulating tumour immunoresponse via MICA/NKG2D pathway. Biomark Res 2023; 11:86. [PMID: 37784183 PMCID: PMC10546648 DOI: 10.1186/s40364-023-00530-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 09/24/2023] [Indexed: 10/04/2023] Open
Abstract
Major histocompatibility complex class I related chain A (MICA) is an important and stress-induced ligand of the natural killer group 2 member D receptor (NKG2D) that is expressed in various tumour cells. Given that the MICA/NKG2D signalling system is critically embedded in the innate and adaptive immune responses, it is particularly involved in the surveillance of cancer and viral infections. Emerging evidence has revealed the important roles of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in different cancer types. We searched for all relevant publications in the PubMed, Scopus and Web of Science database using the keywords ncRNA, MICA, NKG2D, cancer, and miRNAs. All relevant studies published from 2008 to the 2023 were retrieved and collated. Notably, we found that miRNAs can target to NKG2D mRNA and MICA mRNA 3'-untranslated regions (3'-UTR), leading to translation inhibition of NKG2D and MICA degradation. Several immune-related MICA/NKG2D pathways may be dysregulated in cancer with aberrant miRNA expressions. At the same time, the competitive endogenous RNA (ceRNA) hypothesis holds that circRNAs, lncRNAs, and mRNAs induce an abnormal MICA expression by directly targeting downstream miRNAs to mediate mRNA suppression in cancer. This review summarizes the novel mechanism of immune escape in the ncRNA-related MICA/NKG2D pathway mediated by NK cells and cancer cells. Moreover, we identified the miRNA-NKG2D, miRNA-MICA and circRNA/lncRNA/mRNA-miRNA-mRNA/MICA axis. Thus, we were particularly concerned with the regulation of mediated immune escape in the MICA/NKG2D pathway by ncRNAs as potential therapeutic targets and diagnostic biomarkers of immunity and cancer.
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Affiliation(s)
- Jing Zhang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Qizhi Luo
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Xin Li
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Junshuang Guo
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Quan Zhu
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Xiaofang Lu
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Leiyan Wei
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Zhiqing Xiang
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Manqing Peng
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, Hunan, China.
| | - Yizhou Zou
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China.
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16
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Afra F, Mahboobipour AA, Salehi Farid A, Ala M. Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome. Biomed Pharmacother 2023; 165:115104. [PMID: 37393866 DOI: 10.1016/j.biopha.2023.115104] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major proportion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immunosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mechanistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the efficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.
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Affiliation(s)
- Fatemeh Afra
- Clinical Pharmacy Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Mahboobipour
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Salehi Farid
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Ala
- Experimental Medicine Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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17
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Li G, Nikkhoi SK, Hatefi A. Stem cell-assisted enzyme/prodrug therapy makes drug-resistant ovarian cancer cells vulnerable to natural killer cells through upregulation of NKG2D ligands. Med Oncol 2023; 40:110. [PMID: 36862260 PMCID: PMC10794068 DOI: 10.1007/s12032-023-01975-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 02/10/2023] [Indexed: 03/03/2023]
Abstract
Cancer stem-like cells (CSCs) are believed to be responsible for cancer recurrence and metastasis. Therefore, a therapeutic approach is needed to eliminate both rapidly proliferating differentiated cancer cells and slow-growing drug-resistant CSCs. Using established ovarian cancer cells lines as well as ovarian cancer cells isolated from a patient with high-grade drug-resistant ovarian carcinoma, we demonstrate that ovarian CSCs consistently express lower levels of NKG2D ligands (MICA/B and ULBPs) on their surfaces, a mechanism by which they evade natural killer (NK) cells' surveillance. Here, we discovered that exposure of ovarian cancer (OC) cells to SN-38 followed by 5-FU not only acts synergistically to kill the OC cells, but also makes the CSCs vulnerable to NK92 cells through upregulation of NKG2D ligands. Since systemic administration of these two drugs is marred by intolerance and instability, we engineered and isolated an adipose-derived stem cell (ASC) clone, which stably expresses carboxylesterase-2 and yeast cytosine deaminase enzymes to convert irinotecan and 5-FC prodrugs into SN-38 and 5-FU cytotoxic drugs, respectively. Co-incubation of ASCs and prodrugs with drug-resistant OC cells not only led to the death of the drug-resistant OC cells but also made them significantly vulnerable to NK92 cells. This study provides proof of principle for a combined ASC-directed targeted chemotherapy with NK92-assisted immunotherapy to eradicate drug-resistant OC cells.
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Affiliation(s)
- Geng Li
- Department of Pharmaceutics, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA
| | | | - Arash Hatefi
- Department of Pharmaceutics, Rutgers University, 160 Frelinghuysen Road, Piscataway, NJ, 08854-8020, USA.
- Cancer Pharmacology Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.
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18
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Youlin K, Simin L, Jian K, Li Z. Inhibition of miR-20a by pterostilbene facilitates prostate cancer cells killed by NK cells via up-regulation of NKG2D ligands and TGF-β1down-regulation. Heliyon 2023; 9:e14957. [PMID: 37064475 PMCID: PMC10102449 DOI: 10.1016/j.heliyon.2023.e14957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 03/19/2023] [Accepted: 03/22/2023] [Indexed: 03/31/2023] Open
Abstract
Natural killer (NK) cells play a potent role in antitumor immunity via spontaneously eliminating tumor directly. However, some tumors such as prostate cancer constantly escape this immune response by down-regulating cell surface molecule recognition and/or secreting immune impressive cytokines. Here, we found pterostilbene, a natural agent with potent anticancer activity, could enhance expression of major histocompatibility complex class I chain-related proteins A and B (MICA/B) on prostate cancer cells surface, which are ligands of the natural killer group 2 member D (NKG2D) expressed by NK cells, and inhibit TGF-β1 secretion by prostate cancer cells. Further, we discovered that these effects were caused by inhibition of miR-20a in prostate cancer cells by pterostilbene. MiR-20a could target the 3' untranslated region (UTR) of MICA/B, resulting in their expression down-regulation. Inhibition of TGF-β1 function by its specific antibody attenuated its impairment to NKG2D on NK cells. Finally, we observed that pterostilbene-treated prostate cancer cells were more easily to be killed by NK cells. Taken together, our findings demonstrated inhibition of miR-20a by pterostilbene in prostate cancer cells could increase MICA/B expression and decrease TGF-β1 secretion, which enhanced NK cell-mediated cytotoxicity againt prostate cancer cells, suggesting a potential approach for increasing anti-prostate cancer immune.
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Affiliation(s)
- Kuang Youlin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Liang Simin
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Kang Jian
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhang Li
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Corresponding author.
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Holvoet P. Noncoding RNAs Controlling Oxidative Stress in Cancer. Cancers (Basel) 2023; 15:cancers15041155. [PMID: 36831498 PMCID: PMC9954372 DOI: 10.3390/cancers15041155] [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: 01/16/2023] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Mitochondria in cancer cells tend to overproduce reactive oxygen species (ROS), inducing a vicious cycle between mitochondria, ROS, genomic instability, and cancer development. The first part of this review deals with the role of noncoding RNAs in regulating mitochondrial ROS production and the expression of antioxidants in cancer cells, preventing the increase of ROS in the tumor microenvironment. In addition, cytotoxic T and natural killer cells release high levels of ROS, inducing cell death, while anti-immune regulatory T cells, tumor-associated M2 macrophages, and myeloid-derived suppressor cells, at least at the initial stage of tumor growth, release low levels of ROS supporting tumor growth. Therefore, this review's second part deals with noncoding RNAs' role in regulating the metabolic reprogramming of immune cells about ROS release. Furthermore, the enrichment of noncoding RNAs in microvesicles allows communication between cell types in a tumor and between a tumor and tumor-adjacent tissues. Therefore, the third part illustrates how noncoding RNA-containing microvesicles secreted by mesenchymal stem cells and primary tumor cells may primarily aid the shift of immune cells to a pro-oncogenic phenotype. Conversely, microvesicles released by tumor-adjacent tissues may have the opposite effect. Our review reveals that a specific noncoding RNA may affect oxidative stress by several mechanisms, which may have opposite effects on tumor growth. Furthermore, they may be involved in mechanisms other than regulating oxidative stress, which may level out their effects on oxidative stress and tumor growth. In addition, several noncoding RNAs might share a specific function, making it very unlikely that intervening with only one of these noncoding RNAs will block this particular mechanism. Overall, further validation of the interaction between noncoding RNAs about cancer types and stages of tumor development is warranted.
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Affiliation(s)
- Paul Holvoet
- Division of Experimental Cardiology, KU Leuven, 3000 Leuven, Belgium
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20
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Deng Y, Xiao M, Wan AH, Li J, Sun L, Liang H, Wang QP, Yin S, Bu X, Wan G. RNA and RNA Derivatives: Light and Dark Sides in Cancer Immunotherapy. Antioxid Redox Signal 2022; 37:1266-1290. [PMID: 35369726 DOI: 10.1089/ars.2022.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Immunotherapy, which utilizes the patient's immune system to fight tumor cells, has been approved for the treatment of some types of advanced cancer. Recent Advances: The complexity and diversity of tumor immunity are responsible for the varying response rates toward current immunotherapy strategies and highlight the importance of exploring regulators in tumor immunotherapy. Several genetic factors have proved to be critical regulators of tumor immunotherapy. RNAs, including messenger RNAs and non-coding RNAs, play vital and diverse roles in tumorigenesis, metastasis, drug resistance, and immunotherapy response. RNA modifications, including N6-methyladenosine methylation, are involved in tumor immunity. Critical Issues: A critical issue is the lack of summary of the regulatory RNA molecules and their derivatives in mediating immune activities in human cancers that could provide potential applications for tumor immunotherapeutic strategy. Future Directions: This review summarizes the dual roles (the light and dark sides) of RNA and its derivatives in tumor immunotherapy and discusses the development of RNA-based therapies as novel immunotherapeutic strategies for cancer treatment. Antioxid. Redox Signal. 37, 1266-1290.
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Affiliation(s)
- Yuan Deng
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Min Xiao
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Arabella H Wan
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.,Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiarui Li
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Lei Sun
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Heng Liang
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Qiao-Ping Wang
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, China
| | - Sheng Yin
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Xianzhang Bu
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Guohui Wan
- National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation, National Engineering Research Center for New Drug and Druggability (Cultivation), Guangdong Province Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
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21
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Cui M, Liu Y, Cheng L, Li T, Deng Y, Liu D. Research progress on anti-ovarian cancer mechanism of miRNA regulating tumor microenvironment. Front Immunol 2022; 13:1050917. [DOI: 10.3389/fimmu.2022.1050917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/24/2022] [Indexed: 11/11/2022] Open
Abstract
Ovarian cancer is the most deadly malignancy among women, but its complex pathogenesis is unknown. Most patients with ovarian cancer have a poor prognosis due to high recurrence rates and chemotherapy resistance as well as the lack of effective early diagnostic methods. The tumor microenvironment mainly includes extracellular matrix, CAFs, tumor angiogenesis and immune-associated cells. The interaction between tumor cells and TME plays a key role in tumorigenesis, progression, metastasis and treatment, affecting tumor progression. Therefore, it is significant to find new tumor biomarkers and therapeutic targets. MicroRNAs are non-coding RNAs that post-transcriptionally regulate the expression of target genes and affect a variety of biological processes. Studies have shown that miRNAs regulate tumor development by affecting TME. In this review, we summarize the mechanisms by which miRNAs affect ovarian cancer by regulating TME and highlight the key role of miRNAs in TME, which provides new targets and theoretical basis for ovarian cancer treatment.
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22
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Dhuppar S, Murugaiyan G. miRNA effects on gut homeostasis: therapeutic implications for inflammatory bowel disease. Trends Immunol 2022; 43:917-931. [PMID: 36220689 PMCID: PMC9617792 DOI: 10.1016/j.it.2022.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/05/2022] [Accepted: 09/11/2022] [Indexed: 01/12/2023]
Abstract
Inflammatory bowel disease (IBD) spans a range of chronic conditions affecting the gastrointestinal (GI) tract, which are marked by intermittent flare-ups and remissions. IBD results from microbial dysbiosis or a defective mucosal barrier in the gut that triggers an inappropriate immune response in a genetically susceptible person, altering the immune-microbiome axis. In this review, we discuss the regulatory roles of miRNAs, small noncoding RNAs with gene regulatory functions, in the stability and maintenance of the gut immune-microbiome axis, and detail the challenges and recent advances in the use of miRNAs as putative therapeutic agents for treating IBD.
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Affiliation(s)
- Shivnarayan Dhuppar
- Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Current address: Centre for Business Innovation, The Indian School of Business, Hyderabad 500111, India
| | - Gopal Murugaiyan
- Ann Romney Center for Neurological Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
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23
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Otmani K, Rouas R, Lewalle P. OncomiRs as noncoding RNAs having functions in cancer: Their role in immune suppression and clinical implications. Front Immunol 2022; 13:913951. [PMID: 36189271 PMCID: PMC9523483 DOI: 10.3389/fimmu.2022.913951] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Currently, microRNAs have been established as central players in tumorigenesis, but above all, they have opened an important door for our understanding of immune and tumor cell communication. This dialog is largely due to onco-miR transfer from tumor cells to cells of the tumor microenvironment by exosome. This review outlines recent advances regarding the role of oncomiRs in enhancing cancer and how they modulate the cancer-related immune response in the tumor immune microenvironment.MicroRNAs (miRNAs) are a type of noncoding RNA that are important posttranscriptional regulators of messenger RNA (mRNA) translation into proteins. By regulating gene expression, miRNAs enhance or inhibit cancer development and participate in several cancer biological processes, including proliferation, invasion metastasis, angiogenesis, chemoresistance and immune escape. Consistent with their widespread effects, miRNAs have been categorized as oncogenes (oncomiRs) or tumor suppressor (TS) miRNAs. MiRNAs that promote tumor growth, called oncomiRs, inhibit messenger RNAs of TS genes and are therefore overexpressed in cancer. In contrast, TS miRNAs inhibit oncogene messenger RNAs and are therefore underexpressed in cancer. Endogenous miRNAs regulate different cellular pathways in all cell types. Therefore, they are not only key modulators in cancer cells but also in the cells constituting their microenvironments. Recently, it was shown that miRNAs are also involved in intercellular communication. Indeed, miRNAs can be transferred from one cell type to another where they regulate targeted gene expression. The primary carriers for the transfer of miRNAs from one cell to another are exosomes. Exosomes are currently considered the primary carriers for communication between the tumor and its surrounding stromal cells to support cancer progression and drive immune suppression. Exosome and miRNAs are seen by many as a hope for developing a new class of targeted therapy. This review outlines recent advances in understanding the role of oncomiRs in enhancing cancer and how they promote its aggressive characteristics and deeply discusses the role of oncomiRs in suppressing the anticancer immune response in its microenvironment. Additionally, further understanding the mechanism of oncomiR-related immune suppression will facilitate the use of miRNAs as biomarkers for impaired antitumor immune function, making them ideal immunotherapy targets.
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Affiliation(s)
- Khalid Otmani
- Experimental Hematology Laboratory, Hematology Department, Jules Bordet Institute, Brussels, Belgium
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- *Correspondence: Khalid Otmani,
| | - Redouane Rouas
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- Hematological Cell Therapy Unit, Hematology Department, Jules Bordet Institute, Brussels, Belgium
| | - Philippe Lewalle
- Experimental Hematology Laboratory, Hematology Department, Jules Bordet Institute, Brussels, Belgium
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- Hematological Cell Therapy Unit, Hematology Department, Jules Bordet Institute, Brussels, Belgium
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24
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Chen M, Lei N, Tian W, Li Y, Chang L. Recent advances of non-coding RNAs in ovarian cancer prognosis and therapeutics. Ther Adv Med Oncol 2022; 14:17588359221118010. [PMID: 35983027 PMCID: PMC9379276 DOI: 10.1177/17588359221118010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 07/15/2022] [Indexed: 01/17/2023] Open
Abstract
Ovarian cancer (OC) is the third most common gynecological malignancy with the highest mortality worldwide. OC is usually diagnosed at an advanced stage, and the standard treatment is surgery combined with platinum or paclitaxel chemotherapy. However, chemoresistance inevitably appears coupled with the easy recurrence and poor prognosis. Thus, early diagnosis, predicting prognosis, and reducing chemoresistance are of great significance for controlling the progression and improving treatment effects of OC. Recently, much insight has been gained into the non-coding RNA (ncRNA) that is employed for RNAs but does not encode a protein, and many types of ncRNAs have been characterized including long-chain non-coding RNAs, microRNAs, and circular RNAs. Accumulating evidence indicates these ncRNAs play very active roles in OC progression and metastasis. In this review, we briefly discuss the ncRNAs as biomarkers for OC prognosis. We focus on the recent advances of ncRNAs as therapeutic targets in preventing OC metastasis, chemoresistance, immune escape, and metabolism. The novel strategies for ncRNAs-targeted therapy are also exploited for improving the survival of OC patients.
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Affiliation(s)
- Mengyu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ningjing Lei
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wanjia Tian
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yong Li
- Cancer Care Centre, St George Hospital, Level 2, Research and Education Centre, 4-10 South Street, Kogarah, NSW 2217, Australia
| | - Lei Chang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Erqi District, Zhengzhou, Henan 450000, China
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25
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Stress-induced immunosuppression affecting avian influenza virus vaccine immune response through miR-20a-5p/NR4A3 pathway in chicken. Vet Microbiol 2022; 273:109546. [PMID: 35994844 DOI: 10.1016/j.vetmic.2022.109546] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/09/2022] [Accepted: 08/13/2022] [Indexed: 01/10/2023]
Abstract
Stress-induced immunosuppression is one of the most common hazards in poultry intensive production, which often leads to vaccination failure and severe economic losses. At present, there is no report about the function and mechanism of circulating miRNA on stress-induced immunosuppression affecting immune response. In this study, the changes of circulating miR-20a-5p under stress-induced immunosuppressive condition were analyzed by qRT-PCR, and the key time points, tissues and mechanisms for functional regulation of miR-20a-5p in the process of stress-induced immunosuppression affecting avian influenza virus (AIV) vaccine immune response were identified. The results showed that stress-induced immunosuppression down-regulated miR-20a-5p and further affected AIV vaccine immune response, in which 5 day post immunization (dpi) was a key time point, and the heart, lung, and proventriculus were the important tissues. The game relationship analysis between miR-20a-5p and its target nuclear receptor subfamily 4 group A member 3 (NR4A3) gene showed that "miR-20a-5p/NR4A3" pathway was the potential key mechanism of this process, especially for heart and lung. This study provides insights into the molecular mechanisms of stress-induced immunosuppression affecting immune response.
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26
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Busà R, Bulati M, Badami E, Zito G, Maresca DC, Conaldi PG, Ercolano G, Ianaro A. Tissue-Resident Innate Immune Cell-Based Therapy: A Cornerstone of Immunotherapy Strategies for Cancer Treatment. Front Cell Dev Biol 2022; 10:907572. [PMID: 35757002 PMCID: PMC9221069 DOI: 10.3389/fcell.2022.907572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/03/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer immunotherapy has led to impressive advances in cancer treatment. Unfortunately, in a high percentage of patients is difficult to consistently restore immune responses to eradicate established tumors. It is well accepted that adaptive immune cells, such as B lymphocytes, CD4+ helper T lymphocytes, and CD8+ cytotoxic T-lymphocytes (CTLs), are the most effective cells able to eliminate tumors. However, it has been recently reported that innate immune cells, including natural killer cells (NK), dendritic cells (DC), macrophages, myeloid-derived suppressor cells (MDSCs), and innate lymphoid cells (ILCs), represent important contributors to modulating the tumor microenvironment and shaping the adaptive tumor response. In fact, their role as a bridge to adaptive immunity, make them an attractive therapeutic target for cancer treatment. Here, we provide a comprehensive overview of the pleiotropic role of tissue-resident innate immune cells in different tumor contexts. In addition, we discuss how current and future therapeutic approaches targeting innate immune cells sustain the adaptive immune system in order to improve the efficacy of current tumor immunotherapies.
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Affiliation(s)
- Rosalia Busà
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Matteo Bulati
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Ester Badami
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
- Ri.MED Foundation, Palermo, Italy
| | - Giovanni Zito
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | | | - Pier Giulio Conaldi
- Research Department, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT), Palermo, Italy
| | - Giuseppe Ercolano
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
- *Correspondence: Giuseppe Ercolano,
| | - Angela Ianaro
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
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27
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Roy RK, Yadav R, Sharma U, Kaushal Wasson M, Sharma A, Tanwar P, Jain A, Prakash H. Impact of non-coding RNAs on cancer directed immune therapies: Now then and forever. Int J Cancer 2022; 151:981-992. [PMID: 35489027 DOI: 10.1002/ijc.34060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 11/10/2022]
Abstract
Accumulating evidence demonstrates that the host genome's epigenetic modifications are essential for living organisms to adapt to extreme conditions. DNA methylation, covalent modifications of histone, and inter-association of non-coding RNAs facilitate the cellular manifestation of epigenetic changes in the genome. Out of various factors involved in the epigenetic programming of the host, non-coding RNAs (ncRNAs) such as microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA, snoRNA and piRNA are new generation non-coding molecules that influence a variety of cellular processes like immunity, cellular differentiation, and tumor development. During tumor development, temporal changes in miRNA/LncRNA rheostat influence sterile inflammatory responses accompanied by the changes in the carcinogenic signaling in the host. At the cellular level, this is manifested by the up-regulation of Inflammasome and inflammatory pathways, which promotes cancer-related inflammation. Given this, we discuss the potential of lncRNAs, miRNAs, circular RNA, snoRNA and piRNA in regulating inflammation and tumor development in the host. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Roshan Kumar Roy
- Amity Institute of Virology and Immunology, Amity University, India
| | - Rakhi Yadav
- Amity Institute of Virology and Immunology, Amity University, India
| | - Uttam Sharma
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
| | | | - Ashok Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Aklank Jain
- Department of Zoology, Central University of Punjab, Bathinda, Punjab, India
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28
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Ding C, Zheng Y, Li D, Zhu M, Zhu Y. Up-Regulation of miR-1925 by Bone Marrow Mesenchymal Stem Cell (BMSC) Inhibits the Growth of Liver Cancer by Promoting the Anti-Tumor Activity of Natural Killer (NK) Cells. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.2920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) seriously threatens human health and life quality. Natural killer (NK) cells play important roles in liver immune function. Bone marrow mesenchymal stem cell (BMSC) exosomes (Exo) participate in tissue damage. This study explored BMSC-Exo’s effect
on NK cells’ anti-tumor activity. NK cells were isolated from the livers of mice with liver cancer. NK cells with or without BMSC-Exo treatment were co-cultured with liver cancer cells to assess cell proliferation. Administration of BMSC-Exo into mice with liver cancer significantly
suppressed liver cancer cell growth. In addition, BMSC-Exo treatment significantly improved NK cells’ anti-tumor effect whic was related to BMSC-Exo-induced up-regulation of miR-1925. Implantation of BMSC-Exo into mice with liver cancer at different time periods can significantly suppress
liver cancer cell growth. At the same time, BMSC-Exo implantation inhibited the expression of cell proliferation marker protein(Ki67). In vitro study found that BMSC-Exo treatment significantly increased miR-1925 level and the toxicity of NK cells to HCC cells. In addition, miR-1925
overexpression in NK cells significantly increased NK cells’ anti-tumor activity. In conclusion, this study proved that up-regulation of miR-1925 by BMSC can inhibit the growth of liver cancer by promoting the anti-tumor activity of NK cells.
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Affiliation(s)
- Chencheng Ding
- Department of Hepatobiliary, Pancreatic and SPLENIC Surgery, Changxing County People’s Hospital, Huzhou, Zhejiang, 313199, China
| | - Yunjie Zheng
- Department of Hepatobiliary, Pancreatic and SPLENIC Surgery, Changxing County People’s Hospital, Huzhou, Zhejiang, 313199, China
| | - Dan Li
- Department of Hepatobiliary, Pancreatic and SPLENIC Surgery, Changxing County People’s Hospital, Huzhou, Zhejiang, 313199, China
| | - Min Zhu
- Department of Hepatobiliary, Pancreatic and SPLENIC Surgery, Changxing County People’s Hospital, Huzhou, Zhejiang, 313199, China
| | - Yong Zhu
- Department of Gastroenterology, Oncology, Changxing County People’s Hospital, Huzhou, Zhejiang, 313199, China
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29
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Liu M, Zhang H, Li Y, Wang S. Noncoding RNAs Interplay in Ovarian Cancer Therapy and Drug Resistance. Cancer Biother Radiopharm 2022; 37:186-198. [PMID: 35133881 DOI: 10.1089/cbr.2021.0339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Noncoding RNAs (ncRNAs) are several types of RNA that do not encode proteins, but are essential for cell regulation. Ovarian cancer (OC) is a type of gynecological cancer with a high mortality rate and a 5-year prognosis. OC is becoming more common with each passing year, and the symptoms of early-stage OC are sometimes undetectable. Meanwhile, early-stage OC has no symptoms and is difficult to diagnose. Because ncRNA has been shown to affect the development of OC and is widely distributed, it could be employed as a new biomarker for early OC. Furthermore, ncRNA has the potential to promote or inhibit drug resistance in OC, potentially giving a solution to multiple drug resistance. Various prior studies have found that different ncRNAs perform differently in OC. This article examines how mainstream ncRNAs have been expressed in OC in recent years, as well as their function in tumor growth.
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Affiliation(s)
- Min Liu
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
| | - Hui Zhang
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
| | - Yanli Li
- Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, China
| | - Shaojia Wang
- Department of Gynecology, Yunnan Cancer Center, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Kunming, China
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30
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Pottoo FH, Iqubal A, Iqubal MK, Salahuddin M, Rahman JU, AlHajri N, Shehadeh M. miRNAs in the Regulation of Cancer Immune Response: Effect of miRNAs on Cancer Immunotherapy. Cancers (Basel) 2021; 13:6145. [PMID: 34885253 PMCID: PMC8656569 DOI: 10.3390/cancers13236145] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 11/22/2021] [Accepted: 11/24/2021] [Indexed: 02/07/2023] Open
Abstract
In the last few decades, carcinogenesis has been extensively explored and substantial research has identified immunogenic involvement in various types of cancers. As a result, immune checkpoint blockers and other immune-based therapies were developed as novel immunotherapeutic strategies. However, despite being a promising therapeutic option, immunotherapy has significant constraints such as a high cost of treatment, unpredictable toxicity, and clinical outcomes. miRNAs are non-coding, small RNAs actively involved in modulating the immune system's multiple signalling pathways by binding to the 3'-UTR of target genes. miRNAs possess a unique advantage in modulating multiple targets of either the same or different signalling pathways. Therefore, miRNA follows a 'one drug multiple target' hypothesis. Attempts are made to explore the therapeutic promise of miRNAs in cancer so that it can be transported from bench to bedside for successful immunotherapeutic results. Therefore, in the current manuscript, we discussed, in detail, the mechanism and role of miRNAs in different types of cancers relating to the immune system, its diagnostic and therapeutic aspect, the effect on immune escape, immune-checkpoint molecules, and the tumour microenvironment. We have also discussed the existing limitations, clinical success and the prospective use of miRNAs in cancer.
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Affiliation(s)
- Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Ashif Iqubal
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;
- Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Mohammad Kashif Iqubal
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;
- Product Development Department, Sentiss Research Centre, Sentiss Pharma Pvt Ltd., Gurugram 122001, India
| | - Mohammed Salahuddin
- Department of Clinical Pharmacy Research, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Jawad Ur Rahman
- Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Noora AlHajri
- Mayo Clinic, Sheikh Shakhbout Medical City (SSMC), Abu Dhabi 127788, United Arab Emirates
| | - Mustafa Shehadeh
- College of Medicine and Health Sciences, Khalifa University, Abu Dhabi P.O. Box 127788, United Arab Emirates
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31
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Lee EHC, Wong DCP, Ding JL. NK Cells in a Tug-of-War With Cancer: The Roles of Transcription Factors and Cytoskeleton. Front Immunol 2021; 12:734551. [PMID: 34594338 PMCID: PMC8476995 DOI: 10.3389/fimmu.2021.734551] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Natural killer (NK) cells are innate immune cells which play a key role in shaping the immune response against cancer. Initially hailed for their potential to recognise and eliminate tumour cells, their application has been greatly hindered by the immunosuppressive tumour microenvironment (TME) which suppresses NK functions (e.g., cytotoxicity). This dysfunctional state that is accompanied by phenotypic changes such as upregulation of inhibitory receptors and downregulation of activating receptors, forms the basis of what many researchers have referred to as ‘exhausted’ NK cells. However, there is no consensus on whether these phenotypes are sufficient to define an exhausted state of the NK cell. While recent advances in checkpoint inhibition appear to show promise in early-stage pre-clinical studies, much remains to be fully explored and understood in the context of the TME. The TME is where the NK cells are subjected to interaction with various cell types and soluble factors, which could exert an inhibitory effect on NK cytotoxicity. In this review, we provide an overview of the general markers of NK cell exhaustion viz, the surface activating and inhibitory receptors. We also highlight the potential role of T-box transcription factors in characterising such a dysfunctional state and discuss the often-overlooked mechanism of cell cytoskeletal dynamics in regulating NK cell function. These aspects may further contribute to NK exhaustion or NK revival in cancer and may open new avenues to explore cancer treatment strategies.
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Affiliation(s)
- E Hui Clarissa Lee
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Darren Chen Pei Wong
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Jeak Ling Ding
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
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32
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Xu J, Wen J, Li S, Shen X, You T, Huang Y, Xu C, Zhao Y. Immune-Related Nine-MicroRNA Signature for Predicting the Prognosis of Gastric Cancer. Front Genet 2021; 12:690598. [PMID: 34290743 PMCID: PMC8287335 DOI: 10.3389/fgene.2021.690598] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/21/2021] [Indexed: 12/21/2022] Open
Abstract
Recent findings have demonstrated the superiority and utility of microRNAs (miRNAs) as new biomarkers for cancer diagnosis, therapy, and prognosis. In this study, to explore the prognostic value of immune-related miRNAs in gastric cancer (GC), we analyzed the miRNA-expression profiles of 389 patients with GC, using data deposited in The Cancer Genome Atlas database. Using a forward- and backward-variable selection and multivariate Cox regression analyses model, we identified a nine-miRNA signature (the “ImmiRSig,” consisting of miR-125b-5p, miR-99a-3p, miR-145-3p, miR-328-3p, miR-133a-5p, miR-1292-5p, miR-675-3p, miR-92b-5p, and miR-942-3p) in the training cohort that enabled the division of patients into high- and low-risk groups with significantly different survival rates. The ImmiRSig was successfully validated with an independent test cohort of 193 GC patients. Univariate and multivariate Cox regression analyses indicated that the ImmiRSig would serve as an independent prognostic factor after adjusting for other clinical covariates. Pending further prospective validation, the identified ImmiRSig appears to have significant clinical importance in terms of improving outcome predictions and guiding personalized treatment for patients with GC. Finally, significant associations between the ImmiRSig and the half-maximal inhibitory concentrations of chemotherapeutic agents were observed, suggesting that ImmiRSig may predict the clinical efficacy of chemotherapy.
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Affiliation(s)
- Jingxuan Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jian Wen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shuangquan Li
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xian Shen
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Tao You
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yingpeng Huang
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Chongyong Xu
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yaping Zhao
- The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
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Luo X, Xu J, Yu J, Yi P. Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer. Front Immunol 2021; 12:692360. [PMID: 34248988 PMCID: PMC8261131 DOI: 10.3389/fimmu.2021.692360] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/02/2021] [Indexed: 12/21/2022] Open
Abstract
Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.
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Affiliation(s)
- Xin Luo
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianhua Yu
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, United States.,Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, United States
| | - Ping Yi
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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34
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Thomopoulou K, Papadaki C, Monastirioti A, Koronakis G, Mala A, Kalapanida D, Mavroudis D, Agelaki S. MicroRNAs Regulating Tumor Immune Response in the Prediction of the Outcome in Patients With Breast Cancer. Front Mol Biosci 2021; 8:668534. [PMID: 34179081 PMCID: PMC8220200 DOI: 10.3389/fmolb.2021.668534] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 05/27/2021] [Indexed: 12/29/2022] Open
Abstract
MicroRNAs (miRNAs) are key regulators in immune surveillance and immune escape as well as modulators in the metastatic process of breast cancer cells. We evaluated the differential expression of plasma miR-10b, miR-19a, miR-20a, miR-126 and miR-155, which regulate immune response in breast cancer progression and we investigated their clinical relevance in the outcomes of breast cancer patients. Plasma samples were obtained from early (eBC; n = 140) and metastatic (mBC; n = 64) breast cancer patients before adjuvant or first-line chemotherapy, respectively. Plasma miRNA expression levels were assessed by qRT-PCR. We revealed a 4-miRNA panel consisted of miR-19a, miR-20a, miR-126, and miR-155 able to discriminate eBC from mBC patients with an AUC of 0.802 (p < 0.001). Survival analysis in eBC patients revealed that low miR-10b and miR-155 expression was associated with shorter disease free survival (disease free survival; p = 0.012 and p = 0.04, respectively) compared to high expression. Furthermore, miR-126 expression was associated with shorter overall survival (overall survival; p = 0.045). In multivariate analysis the number of infiltrated axillary lymph nodes and low miR-10b expression independently predicted for shorter DFS (HR: 2.538; p = 0.002 and HR: 1.943; p = 0.033, respectively) and axillary lymph nodes and low miR-126 for shorter OS (HR: 3.537; p = 0.001 and HR: 2.558; p = 0.018). In the subgroup of triple negative breast cancer (TNBC) patients, low miR-155 expression independently predicted for shorter DFS (HR: 5.056; p = 0.037). Accordingly in mBC, patients with low miR-10b expression had shorter progression free survival and OS compared to patients with high expression (p = 0.0017 and p = 0.042, respectively). In multivariate analysis, recurrent disease and low miR-10b expression independently predicted for shorter PFS (HR: 2.657; p = 0.001 and HR: 1.920; p = 0.017, respectively), whereas performance status two independently predicted for shorter OS (HR: 2.031; p = 0.03). In summary, deregulated expression of circulating miRNAs involved in tumor and immune cell interactions evaluated before adjuvant and 1st-line chemotherapy can distinguish disease status and emerge as independent predictors for outcomes of breast cancer patients.
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Affiliation(s)
- Konstantina Thomopoulou
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Chara Papadaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Alexia Monastirioti
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - George Koronakis
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
| | - Anastasia Mala
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
| | - Despoina Kalapanida
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
| | - Dimitrios Mavroudis
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
| | - Sofia Agelaki
- Department of Medical Oncology, University General Hospital, Crete, Heraklion, Greece
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Greece
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35
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Xing Y, Ruan G, Ni H, Qin H, Chen S, Gu X, Shang J, Zhou Y, Tao X, Zheng L. Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression. Front Immunol 2021; 12:624725. [PMID: 34084160 PMCID: PMC8167795 DOI: 10.3389/fimmu.2021.624725] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.
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Affiliation(s)
- Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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36
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Mondal P, Kaur B, Natesh J, Meeran SM. The emerging role of miRNA in the perturbation of tumor immune microenvironment in chemoresistance: Therapeutic implications. Semin Cell Dev Biol 2021; 124:99-113. [PMID: 33865701 DOI: 10.1016/j.semcdb.2021.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023]
Abstract
Chemoresistance is a major hindrance in cancer chemotherapies, a leading cause of tumor recurrence and cancer-related deaths. Cancer cells develop numerous strategies to elude immune attacks and are regulated by immunological factors. Cancer cells can alter the expression of several immune modulators to upregulate the activities of immune checkpoint pathways. Targeting the immune checkpoint inhibitors is a part of the cancer immunotherapy altered during carcinogenesis. These immune modulators have the capability to reprogram the tumor microenvironment, thereby change the efficacy of chemotherapeutics. In general, the sensitivity of drugs is reduced in the immunosuppressive tumor microenvironment, resulting in chemoresistance and tumor relapse. The regulation of microRNAs (miRNAs) is well established in cancer initiation, progression, and therapy. Intriguingly, miRNA affects cancer immune surveillance and immune response by targeting immune checkpoint inhibitors in the tumor microenvironment. miRNAs alter the gene expression at the post-transcriptional level, which modulates both innate and adaptive immune systems. Alteration of tumor immune microenvironment influences drug sensitivity towards cancer cells. Besides, the expression profile of immune-modulatory miRNAs can be used as a potential biomarker to predict the response and clinical outcomes in cancer immunotherapy and chemotherapy. Recent evidences have revealed that cancer-derived immune-modulatory miRNAs might be promising targets to counteract cancer immune escape, thereby increasing drug efficacy. In this review, we have compiled the role of miRNAs in overcoming the chemoresistance by modulating tumor microenvironment and discussed their preclinical and clinical implications.
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Affiliation(s)
- Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bhavjot Kaur
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India
| | - Jagadish Natesh
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Papadaki C, Thomopoulou K, Monastirioti A, Koronakis G, Papadaki MA, Rounis K, Vamvakas L, Nikolaou C, Mavroudis D, Agelaki S. MicroRNAs Regulating Tumor and Immune Cell Interactions in the Prediction of Relapse in Early Stage Breast Cancer. Biomedicines 2021; 9:biomedicines9040421. [PMID: 33924670 PMCID: PMC8069787 DOI: 10.3390/biomedicines9040421] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/10/2021] [Accepted: 04/11/2021] [Indexed: 11/20/2022] Open
Abstract
MicroRNAs (miRNAs) are involved in the regulation of immune response and hold an important role in tumor immune escape. We investigated the differential expression of the immunomodulatory miR-10b, miR-19a, miR-20a, miR-126, and miR-155 in the plasma of healthy women and patients with early stage breast cancer and interrogated their role in the prediction of patients’ relapse. Blood samples were obtained from healthy women (n = 20) and patients with early stage breast cancer (n = 140) before adjuvant chemotherapy. Plasma miRNA expression levels were assessed by RT-qPCR. Relapse predicting models were developed using binary logistic regression and receiver operating curves (ROC) were constructed to determine miRNA sensitivity and specificity. Only miR-155 expression was lower in patients compared with healthy women (p = 0.023), whereas miR-155 and miR-10b were lower in patients who relapsed compared with healthy women (p = 0.039 and p = 0.002, respectively). MiR-155 expression combined with axillary lymph node infiltration and tumor grade demonstrated increased capability in distinguishing relapsed from non-relapsed patients [(area under the curve, (AUC = 0.861; p < 0.001)]. Combined miR-19a and miR-20a expression had the highest performance in discriminating patients with early relapse (AUC = 0.816; p < 0.001). Finally, miR-10b in combination with lymph node status and grade had the highest accuracy to discriminate patients with late relapse (AUC = 0.971; p < 0.001). The robustness of the relapse predicting models was further confirmed in a 10-fold cross validation. Deregulation of circulating miRNAs involved in tumor-immune interactions may predict relapse in early stage breast cancer. Their successful clinical integration could potentially address the significance challenge of treatment escalation or de-escalation according to the risk of recurrence.
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Affiliation(s)
- Chara Papadaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Vassilika Vouton, 71003 Crete, Greece; (C.P.); (A.M.); (M.A.P.); (D.M.)
| | - Konstantina Thomopoulou
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
| | - Alexia Monastirioti
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Vassilika Vouton, 71003 Crete, Greece; (C.P.); (A.M.); (M.A.P.); (D.M.)
| | - George Koronakis
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
| | - Maria A. Papadaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Vassilika Vouton, 71003 Crete, Greece; (C.P.); (A.M.); (M.A.P.); (D.M.)
| | - Konstantinos Rounis
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
| | - Lambros Vamvakas
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
| | - Christoforos Nikolaou
- Department of Biology, University of Crete, Heraklion, Vassilika Vouton, 70013 Crete, Greece;
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation of Research and Technology (FORTH), Heraklion, Vassilika Vouton, 70013 Crete, Greece
- Biomedical Science Research Center “Alexander Fleming”, Institute of Bioinnovation, 16672 Athens, Greece
| | - Dimitrios Mavroudis
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Vassilika Vouton, 71003 Crete, Greece; (C.P.); (A.M.); (M.A.P.); (D.M.)
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
| | - Sofia Agelaki
- Laboratory of Translational Oncology, School of Medicine, University of Crete, Heraklion, Vassilika Vouton, 71003 Crete, Greece; (C.P.); (A.M.); (M.A.P.); (D.M.)
- Department of Medical Oncology, University General Hospital of Heraklion, Vassilika Vouton, 71110 Crete, Greece; (K.T.); (G.K.); (K.R.); (L.V.)
- Correspondence: ; Tel.: +30-281-039-2438
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Zou X, Zhao Y, Liang X, Wang H, Zhu Y, Shao Q. Double Insurance for OC: miRNA-Mediated Platinum Resistance and Immune Escape. Front Immunol 2021; 12:641937. [PMID: 33868274 PMCID: PMC8047328 DOI: 10.3389/fimmu.2021.641937] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer (OC) is still the leading cause of death among all gynecological malignancies, despite the recent progress in cancer therapy. Immune escape and drug resistance, especially platinum-based chemotherapy, are significant factors causing disease progression, recurrence and poor prognosis in OC patients. MicroRNAs(miRNAs) are small noncoding RNAs, regulating gene expression at the transcriptional level. Accumulating evidence have indicated their crucial roles in platinum resistance. Importantly, they also act as mediators of tumor immune escape/evasion. In this review, we summarize the recent study of miRNAs involved in platinum resistance of OC and systematically analyses miRNAs involved in the regulation of OC immune escape. Further understanding of miRNAs roles and their possible mechanisms in platinum resistance and tumor escape may open new avenues for improving OC therapy.
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Affiliation(s)
- Xueqin Zou
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yangjing Zhao
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xiuting Liang
- Department of Obstetrics and Gynecology, Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou, China
| | - Hui Wang
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanling Zhu
- Department of Obstetrics and Gynecology, Xuzhou Hospital Affiliated to Jiangsu University, Xuzhou, China
| | - Qixiang Shao
- Reproductive Sciences Institute, Jiangsu University, Zhenjiang, China.,Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China.,Jiangsu College of Nursing, School of Medical Science and Laboratory Medicine, Huai'an, China
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39
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DHA Abolishes the Detrimental Effect of Docetaxel on Downregulation of the MICA via Decreasing the Expression Level of MicroRNA-20a in Gastric Cancer. J Gastrointest Cancer 2021; 51:545-551. [PMID: 31368060 DOI: 10.1007/s12029-019-00280-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND MHC class I chain-related protein A (MICA) is a membrane glycoprotein expressed abnormally on some malignant cells including gastric cancer (GC) cell and elicits anti-tumor immune responses. Downregulation of MICA expression could lead to immune-evasion of cancer cells. OBJECTIVE(S) In this study, we aimed to investigate the effect of docosahexaenoic acid (DHA) and docetaxel alone or in combination on the expression level of MICA and its regulating microRNA (miRNA), miR-20a in MKN45 GC cell line. METHOD(S) MKN45 GC cell line was cultured and MTT assay was performed to determine IC50 of docetaxel. Cells were treated by 18.5 μM docetaxel and 100 μM DHA. After that, RNA extraction and cDNA synthesis were done and the expression level of MICA and miR-20a were determined by quantitative real-time PCR for both treated and untreated cell lines. RESULTS Our findings showed less downregulation of the expression level of MICA by the combination of docetaxel/DHA (5.34-fold) compared with docetaxel (45.45-fold) and DHA (55.55-fold). Consistently, combination therapy led to the more downregulation of the expression level of the miR-20a (5.20-fold) in comparison to docetaxel (2.38-fold) and DHA (1.60-fold). CONCLUSION(S) As an unwanted effect of docetaxel therapy in GC, downregulation of MICA expression could lead to weak anti-tumor immune responses. By increasing the expression level of MICA, combination therapy of docetaxel with DHA would be useful to overcome this side effect.
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Kumar V, Gupta S, Varma K, Sachan M. MicroRNA as Biomarker in Ovarian Cancer Management: Advantages and Challenges. DNA Cell Biol 2020; 39:2103-2124. [PMID: 33156705 DOI: 10.1089/dna.2020.6024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer is the most prevalent gynecological malignancy affecting women throughout the globe. Ovarian cancer has several subtypes, including epithelial ovarian cancer (EOC) with a whopping incidence rate of 239,000 per year, making it the sixth most common gynecological malignancy worldwide. Despite advancement of detection and therapeutics, death rate accounts for 152,000 per annum. Several protein-based biomarkers such as CA125 and HE4 are currently being used for diagnosis, but their sensitivity and specificity for early detection of ovarian cancer are under question. MicroRNA (a small noncoding RNA molecule that participates in post-transcription regulation of gene expression) and its functional deregulation in most cancers have been discovered in the previous two decades. Studies support that miRNA deregulation has an epigenetic component as well. Aberrant miRNA expression is often correlated with the form of EOC tumor, histological grade, prognosis, and FIGO stage. In this review, we addressed epigenetic regulation of miRNAs, the latest research on miRs as a biomarker in the detection of EOC, and tailored assays to use miRNAs as a biomarker in ovarian cancer diagnosis.
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Affiliation(s)
- Vivek Kumar
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George Medical University, Lucknow, India
| | - Kachnar Varma
- Department of Pathology, Motilal Nehru Medical College, Allahabad, India
| | - Manisha Sachan
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, India
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41
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Guo L, Chen Y, Wang J, Chen C. Down-regulation of UL16-binding protein 3 mediated by interferon-gamma impairs immune killing in nasopharyngeal carcinoma. Am J Transl Res 2020; 12:6509-6523. [PMID: 33194048 PMCID: PMC7653630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/13/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Nasopharyngeal carcinoma (NPC) is a malignant tumor characterized by a large number of tumor-infiltrating lymphocytes and high expression of programmed death ligand-1 (PD-L1). Interferon-gamma (IFN-γ) has proven to be the strongest inducers of PD-L1. This study aims at investigating the effect of IFN-γ on the expression of natural killer group 2, member D ligands (NKG2DLs), a series of immune-activating proteins, and their further effect on immune killing in NPC. METHODS RNA-seq data from the Gene Expression Omnibus database was downloaded and analyzed for the correlation between IFN-γ and NKG2DLs. IHC staining of clinical biopsy samples was performed to support the correlation between IFN-γ and ULBP3. Different NPC cell lines were treated with IFN-γ (100 U/ml) and the expression of PD-L1 and ULBP3 were detected at different time points. The 5-8F cell lines with PD-L1 over-expression and ULBP3 knockout were established and the T-cell cytotoxicity assay was performed to investigate the effect of ULPB3 on cytotoxicity. RESULTS Correlation analysis and IHC staining showed that the expression of ULBP3 had a significant negative correlation with IFN-γ in NPC patients. The vitro assays revealed that ULBP3 can be time-dependently down-regulated by IFN-γ. The cytotoxicity of CD8+ T-cells that were co-cultured with ULBP3 knockout 5-8F cells was significantly impaired compared to wild type 5-8F cells. CONCLUSIONS IFN-γ can significantly down-regulate the expression of ULBP3 in NPC. And the down-regulation of ULBP3 and the up-regulation of PD-L1 are both mediated by IFN-γ and may collectively play a role in the inhibition of immune killing in NPC.
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Affiliation(s)
- Lingling Guo
- Department of Radiation Oncology of Head and Neck Cancers, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- The School of Clinical Medicine, Fujian Medical UniversityFuzhou 350000, China
| | - Yu Chen
- Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- Cancer Bio-immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- Fujian Key Laboratory of Translational MedicineFuzhou 350000, China
| | - Jing Wang
- Department of Radiation Oncology of Head and Neck Cancers, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- The School of Clinical Medicine, Fujian Medical UniversityFuzhou 350000, China
| | - Chuanben Chen
- Department of Radiation Oncology of Head and Neck Cancers, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- Cancer Bio-immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer HospitalFuzhou 350000, China
- Fujian Key Laboratory of Translational MedicineFuzhou 350000, China
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42
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Nguyen VHL, Yue C, Du KY, Salem M, O’Brien J, Peng C. The Role of microRNAs in Epithelial Ovarian Cancer Metastasis. Int J Mol Sci 2020; 21:ijms21197093. [PMID: 32993038 PMCID: PMC7583982 DOI: 10.3390/ijms21197093] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer, and the major cause of death is mainly attributed to metastasis. MicroRNAs (miRNAs) are a group of small non-coding RNAs that exert important regulatory functions in many biological processes through their effects on regulating gene expression. In most cases, miRNAs interact with the 3′ UTRs of target mRNAs to induce their degradation and suppress their translation. Aberrant expression of miRNAs has been detected in EOC tumors and/or the biological fluids of EOC patients. Such dysregulation occurs as the result of alterations in DNA copy numbers, epigenetic regulation, and miRNA biogenesis. Many studies have demonstrated that miRNAs can promote or suppress events related to EOC metastasis, such as cell migration, invasion, epithelial-to-mesenchymal transition, and interaction with the tumor microenvironment. In this review, we provide a brief overview of miRNA biogenesis and highlight some key events and regulations related to EOC metastasis. We summarize current knowledge on how miRNAs are dysregulated, focusing on those that have been reported to regulate metastasis. Furthermore, we discuss the role of miRNAs in promoting and inhibiting EOC metastasis. Finally, we point out some limitations of current findings and suggest future research directions in the field.
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Affiliation(s)
- Vu Hong Loan Nguyen
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
| | - Chenyang Yue
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
| | - Kevin Y. Du
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
| | - Mohamed Salem
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
| | - Jacob O’Brien
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
| | - Chun Peng
- Department of Biology, York University, Toronto, ON M3J 1P3, Canada; (V.H.L.N.); (C.Y.); (K.Y.D.); (M.S.); (J.O.)
- Centre for Research in Biomolecular Interactions, York University, Toronto, ON M3J 1P3, Canada
- Correspondence:
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43
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Cantoni C, Wurzer H, Thomas C, Vitale M. Escape of tumor cells from the NK cell cytotoxic activity. J Leukoc Biol 2020; 108:1339-1360. [PMID: 32930468 DOI: 10.1002/jlb.2mr0820-652r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022] Open
Abstract
In recent years, NK cells, initially identified as potent cytotoxic effector cells, have revealed an unexpected complexity, both at phenotypic and functional levels. The discovery of different NK cell subsets, characterized by distinct gene expression and phenotypes, was combined with the characterization of the diverse functions NK cells can exert, not only as circulating cells, but also as cells localized or recruited in lymphoid organs and in multiple tissues. Besides the elimination of tumor and virus-infected cells, these functions include the production of cytokines and chemokines, the regulation of innate and adaptive immune cells, the influence on tissue homeostasis. In addition, NK cells display a remarkable functional plasticity, being able to adapt to the environment and to develop a kind of memory. Nevertheless, the powerful cytotoxic activity of NK cells remains one of their most relevant properties, particularly in the antitumor response. In this review, the process of tumor cell recognition and killing mediated by NK cells, starting from the generation of cytolytic granules and recognition of target cell, to the establishment of the NK cell immunological synapse, the release of cytotoxic molecules, and consequent tumor cell death is described. Next, the review focuses on the heterogeneous mechanisms, either intrinsic to tumors or induced by the tumor microenvironment, by which cancer cells can escape the NK cell-mediated attack.
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Affiliation(s)
- Claudia Cantoni
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.,Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Hannah Wurzer
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.,Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Clément Thomas
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Massimo Vitale
- UO Immunologia, IRCCS Ospedale Policlinico San Martino Genova, Genoa, Italy
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44
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Alshamrani AA. Roles of microRNAs in Ovarian Cancer Tumorigenesis: Two Decades Later, What Have We Learned? Front Oncol 2020; 10:1084. [PMID: 32850313 PMCID: PMC7396563 DOI: 10.3389/fonc.2020.01084] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/29/2020] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one of the top gynecological malignancies that cause deaths among females in the United States. At the molecular level, significant progress has been made in our understanding of ovarian cancer development and progression. MicroRNAs (miRNAs) are short, single-stranded, highly conserved non-coding RNA molecules (19–25 nucleotides) that negatively regulate target genes post-transcriptionally. Over the last two decades, mounting evidence has demonstrated the aberrant expression of miRNAs in different human malignancies, including ovarian carcinomas. Deregulated miRNAs can have profound impacts on various cancer hallmarks by repressing tumor suppressor genes. This review will discuss up-to-date knowledge of how the aberrant expression of miRNAs and their targeted genes drives ovarian cancer initiation, proliferation, survival, and resistance to chemotherapies. Understanding the mechanisms by which these miRNAs affect these hallmarks should allow the development of novel therapeutic strategies to treat these lethal malignancies.
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Affiliation(s)
- Ali A Alshamrani
- Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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45
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Chitnis NS, Shieh M, Monos D. Regulatory noncoding RNAs and the major histocompatibility complex. Hum Immunol 2020; 82:532-540. [PMID: 32636038 DOI: 10.1016/j.humimm.2020.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/21/2020] [Accepted: 06/09/2020] [Indexed: 12/15/2022]
Abstract
The Major Histocompatibility Complex (MHC) is a 4 Mbp genomic region located on the short arm of chromosome 6. The MHC region contains many key immune-related genes such as Human Leukocyte Antigens (HLAs). There has been a growing realization that, apart from MHC encoded proteins, RNAs derived from noncoding regions of the MHC-specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)-play a significant role in cellular regulation. Furthermore, regulatory noncoding RNAs (ncRNAs) derived from other parts of the genome fine-tune the expression of many immune-related MHC proteins. Although the field of ncRNAs of the MHC is a research area that is still in its infancy, ncRNA regulation of MHC genes has already been shown to be vital for immune function, healthy pregnancy and cellular homeostasis. Dysregulation of this intricate network of ncRNAs can lead to serious perturbations in homeostasis and subsequent disease.
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Affiliation(s)
- Nilesh Sunil Chitnis
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Mengkai Shieh
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Dimitri Monos
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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46
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Wang J, Zhu M, Zhou X, Wang T, Xi Y, Jing Z, Xi W. MiR-140-3p inhibits natural killer cytotoxicity to human ovarian cancer via targeting MAPK1. J Biosci 2020. [DOI: 10.1007/s12038-020-00036-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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47
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Yi M, Xu L, Jiao Y, Luo S, Li A, Wu K. The role of cancer-derived microRNAs in cancer immune escape. J Hematol Oncol 2020; 13:25. [PMID: 32222150 PMCID: PMC7103070 DOI: 10.1186/s13045-020-00848-8] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/14/2020] [Indexed: 12/18/2022] Open
Abstract
During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.
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Affiliation(s)
- Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Linping Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Ying Jiao
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Suxia Luo
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
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48
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Zhang L, Xu X, Su X. Noncoding RNAs in cancer immunity: functions, regulatory mechanisms, and clinical application. Mol Cancer 2020; 19:48. [PMID: 32122338 PMCID: PMC7050126 DOI: 10.1186/s12943-020-01154-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
It is well acknowledged that immune system is deeply involved in cancer initiation and progression, and can exert both pro-tumorigenic and anti-tumorigenic effects, depending on specific microenvironment. With the better understanding of cancer-associated immune cells, especially T cells, immunotherapy was developed and applied in multiple cancers and exhibits remarkable efficacy. However, currently only a subset of patients have responses to immunotherapy, suggesting that a boarder view of cancer immunity is required. Non-coding RNAs (ncRNAs), mainly including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are identified as critical regulators in both cancer cells and immune cells, thus show great potential to serve as new therapeutic targets to improve the response of immunotherapy. In this review, we summarize the functions and regulatory mechanisms of ncRNAs in cancer immunity, and highlight the potential of ncRNAs as novel targets for immunotherapy.
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Affiliation(s)
- Le Zhang
- Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, 1 Tong Dao Street, Huimin District, Hohhot, 010050, Inner Mongolia, China
| | - Xiaonan Xu
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, FL, 33612-9497, USA
| | - Xiulan Su
- Clinical Medical Research Center of the Affiliated Hospital, Inner Mongolia Medical University, 1 Tong Dao Street, Huimin District, Hohhot, 010050, Inner Mongolia, China.
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49
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Pesce S, Greppi M, Ferretti E, Obino V, Carlomagno S, Rutigliani M, Thoren FB, Sivori S, Castagnola P, Candiani S, Marcenaro E. miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy. Front Cell Dev Biol 2020; 8:119. [PMID: 32161759 PMCID: PMC7053181 DOI: 10.3389/fcell.2020.00119] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/11/2020] [Indexed: 12/16/2022] Open
Abstract
The incidence of certain forms of tumors has increased progressively in recent years and is expected to continue growing as life expectancy continues to increase. Tumor-infiltrating NK cells may contribute to develop an anti-tumor response. Optimized combinations of different cancer therapies, including NK cell-based approaches for targeting tumor cells, have the potential to open new avenues in cancer immunotherapy. Functional inhibitory receptors on NK cells are needed to prevent their attack on healthy cells. Nevertheless, disruption of inhibitory receptors function on NK cells increases the cytotoxic capacity of NK cells against cancer cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that target mRNA and thus regulate the expression of genes involved in the development, maturation, and effector functions of NK cells. Therapeutic strategies that target the regulatory effects of miRNAs have the potential to improve the efficiency of cancer immunotherapy. Interestingly, emerging evidence points out that some miRNAs can, directly and indirectly, control the surface expression of immune checkpoints on NK cells or that of their ligands on tumor cells. This suggests a possible use of miRNAs in the context of anti-tumor therapy. This review provides the current overview of the connections between miRNAs and regulation of NK cell functions and discusses the potential of these miRNAs as innovative biomarkers/targets for cancer immunotherapy.
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Affiliation(s)
- Silvia Pesce
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Marco Greppi
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Elisa Ferretti
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Valentina Obino
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Simona Carlomagno
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Mariangela Rutigliani
- Histological and Anatomical Pathology Unit, Department of Laboratory and Service, E.O. Galliera Hospital, Genova, Italy
| | - Fredrik B Thoren
- Tumor Immunology Laboratory (TIMM) Laboratory at Sahlgrenska Cancer Center, Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Simona Sivori
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | | | - Simona Candiani
- Department of Earth Science, Environment and Life (DISTAV), University of Genoa, Genoa, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
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50
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Xiao Z, Chen S, Feng S, Li Y, Zou J, Ling H, Zeng Y, Zeng X. Function and mechanisms of microRNA-20a in colorectal cancer. Exp Ther Med 2020; 19:1605-1616. [PMID: 32104211 PMCID: PMC7027132 DOI: 10.3892/etm.2020.8432] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/29/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-associated mortality worldwide. CRC currently has no specific biomarkers to promote its diagnosis and treatment and the underlying mechanisms regulating its pathogenesis have not yet been determined. MicroRNAs (miRs) are small, non-coding RNAs that exhibit regulatory functions and have been demonstrated to serve a crucial role in the post-transcriptional regulatory processes of gene expression that is associated with cell physiology and disease progression. Recently, abnormal miR-20a expression has been identified in a number of cancers types and this has become a novel focus within cancer research. High levels of miR-20a expression have been identified in CRC tissues, serum and plasma. In a recent study, miR-20a was indicated to be present in feces and to exhibit a high sensitivity to CRC. Therefore, miR-20a may be used as a marker for CRC and an indicator that can prevent the invasive examination of patients with this disease. Changes in the expression of miR-20a during chemotherapy can be used as a biomarker for monitoring resistance to treatment. In conclusion, miR-20a exhibits the potential for clinical application as a novel diagnostic biomarker and therapeutic target for use in patients with CRC. The present study focused on the role and mechanisms of miR-20a in CRC.
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Affiliation(s)
- Zheng Xiao
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shi Chen
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Shujun Feng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yukun Li
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Juan Zou
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hui Ling
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Ying Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,School of Nursing, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xi Zeng
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, University of South China, Hengyang, Hunan 421001, P.R. China.,Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, P.R. China
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