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Gu C, ChenLiu Z, Wu Q, Tang D. ncRNAs as Key Regulators in Gastric Cancer: From Molecular Subtyping to Therapeutic Targets. Ann Surg Oncol 2025:10.1245/s10434-025-17368-9. [PMID: 40358781 DOI: 10.1245/s10434-025-17368-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Accepted: 04/08/2025] [Indexed: 05/15/2025]
Abstract
Gastric cancer (GC) poses a major global health challenge, underscoring the need for advanced diagnostic and therapeutic approaches. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators in GC, with their dysregulated expression driving key processes such as tumorigenesis, metastasis, immune evasion, and chemoresistance. The functional diversity of ncRNAs across different GC molecular subtypes highlights their potential as biomarkers for improved subtype classification and patient stratification. Beyond their diagnostic value, ncRNAs demonstrate critical regulatory functions in tumor biology, establishing these RNA molecules as promising targets for therapeutic development. Strategies based on RNA hold considerable promise for addressing critical challenges such as immune escape and drug resistance by modulating key signaling pathways. These approaches can enhance immune responses, reprogram the tumor microenvironment, and reverse resistance mechanisms that compromise treatment efficacy, thereby improving clinical outcomes. Although ncRNAs represent a promising frontier in GC precision medicine, further research is required to fully harness their clinical potential.
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Affiliation(s)
- Chen Gu
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Zhenni ChenLiu
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Qihang Wu
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
- Northern Jiangsu People's Hospital, Yangzhou, China.
- The Yangzhou Clinical Medical College of Xuzhou Medical University, Xuzhou Medical University, Yangzhou, China.
- Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Yangzhou, China.
- The Yangzhou School of Clinical Medicine of Dalian Medical University, Dalian Medical University, Yangzhou, China.
- The Yangzhou School of Clinical Medicine of Nanjing Medical University, Yangzhou, China.
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2
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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Guo Q, Zhou Y, Xie T, Yuan Y, Li H, Shi W, Zheng L, Li X, Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis 2024; 11:101043. [PMID: 38292177 PMCID: PMC10825311 DOI: 10.1016/j.gendis.2023.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/25/2023] [Indexed: 02/01/2024] Open
Abstract
There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Huilong Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Wanjin Shi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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Sun QH, Kuang ZY, Zhu GH, Ni BY, Li J. Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers. World J Gastrointest Oncol 2024; 16:300-313. [PMID: 38425402 PMCID: PMC10900144 DOI: 10.4251/wjgo.v16.i2.300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/31/2023] [Accepted: 01/19/2024] [Indexed: 02/02/2024] Open
Abstract
MicroRNAs (miRNAs) have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells (CSCs). The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells (GCSCs). Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs. This review summarizes the coding process and biological functions of miRNAs and demonstrates their role and efficacy in gastric cancer (GC) metastasis, drug resistance, and apoptosis, especially in the regulatory mechanism of GCSCs. It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis, apart from the initial formation of GC. It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC. We believe that this review may help in designing novel therapeutic approaches for GC.
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Affiliation(s)
- Qian-Hui Sun
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Zi-Yu Kuang
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Guang-Hui Zhu
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Bao-Yi Ni
- Department of Oncology, Heilongjiang University of Chinese Medicine, Harbin 150040, Heilongjiang Province, China
| | - Jie Li
- Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
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Ahuja S, Zaheer S. Multifaceted TGF-β signaling, a master regulator: From bench-to-bedside, intricacies, and complexities. Cell Biol Int 2024; 48:87-127. [PMID: 37859532 DOI: 10.1002/cbin.12097] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 09/08/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor-β (TGF-β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF-β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF-β causes extracellular matrix deposition, epithelial-mesenchymal transition, cancer-associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF-β in inflammation, fibrosis, and carcinogenesis. As TGF-β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF-β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. There is a need for careful dosing of TGF-β drugs for therapeutic use and patient selection.
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Affiliation(s)
- Sana Ahuja
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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Ni T, Chu Z, Tao L, Zhao Y, Lv M, Zhu M, Luo Y, Sunagawa M, Wang H, Liu Y. Celastrus orbiculatus extract suppresses gastric cancer stem cells through the TGF-β/Smad signaling pathway. J Nat Med 2024; 78:100-113. [PMID: 37817006 DOI: 10.1007/s11418-023-01748-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 08/31/2023] [Indexed: 10/12/2023]
Abstract
Cancer stem cells (CSCs) are the primary source of tumor recurrence and chemoresistance, which complicates tumor treatment and has a significant impact on poor patient prognosis. Therefore, the discovery of inhibitors that specifically target CSCs is warranted. Previous research has established that the TGF-β/Smad signaling pathway is critical for the maintenance of CSCs phenotype, thus facilitating CSCs transformation. In this regard, Celastrus orbiculatus ethyl acetate extract (COE) was shown to exert anticancer properties; however, its therapeutic impact on gastric cancer stem cells (GCSCs) remains unknown. We here demonstrate that COE displayed a strong inhibitory effect on GCSCs growth and CSCs markers. Moreover, COE was shown to efficiently inhibit the development of tumor spheres and accelerate GCSCs apoptosis. Mechanistically, we established that COE could suppress the stemness phenotype of GCSCs by inhibiting the activity of the TGF-β/Smad signaling pathway. To summarize, our data indicate that COE suppresses the malignant biological phenotype of GCSCs via the TGF-β/Smad signaling pathway. These findings shed new light on the anticancer properties of COE and suggest new strategies for the development of efficient GCSCs therapeutics.
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Affiliation(s)
- Tengyang Ni
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Zewen Chu
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Li Tao
- Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, People's Republic of China
| | - Yang Zhao
- Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, People's Republic of China
| | - Mengying Lv
- Department of Pharmacy, College of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, People's Republic of China
| | - Miao Zhu
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Yuanyuan Luo
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Masataka Sunagawa
- Department of Physiology, School of Medicine, Showa University, Tokyo, 142, Japan
| | - Haibo Wang
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China.
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China.
| | - Yanqing Liu
- TCM Department, The Affiliated Hospital of Yangzhou University, Yangzhou University, No. 136, Jiangyang Middle Road, Yangzhou, 225001, Jiangsu, People's Republic of China.
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People's Republic of China.
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Zeng Z, Fu M, Hu Y, Wei Y, Wei X, Luo M. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol Cancer 2023; 22:172. [PMID: 37853437 PMCID: PMC10583419 DOI: 10.1186/s12943-023-01877-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Minyang Fu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuan Hu
- Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Min Luo
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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Pessôa R, de Souza DRV, Nukui Y, Pereira J, Fernandes LA, Marcusso RN, de Oliveira ACP, Casseb J, da Silva Duarte AJ, Sanabani SS. Small RNA Profiling in an HTLV-1-Infected Patient with Acute Adult T-Cell Leukemia-Lymphoma at Diagnosis and after Maintenance Therapy: A Case Study. Int J Mol Sci 2023; 24:10643. [PMID: 37445821 DOI: 10.3390/ijms241310643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Small RNAs (sRNAs) are epigenetic regulators of essential biological processes associated with the development and progression of leukemias, including adult T-cell leukemia/lymphoma (ATLL) caused by human T-cell lymphotropic virus type 1 (HTLV-1), an oncogenic human retrovirus originally discovered in a patient with adult T-cell leukemia/lymphoma. Here, we describe the sRNA profile of a 30-year-old woman with ATLL at the time of diagnosis and after maintenance therapy with the aim of correlating expression levels with response to therapy.
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Affiliation(s)
- Rodrigo Pessôa
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo 04039-002, Brazil
| | - Daniela Raguer Valadão de Souza
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo 04039-002, Brazil
| | - Youko Nukui
- Department of Hematology, Faculty of Medicine, University of São Paulo, São Paulo 05403-000, Brazil
| | - Juliana Pereira
- Department of Hematology, Faculty of Medicine, University of São Paulo, São Paulo 05403-000, Brazil
| | - Lorena Abreu Fernandes
- Postgraduate Program in Translational Medicine, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo 04039-002, Brazil
| | - Rosa Nascimento Marcusso
- Department of Neurology, Emilio Ribas Institute of Infectious Diseases, São Paulo 01246-900, Brazil
| | | | - Jorge Casseb
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of São Paulo, São Paulo 05403-000, Brazil
| | - Alberto José da Silva Duarte
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of São Paulo, São Paulo 05403-000, Brazil
| | - Sabri Saeed Sanabani
- Laboratory of Medical Investigation LIM-56, Division of Dermatology, Medical School, University of São Paulo, São Paulo 05403-000, Brazil
- Laboratory of Medical Investigation Unit 03, Clinics Hospital, Faculty of Medicine, University of São Paulo, São Paulo 05403-000, Brazil
- Laboratory of Dermatology and Immunodeficiency, LIM56/03, Instituto de Medicina Tropical de São Paulo Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 470 3° andar, São Paulo 05403-000, Brazil
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Fathi D, Elballal MS, Elesawy AE, Abulsoud AI, Elshafei A, Elsakka EG, Ismail A, El-Mahdy HA, Elrebehy MA, Doghish AS. An emphasis on the interaction of signaling pathways highlights the role of miRNAs in the etiology and treatment resistance of gastric cancer. Life Sci 2023; 322:121667. [PMID: 37023952 DOI: 10.1016/j.lfs.2023.121667] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/01/2023] [Accepted: 04/03/2023] [Indexed: 04/07/2023]
Abstract
Gastric cancer (GC) is 4th in incidence and mortality rates globally. Several genetic and epigenetic factors, including microRNAs (miRNAs), affect its initiation and progression. miRNAs are short chains of nucleic acids that can regulate several cellular processes by controlling their gene expression. So, dysregulation of miRNAs expressions is associated with GC initiation, progression, invasion capacity, apoptosis evasions, angiogenesis, promotion and EMT enhancement. Of important pathways in GC and controlled by miRNAs are Wnt/β-catenin signaling, HMGA2/mTOR/P-gp, PI3K/AKT/c-Myc, VEGFR and TGFb signaling. Hence, this review was conducted to review an updated view of the role of miRNAs in GC pathogenesis and their modulatory effects on responses to different GC treatment modalities.
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10
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Manni W, Min W. Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm (Beijing) 2022; 3:e176. [PMID: 36226253 PMCID: PMC9534377 DOI: 10.1002/mco2.176] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/20/2022] [Accepted: 08/22/2022] [Indexed: 11/07/2022] Open
Abstract
Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.
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Affiliation(s)
- Wang Manni
- Department of Biotherapy, Cancer Center, West China HospitalSichuan UniversityChengduP. R. China
| | - Wu Min
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
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11
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Huang Q, Wu L, Wang Y, Kong X, Xiao X, Huang Q, Li M, Zhai Y, Shi F, Zhao R, Zhong J, Xiong L. Caveolin-1-deficient fibroblasts promote migration, invasion, and stemness via activating the TGF-β/Smad signaling pathway in breast cancer cells. Acta Biochim Biophys Sin (Shanghai) 2022; 54:1587-1598. [PMID: 36604141 PMCID: PMC9827800 DOI: 10.3724/abbs.2022150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Cancer-associated fibroblasts (CAFs) represent one of the main components in the tumor stroma and play a key role in breast cancer progression. Transforming growth factor-β (TGF-β) has been established to mediate breast cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) and stemness of cancer cells. Caveolin-1 (CAV-1) is a scaffold protein of caveolae that is related to the proliferation and metabolism of cancer cells. It is now well demonstrated that CAV-1 deficiency in the tumor stroma is positively correlated with distant metastasis, but the mechanism remains unclear. Here, we explore whether CAV-1-deficient fibroblasts play an essential role in the EMT and stemness of breast cancer cells (BCCs) through TGF-β signaling. We establish a specific small interfering RNA (siRNA) to inhibit CAV-1 expression in fibroblasts and coculture them with BCCs to investigate the effect of CAV‑1-deficient fibroblasts and the tumor microenvironment on breast cancer progression. This study refreshingly points out that CAV-1 deficiency in fibroblasts enhances TGF-β1 secretion and then activates the TGF-β1/Smad signaling pathway of BCCs, thus promoting the metastasis and stemness of BCCs. Collectively, our findings indicate an unexpected role of CAV-1 deficiency in fibroblasts and the tumor microenvironment as a permissive factor, which is regulated by the TGF-β1 signaling pathway in BCCs.
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Affiliation(s)
- Qingyun Huang
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Longyuan Wu
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Yi Wang
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Xinyu Kong
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Xinhua Xiao
- The First Affiliated HospitalNanchang UniversityNanchang330006China
| | - Qiyuan Huang
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Miao Li
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Yujia Zhai
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Fuxiu Shi
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Ruichen Zhao
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Junpei Zhong
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China
| | - Lixia Xiong
- Department of PathophysiologyMedical CollegeNanchang UniversityNanchang330006China,Key Laboratory of Functional and Clinical Translational MedicineFujian Province UniversityXiamen361023China,Correspondence address. Tel: +86-791-86360565;
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12
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Vadhan A, Hou MF, Vijayaraghavan P, Wu YC, Hu SCS, Wang YM, Cheng TL, Wang YY, Yuan SSF. CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2. Biomedicines 2022; 10:2488. [PMID: 36289750 PMCID: PMC9599046 DOI: 10.3390/biomedicines10102488] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/29/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
The primary cause of breast cancer mortality is the metastatic invasion of cancerous stem cells (CSC). Cluster of differentiation 44 (CD44) is a well-known CSC marker in various cancers, as well as a key role player in metastasis and relapse of breast cancer. CD44 is a cell-membrane embedded protein, and it interacts with different proteins to regulate cancer cell behavior. Transcription factor forkhead box protein A2 (FOXA2) acts as an important regulator in multiple cancers, including breast cancer. However, the biological significance of CD44-FOXA2 association in breast cancer metastasis remains unclear. Herein, we observed that CD44 expression was higher in metastatic lymph nodes compared to primary tumors using a flow cytometric analysis. CD44 overexpression in breast cancer cell lines significantly promoted cell migration and invasion abilities, whereas the opposite effects occurred upon the knockdown of CD44. The stem cell array analysis revealed that FOXA2 expression was upregulated in CD44 knockdown cells. However, the knockdown of FOXA2 in CD44 knockdown cells reversed the effects on cell migration and invasion. Furthermore, we found that CD44 mediated FOXA2 localization in breast cancer cells through the AKT pathway. Moreover, the immunofluorescence assay demonstrated that AKT inhibitor wortmannin and AKT activator SC79 treatment in breast cancer cells impacted FOXA2 localization. Collectively, this study highlights that CD44 promotes breast cancer metastasis by downregulating nuclear FOXA2.
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Affiliation(s)
- Anupama Vadhan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Priya Vijayaraghavan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Chia Wu
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Stephen Chu-Sung Hu
- Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Yun-Ming Wang
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan
- Department of Biomedical Science and Environmental Biology, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tian-Lu Cheng
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yen-Yun Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Shyng-Shiou F. Yuan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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13
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Rao X, Zhang C, Luo H, Zhang J, Zhuang Z, Liang Z, Wu X. Targeting Gastric Cancer Stem Cells to Enhance Treatment Response. Cells 2022; 11:cells11182828. [PMID: 36139403 PMCID: PMC9496718 DOI: 10.3390/cells11182828] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.
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14
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Panoramic view of microRNAs in regulating cancer stem cells. Essays Biochem 2022; 66:345-358. [PMID: 35996948 DOI: 10.1042/ebc20220007] [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: 06/13/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 12/17/2022]
Abstract
Cancer stem cells (CSCs) are a subgroup of tumor cells, possessing the abilities of self-renewal and generation of heterogeneous tumor cell lineages. They are believed to be responsible for tumor initiation, metastasis, as well as chemoresistance in human malignancies. MicroRNAs (miRNAs) are small noncoding RNAs that play essential roles in various cellular activities including CSC initiation and CSC-related properties. Mature miRNAs with ∼22 nucleotides in length are generated from primary miRNAs via its precursors by miRNA-processing machinery. Extensive studies have demonstrated that mature miRNAs modulate CSC initiation and stemness features by regulating multiple pathways and targeting stemness-related factors. Meanwhile, both miRNA precursors and miRNA-processing machinery can also affect CSC properties, unveiling a new insight into miRNA function. The present review summarizes the roles of mature miRNAs, miRNA precursors, and miRNA-processing machinery in regulating CSC properties with a specific focus on the related molecular mechanisms, and also outlines the potential application of miRNAs in cancer diagnosis, predicting prognosis, as well as clinical therapy.
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15
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miR-106b as an emerging therapeutic target in cancer. Genes Dis 2022; 9:889-899. [PMID: 35685464 PMCID: PMC9170583 DOI: 10.1016/j.gendis.2021.02.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 01/24/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) comprise short non-coding RNAs that function in regulating the expression of tumor suppressors or oncogenes and modulate oncogenic signaling pathways in cancer. miRNAs expression alters significantly in several tumor tissues and cancer cell lines. For example, miR-106b functions as an oncogene and increases in multiple cancers. The miR-106b directly targets genes involved in tumorigenesis, proliferation, invasion, migration, and metastases. This review has focused on the miR-106b function and its downstream target in different cancers and provide perspective into how miR-106 regulates cancer cell proliferation, migration, invasion, and metastases by regulating the tumor suppressor genes. Since miRNAs-based therapies are currently being developed to enhance cancer therapy outcomes, miR-106b could be an attractive and prospective candidate in different cancer types for detection, diagnosis, and prognosis assessment in the tumor.
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16
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Du W, Zhang L, Li X, Ling G, Zhang P. Nuclear targeting Subcellular-delivery nanosystems for precise cancer treatment. Int J Pharm 2022; 619:121735. [DOI: 10.1016/j.ijpharm.2022.121735] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/27/2022] [Accepted: 04/06/2022] [Indexed: 12/20/2022]
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17
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Liu Y, Ao X, Ji G, Zhang Y, Yu W, Wang J. Mechanisms of Action And Clinical Implications of MicroRNAs in the Drug Resistance of Gastric Cancer. Front Oncol 2021; 11:768918. [PMID: 34912714 PMCID: PMC8667691 DOI: 10.3389/fonc.2021.768918] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors of digestive systems worldwide, with high recurrence and mortality. Chemotherapy is still the standard treatment option for GC and can effectively improve the survival and life quality of GC patients. However, with the emergence of drug resistance, the clinical application of chemotherapeutic agents has been seriously restricted in GC patients. Although the mechanisms of drug resistance have been broadly investigated, they are still largely unknown. MicroRNAs (miRNAs) are a large group of small non-coding RNAs (ncRNAs) widely involved in the occurrence and progression of many cancer types, including GC. An increasing amount of evidence suggests that miRNAs may play crucial roles in the development of drug resistance by regulating some drug resistance-related proteins as well as gene expression. Some also exhibit great potential as novel biomarkers for predicting drug response to chemotherapy and therapeutic targets for GC patients. In this review, we systematically summarize recent advances in miRNAs and focus on their molecular mechanisms in the development of drug resistance in GC progression. We also highlight the potential of drug resistance-related miRNAs as biomarkers and therapeutic targets for GC patients.
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Affiliation(s)
- Ying Liu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China.,School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Xiang Ao
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Guoqiang Ji
- Clinical Laboratory, Linqu People's Hospital, Linqu, China
| | - Yuan Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Wanpeng Yu
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
| | - Jianxun Wang
- School of Basic Medical Sciences, Qingdao Medical College, Qingdao University, Qingdao, China
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18
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Song F, Yang Z, Li L, Wei Y, Tang X, Liu S, Yu M, Chen J, Wang S, Fu J, Zhang K, Yang P, Yang X, Chen Z, Zhang B, Wang H. MiR-552-3p promotes malignant progression of gallbladder carcinoma by reactivating the Akt/β-catenin signaling pathway due to inhibition of the tumor suppressor gene RGMA. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1374. [PMID: 34733926 PMCID: PMC8506546 DOI: 10.21037/atm-21-2013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/23/2021] [Indexed: 11/06/2022]
Abstract
Background Gallbladder carcinoma (GBC) remains a highly lethal disease worldwide. MiR-552 family members promote the malignant progression of a variety of digestive system tumors, but the role of miR-552-3p in GBC has not been elucidated. miR-552-3p was predicted to target the 3'-untranslated region (3'UTR) of the mRNA for the tumor suppressor gene "repulsive guidance molecule BMP co-receptor a" (RGMA). The aim of the present study was to clarify the roles and mechanisms of miR-552-3p targeting RGMA in the malignant progression of GBC. Methods In vitro: expression of miR-552-3p was detected by real-time quantitative PCR (qRT-PCR) in tumor and non-tumor adjacent tissues (NATs). Lentivirus-miR-552-3p was employed to knockdown this miRNA in GBC cell lines. Stem cell-related transcription factors and markers were assessed by qRT-PCR. Cell Counting Kit-8 (CCK-8), sphere formation and transwell assays were used to determine the malignant phenotypes of GBC cells. Targeting the 3'UTR of RGMA by miR-552-3p was verified by integrated analysis including bioinformatics prediction, luciferase assays, measures of changes of gene expression and rescue experiments. In vivo: mouse models of subcutaneous tumors and lung metastases were established to observe the effect of miR-552-3p on tumorigenesis and organ metastasis, respectively. Results MiR-552-3p was abnormally highly expressed in GBC tissues and cancer stem cells. Interference with miR-552-3p in SGC-996 and GBC-SD cells significantly inhibited GBC stem cell expansion. Reciprocally, miR-552-3p promoted GBC cell proliferation, migration and invasion both in vitro and in vivo; hence, interference with this miRNA impeded the malignant progression of GBC. Furthermore, the important tumor suppressor gene RGMA was identified as a target of miR-552-3p. The effects of miR-552-3p on cell proliferation and metastasis were abrogated or enhanced by gain or loss of RGMA function, respectively. Mechanistically, miR-552-3p promoted GBC progression by reactivating the Akt/β-catenin pathway and epithelial-mesenchymal transformation (EMT). Clinically, miR-552-3p correlated with multi-malignant characteristics of GBC and acted as a prognostic marker for GBC outcome. Conclusions MiR-552-3p promotes the malignant progression of GBC by inhibiting the mRNA of the tumor suppressor gene RGMA, resulting in reactivation of the Akt/β-catenin signaling pathway.
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Affiliation(s)
- Fengliang Song
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China
| | - Zhao Yang
- Department of Hepatic Surgery II, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Liang Li
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Yanping Wei
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Xuewu Tang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Shuowu Liu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Miao Yu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jin Chen
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Suyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Jingbo Fu
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China
| | - Kecheng Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Pinghua Yang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xinwei Yang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zhong Chen
- Department of General Surgery, The Affiliated Hospital of Nantong University, Nantong, China
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.,National Center for Liver Cancer, Shanghai, China.,National Laboratory for Oncogenes and Related Genes, Cancer Institute, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
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19
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Liu Z, Ren Y, Meng L, Li L, Beatson R, Deng J, Zhang T, Liu J, Han X. Epigenetic Signaling of Cancer Stem Cells During Inflammation. Front Cell Dev Biol 2021; 9:772211. [PMID: 34722553 PMCID: PMC8554148 DOI: 10.3389/fcell.2021.772211] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Malignant tumors pose a great challenge to human health, which has led to many studies increasingly elucidating the tumorigenic process. Cancer Stem Cells (CSCs) have profound impacts on tumorigenesis and development of drug resistance. Recently, there has been increased interest in the relationship between inflammation and CSCs but the mechanism underlying this relationship has not been fully elucidated. Inflammatory cytokines produced during chronic inflammation activate signaling pathways that regulate the generation of CSCs through epigenetic mechanisms. In this review, we focus on the effects of inflammation on cancer stem cells, particularly the role of signaling pathways such as NF-κB pathway, STAT3 pathway and Smad pathway involved in regulating epigenetic changes. We hope to provide a novel perspective for improving strategies for tumor treatment.
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Affiliation(s)
- Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lingfang Meng
- Department of Ultrasound, Zhengzhou Sixth People's Hospital, Henan Infectious Disease Hospital, Zhengzhou, China
| | - Lifeng Li
- Internet Medical and System Applications of National Engineering Laboratory, Zhengzhou, China
| | - Richard Beatson
- School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Jinhai Deng
- Richard Dimbleby Laboratory of Cancer Research, School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Tengfei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Interventional Institute of Zhengzhou University, Zhengzhou, China.,Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, China
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20
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Becerril-Rico J, Alvarado-Ortiz E, Toledo-Guzmán ME, Pelayo R, Ortiz-Sánchez E. The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor. Stem Cell Res Ther 2021; 12:498. [PMID: 34503571 PMCID: PMC8428093 DOI: 10.1186/s13287-021-02562-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Cross talk between cancer cells and the immune system is determinant for cancer progression. Emerging evidence demonstrates that GC characteristics such as metastasis, treatment resistance, and disease recurrence are associated with a tumor subpopulation called gastric cancer stem cells (GCSCs). However, the specific interaction between GCSCs and the immune microenvironment is still under investigation. Although immune evasion has been well described for cancer stem cells (CSCs), recent studies show that GCSCs can also regulate the immune system and even benefit from it. This review will provide an overview of bidirectional interactions between CSCs and immune cells in GC, compiling relevant data about how CSCs can induce leukocyte reprogramming, resulting in pro-tumoral immune cells that orchestrate promotion of metastasis, chemoresistance, tumorigenicity, and even increase in number of cancer cells with stem properties. Some immune cells studied are tumor-associated macrophages (TAMs), neutrophils, Th17 and T regulatory (Treg) cells, mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs), as well as the signaling pathways involved in these pro-tumoral activities. Conversely, although there are cytotoxic leukocytes that can potentially eliminate GCSCs, we describe mechanisms for immune evasion in GCSCs and their clinical implications. Furthermore, we describe current available immunotherapy targeting GCSC-related markers as possible treatment for GC, discussing how the CSC-modified immune microenvironment can mitigate or inactivate these immunotherapies, limiting their effectiveness. Finally, we summarize key concepts and relevant evidence to understand the cross talk between GCSCs and the immune microenvironment as an important process for effective design of therapies against GCSCs that improve the outcome of patients with GC.
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Affiliation(s)
- Jared Becerril-Rico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Eduardo Alvarado-Ortiz
- Programa de Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Mariel E Toledo-Guzmán
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico
| | - Rosana Pelayo
- Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
| | - Elizabeth Ortiz-Sánchez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Ciudad de México, Mexico.
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21
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Li Q, Li Y, Jiang H, Xiao Z, Wu X, Zhang H, Zhao Y, Du F, Chen Y, Wu Z, Li J, Hu W, Cho CH, Shen J, Li M. Vitamin D suppressed gastric cancer cell growth through downregulating CD44 expression in vitro and in vivo. Nutrition 2021; 91-92:111413. [PMID: 34450383 DOI: 10.1016/j.nut.2021.111413] [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: 04/08/2021] [Revised: 06/30/2021] [Accepted: 07/06/2021] [Indexed: 12/31/2022]
Abstract
OBJECTIVES Vitamin D deficiency was found to be associated with increased risk for gastric cancer (GC). We previously found that vitamin D inhibited GC cell growth in vitro. However, the in vivo antitumor effect of vitamin D in GC as well as the underlying mechanisms are not well understood. The aim of this study was to investigate the anticancer effect of vitamin D on GC both in vitro and in vivo. METHODS Human GC cells MKN45, MKN28, and KATO III were used. The expressions of vitamin D receptor (VDR) and CD44 were downregulated by using predesigned siRNA molecules. Cell viability was evaluated by methyl thiazolyl tetrazolium assay. Soft agar assay was used for colony formation of GC cells. Flow cytometry was used to assess CD44-positive cell population. CD44high cancer cells were enriched by using anti-CD44-conjugated magnetic microbeads. Quantitative real-time polymerase chain reaction and Western blot were performed to detect gene and protein expressions, respectively. Clinical samples were collected for evaluation of the correlation of VDR and CD44 expression. Orthotopic tumor-bearing mice were established to evaluate the antitumor effect of vitamin D. RESULTS The results showed that the active form of vitamin D, 1,25(OH)2D3, had a remarkable inhibitory effect in CD44-expressing human GC MKN45 and KATO III cells, but not in CD44-null MKN28 cells. The gene expressions of CD44 and VDR in GC cell lines and GC patient tissues were positively correlated. Furthermore, 1,25(OH)2D3 suppressed MKN45 and KATO III cell growth through VDR-induced suppression of CD44. Additionally, we demonstrated that 1,25(OH)2D3 inhibited Wnt/β-catenin signaling pathway, which might lead to the downregulation of CD44. In an orthotopic GC nude mice model, both oral intake of vitamin D and intraperitoneal injection with 1,25(OH)2D3 could significantly inhibit orthotopic GC growth and CD44 expression in vivo. CONCLUSION To our knowledge, this study provided the first evidence that vitamin D suppressed GC cell growth both in vitro and in vivo through downregulating CD44. The present study sheds light on repurposing vitamin D as a potential therapeutic agent for GC prevention and treatment.
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Affiliation(s)
- Qianxiu Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Yifan Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Houxiang Jiang
- Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Sichuan, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Hanyu Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; Department of Gastrointestinal Surgery, the First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wanna Medical College), Anhui, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China
| | - Zhigui Wu
- Department of Pharmacy, the Affiliated Hospital of Southwest Medical University, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Sichuan, China
| | - Wei Hu
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Guangdong, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China.
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Sichuan, China; South Sichuan Institute of Translational Medicine, Sichuan, China.
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22
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Dai ZT, Xiang Y, Duan YY, Wang J, Li JP, Zhang HM, Cheng C, Wang Q, Zhang TC, Liao XH. MiR-17-5p and MKL-1 modulate stem cell characteristics of gastric cancer cells. Int J Biol Sci 2021; 17:2278-2293. [PMID: 34239355 PMCID: PMC8241736 DOI: 10.7150/ijbs.57338] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 05/22/2021] [Indexed: 12/13/2022] Open
Abstract
Effectively targeting cancer stem cells to treat cancer has great therapeutic prospects. However, the effect of microRNA miR-17/MKL-1 on gastric cancer stem cells has not been studied yet. This study preliminarily explored the mechanism of miR-17/MKL-1 in gastric cancer stem cells. Many previous reports have indicated that microRNA and EMT regulated cancer stem cell characteristics, and miR-17 and MKL-1 were involved as a critical gene in migration and invasion in the EMT pathway. Through RT-PCR, Western Blot, flow cytometry, immunofluorescence, sphere formation xenograft tumor assays and drug resistance, the role of miR-17-5p and MKL-1 on promoting stem cell-like properties of gastric cancer were verified in vivo and vitro. Next, MKL-1 targets CD44, EpCAM, and miR -17-5p promoter verified by luciferase assay and ChIP. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. It is found that MKL-1 promotes expression by targeting miR-17, CD44 and EpCAM promoters. Besides, the TCGA database analysis found that both miR-17-5p and MKL-1 increased in gastric cancer, and the prognostic survival of the MKL-1 high expression group was reduced. These findings reveal new regulatory signaling pathways for gastric cancer stem cells, thus it give new insights on potential early diagnosis and/or molecular therapy for gastric cancer.
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Affiliation(s)
- Zhou-Tong Dai
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Yuan Xiang
- Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Hubei, 430014, P.R. China
| | - Yuan-Yuan Duan
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jun Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Jia Peng Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Hui-Min Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Chao Cheng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qiong Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
| | - Tong-Cun Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China.,Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education and Tianjin, College of Biotechnology, Tianjin University of Science and Technology, Tinajin, 300457, P.R. China
| | - Xing-Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Hubei, 430081, P.R. China
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23
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Tian W, Li J, Wang Z, Zhang T, Han Y, Liu Y, Chu W, Liu Y, Yang B. HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial-mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/ β-catenin signaling activation. Acta Pharm Sin B 2021; 11:1592-1606. [PMID: 34221870 PMCID: PMC8245914 DOI: 10.1016/j.apsb.2021.03.040] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/27/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023] Open
Abstract
HYD-PEP06, an endostatin-modified polypeptide, has been shown to produce effective anti-colorectal carcinoma effects through inhibiting epithelial-mesenchymal transition (EMT). However, whether HYD-PEP06 has similar suppressive effect on hepatocellular carcinoma (HCC) remained unknown. In this study, HYD-PEP06 inhibited metastasis and EMT but not proliferation in vitro. Cignal finder pathway reporter array and Western blot analysis revealed that HYD-PEP06 suppressed HCCLM3 cell metastasis and EMT by inhibiting the PI3K/AKT pathway. Moreover, HYD-PEP06 exerted anti-metastasis effects in HepG2 cancer stem-like cells (CSCs) via suppressing the WNT/β-catenin signaling pathway. Finally, in HCCLM3 tumor-bearing BALB/c nu/nu nude mice, HYD-PEP06 substantially suppressed tumor growth, lung metastasis and HCC progress. Our results suggest that HYD-PEP06 inhibits the metastasis and EMT of HCC and CSCs as well, and thus has the potential as an agent for HCC treatment.
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Affiliation(s)
- Wei Tian
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jiatong Li
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Zhuo Wang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Tong Zhang
- The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Ying Han
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yanyan Liu
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Wenfeng Chu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yu Liu
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Baofeng Yang
- Department of Pharmacology (the State-Province Key Laboratories of Biomedicine Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
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24
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Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci 2021; 277:119465. [PMID: 33831426 DOI: 10.1016/j.lfs.2021.119465] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/01/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) control the dynamics of tumorigenesis by self-renewal ability and differentiation potential. These properties contribute towards tumor malignancy, metastasis, cellular heterogeneity, and immune escape, which are regulated by multiple signaling pathways. The CSCs are chemoresistant and cause cancer recurrence, generally recognized as a small side-population that eventually leads to tumor relapse. Despite many treatment options available, none can be considered entirely efficient due to a lack of specificity and dose limitation. This review primarily highlights the processes involved in CSCs development and maintenance. Secondly, the current effective therapies based on stem cells, cell-free therapies that involve exosomes and miRNAs, and photodynamic therapy have been discussed. Also, the inhibitors that specifically target various signaling pathways, which can be used in combination to control CSCs kinetics have been highlighted. Conclusively, this comprehensive review is a detailed study of recently developed novel treatment strategies that will facilitate in coming up with better-targeted approaches against CSCs.
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Affiliation(s)
| | - Zoya Mann
- Independent Researcher, New Delhi, India
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25
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Gomari MM, Farsimadan M, Rostami N, Mahmoudi Z, Fadaie M, Farhani I, Tarighi P. CD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2021; 787:108374. [PMID: 34083044 DOI: 10.1016/j.mrrev.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 12/23/2020] [Accepted: 03/18/2021] [Indexed: 12/24/2022]
Abstract
Among cell surface markers, CD44 is considered the main marker for identifying and isolating the cancer stem cells (CSCs) among other cells and has attracted significant attention in a variety of research areas. Many studies have shown the essential roles of CD44 in initiation, metastasis, and tumorigenesis in different types of cancer; however, the validity of CD44 as a therapeutic or diagnostic target has not been fully confirmed in some other studies. Whereas the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene and related variants with cancer risk have been observed in clinical investigations, the significance of these findings remains controversial. Here, we aimed to provide an up-to-date overview of recent studies on the association of CD44 polymorphisms and its variants with different kinds of cancer to determine whether or not it can be used as an appropriate candidate for cancer tracking.
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Affiliation(s)
- Mohammad Mahmoudi Gomari
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marziye Farsimadan
- Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran
| | - Neda Rostami
- Department of Chemical Engineering, Faculty of Engineering, Arak University, Iran
| | - Zahra Mahmoudi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Fadaie
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ibrahim Farhani
- Department of Medical Biotechnology, Faculty of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Golestan, Iran
| | - Parastoo Tarighi
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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26
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Rodrigues ACBDC, Costa RGA, Silva SLR, Dias IRSB, Dias RB, Bezerra DP. Cell signaling pathways as molecular targets to eliminate AML stem cells. Crit Rev Oncol Hematol 2021; 160:103277. [PMID: 33716201 DOI: 10.1016/j.critrevonc.2021.103277] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/25/2021] [Accepted: 02/27/2021] [Indexed: 02/08/2023] Open
Abstract
Acute myeloid leukemia (AML) remains the most lethal of leukemias and a small population of cells called leukemic stem cells (LSCs) has been associated with disease relapses. Some cell signaling pathways play an important role in AML survival, proliferation and self-renewal properties and are abnormally activated or suppressed in LSCs. This includes the NF-κB, Wnt/β-catenin, Hedgehog, Notch, EGFR, JAK/STAT, PI3K/AKT/mTOR, TGF/SMAD and PPAR pathways. This review aimed to discuss these pathways as molecular targets for eliminating AML LSCs. Herein, inhibitors/activators of these pathways were summarized as a potential new anti-AML therapy capable of eliminating LSCs to guide future researches. The clinical use of cell signaling pathways data can be useful to enhance the anti-AML therapy.
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Affiliation(s)
| | - Rafaela G A Costa
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Suellen L R Silva
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Ingrid R S B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Rosane B Dias
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Daniel P Bezerra
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.
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27
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Hwang GR, Yuen JG, Ju J. Roles of microRNAs in Gastrointestinal Cancer Stem Cell Resistance and Therapeutic Development. Int J Mol Sci 2021; 22:ijms22041624. [PMID: 33562727 PMCID: PMC7915611 DOI: 10.3390/ijms22041624] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Resistance to cancer treatment is one of the major challenges currently faced when treating gastrointestinal (GI) cancers. A major contributing factor to this resistance is the presence of cancer stem cells (CSCs) in GI cancers (e.g., colorectal, pancreatic, gastric, liver cancer). Non-coding RNAs, such as microRNAs (miRNAs), have been found to regulate several key targets that are responsible for cancer stemness, and function as oncogenic miRNAs (oncomiRs) or tumor suppressor miRNAs. As a result, several miRNAs have been found to alter, or be altered by, the expression of CSC-defining markers and their related pathways. These miRNAs can be utilized to affect stemness in multiple ways, including directly targeting CSCs and enhancing the efficacy of cancer therapeutics. This review highlights current studies regarding the roles of miRNAs in GI CSCs, and efforts towards the development of cancer therapeutics.
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28
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Gómez-Gil V. Therapeutic Implications of TGFβ in Cancer Treatment: A Systematic Review. Cancers (Basel) 2021; 13:379. [PMID: 33498521 PMCID: PMC7864190 DOI: 10.3390/cancers13030379] [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: 12/21/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/24/2022] Open
Abstract
Transforming growth factor β (TGFβ) is a pleiotropic cytokine that participates in a wide range of biological functions. The alterations in the expression levels of this factor, or the deregulation of its signaling cascade, can lead to different pathologies, including cancer. A great variety of therapeutic strategies targeting TGFβ, or the members included in its signaling pathway, are currently being researched in cancer treatment. However, the dual role of TGFβ, as a tumor suppressor or a tumor-promoter, together with its crosstalk with other signaling pathways, has hampered the development of safe and effective treatments aimed at halting the cancer progression. This systematic literature review aims to provide insight into the different approaches available to regulate TGFβ and/or the molecules involved in its synthesis, activation, or signaling, as a cancer treatment. The therapeutic strategies most commonly investigated include antisense oligonucleotides, which prevent TGFβ synthesis, to molecules that block the interaction between TGFβ and its signaling receptors, together with inhibitors of the TGFβ signaling cascade-effectors. The effectiveness and possible complications of the different potential therapies available are also discussed.
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Affiliation(s)
- Verónica Gómez-Gil
- Department of Biomedical Sciences (Area of Pharmacology), School of Medicine and Health Sciences, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain
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29
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Exosome-mediated delivery of functionally active miRNA-375-3p mimic regulate epithelial mesenchymal transition (EMT) of colon cancer cells. Life Sci 2021; 269:119035. [PMID: 33450254 DOI: 10.1016/j.lfs.2021.119035] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/20/2020] [Accepted: 01/03/2021] [Indexed: 12/12/2022]
Abstract
AIMS EMT is the process by which a polarized epithelial cell undergoes several changes leading to highly invasive and fibroblast-like morphology. It has been described that miR-375 is inversely associated with EMT in cancerous patients and can effectively inhibit invasion and migration of tumor cells. Here, we investigate whether miR-375 mimic delivered by tumor-derived exosomes could reverse EMT process. MAIN METHODS The exosomes were isolated from HT-29 and SW480. Subsequently, exosomes were loaded with miR-375-3p mimic applying modified calcium chloride method. Quantitative real-time PCR was used for evaluation of the loading efficiency of miR-375 mimic in the exosomes. The effects of miR-375 loaded tumor exosomes (TEXomiR) on EMT process investigated using flow cytometry, cell morphology, and invasion and migration assay. KEY FINDINGS The in vitro results showed that the tumor derived exosomes can efficiently deliver miR-375 mimic to reduce the expression of β-catenin, vimentin, ZEB1, and snail. In contrast, TEXomiR significantly increased the expression of E- cadherin in EMT process. Furthermore, the migration and invasion abilities of HT-29 and SW480 cells were inhibited by TEXomiR. The expression of CD44 and CD133 are increased in EMT process. Flow cytometry evaluation demonstrated that treatment with TEXomiR significantly decreased the expression of CD44 and CD133 in SW480 cell line. SIGNIFICANCE Our results imply that colon cancer cells-derived exosomes could be used as an effective nonvehicle to deliver miR-375-3p mimic. Moreover, TEXomiR may be a potent therapeutic agent for the treatment of metastatic colorectal cancer.
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30
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Ahadi A. A systematic review of microRNAs as potential biomarkers for diagnosis and prognosis of gastric cancer. Immunogenetics 2021; 73:155-161. [PMID: 33399935 DOI: 10.1007/s00251-020-01201-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is the third leading cause of global cancer morbidity and mortality. One of the significant challenges in GC treatment is that most GC patients are diagnosed with advanced-stage disease due to the lack of suitable biomarkers. Recent studies have shown that microRNAs (miRNAs) can acts as a potential biomarker in GC diagnosis and prognosis. I performed a systematic review of published miRNA studies in GC, which includes the miRNA expression profiles between GC tissues and normal tissues and also miRNA studies to evaluate their potential value in the diagnosis and prognosis of GC. Among the studies, upregulation of miR-21, miR-106b, miR-25, miR-214, miR-18a, miR-191, and miR-93 and downregulation of miR-375, miR-148a, miR-92, miR-155, and miR-564 were observed in GC tissues. In evaluating of diagnosis value of miRNAs, the study was performed on a combined miRNA include miR-21, miR-93, miR-106a, and miR-106b indicated the panel of these miRNAs have the highest AUC 0.887 to discriminate GC patients from healthy. Also, miR-940 with a sensitivity of 81.25% and specificity of 98.57% may be used for diagnostic biomarkers for GC. Finally, the pooled prognostic result of miR-21 for hazard ratios (HR) was 1.260 (95% CI 0.370-4.330, P < 0.001), showing that miR-21 could predict poor survival in GC patients. This systematic review can confirm that we need to find a miRNA or a panel of miRNAs with high sensitivity and specificity for further exploration to investigate a better diagnostic or therapeutic tool for personalized management of GC patients.
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Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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31
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Liu C, Sheng M, Lin L, Li H, Guo S, Zhang J, Chen G, Chen H. NANOG regulates the proliferation of PCSCs via the TGF-β1/SMAD pathway. Open Med (Wars) 2020; 15:841-849. [PMID: 33336042 PMCID: PMC7712027 DOI: 10.1515/med-2020-0221] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 07/19/2020] [Accepted: 07/26/2020] [Indexed: 12/22/2022] Open
Abstract
Purpose In prostate cancer, castration resistance is a factor that frequently leads to death in individuals with this disease. Recent studies have suggested that prostate cancer stem cells (PCSCs) are pivotal regulators in the establishment of castration resistance. The nanog homeobox (NANOG) and the transforming growth factor (TGF)-β1/drosophila mothers against decapentaplegic protein (SMAD) signaling pathways are involved in several cancer stem cells but are not involved in PCSCs. The purpose of this study is to investigate the effect of NANOG on the proliferation of PCSCs regulated by the TGF-β1/SMAD signaling pathway. Methods In this study, we used flow cytometry to isolate CD44+/CD133+/NANOG+ PCSCs from DU145 prostate cancer cells. Then we used short hairpin RNA to silence NANOG and observed the biological behavior and the TGF-β1/SMAD signal of PCSCs. Results NANOG decreased PCSC proliferation, increased apoptosis, and blocked cell cycling at G0/G1. Furthermore, reduction in the TGF-β1, p15, and p-SMAD2 expression was observed. Conclusion These findings suggest that NANOG positively regulates the growth of PCSCs through the TGF-β1/SMAD signaling pathway.
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Affiliation(s)
- Changming Liu
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Mingxiong Sheng
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Liheng Lin
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Huizhang Li
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Shanming Guo
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Jiabin Zhang
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Guangbing Chen
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
| | - Huihong Chen
- The Department of Urology, Mindong Hospital Affiliated to Fujian Medical University, Fuan, Fujian 355000, People's Republic of China
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32
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de Ceuninck van Capelle C, Spit M, Ten Dijke P. Current perspectives on inhibitory SMAD7 in health and disease. Crit Rev Biochem Mol Biol 2020; 55:691-715. [PMID: 33081543 DOI: 10.1080/10409238.2020.1828260] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs). SMAD7, one of the I-SMADs, is an essential negative regulator of the pleiotropic TGF-β and bone morphogenetic protein (BMP) signaling pathways. In a negative feedback loop, SMAD7 inhibits TGF-β signaling by providing competition for TGF-β type-1 receptor (TβRI), blocking phosphorylation and activation of SMAD2. Moreover, SMAD7 recruits E3 ubiquitin SMURF ligases to the type I receptor to promote ubiquitin-mediated proteasomal degradation. In addition to its role in TGF-β and BMP signaling, SMAD7 is regulated by and implicated in a variety of other signaling pathways and functions as a mediator of crosstalk. This review is focused on SMAD7, its function in TGF-β and BMP signaling, and its role as a downstream integrator and crosstalk mediator. This crucial signaling molecule is tightly regulated by various mechanisms. We provide an overview of the ways by which SMAD7 is regulated, including noncoding RNAs (ncRNAs) and post-translational modifications (PTMs). Finally, we discuss its role in diseases, such as cancer, fibrosis, and inflammatory bowel disease (IBD).
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Affiliation(s)
| | - Maureen Spit
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands
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33
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McElhinney JMWR, Hasan A, Sajini AA. The epitranscriptome landscape of small noncoding RNAs in stem cells. Stem Cells 2020; 38:1216-1228. [PMID: 32598085 PMCID: PMC7586957 DOI: 10.1002/stem.3233] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 05/04/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
Stem cells (SCs) are unique cells that have an inherent ability to self‐renew or differentiate. Both fate decisions are strongly regulated at the molecular level via intricate signaling pathways. The regulation of signaling networks promoting self‐renewal or differentiation was thought to be largely governed by the action of transcription factors. However, small noncoding RNAs (ncRNAs), such as vault RNAs, and their post‐transcriptional modifications (the epitranscriptome) have emerged as additional regulatory layers with essential roles in SC fate decisions. RNA post‐transcriptional modifications often modulate RNA stability, splicing, processing, recognition, and translation. Furthermore, modifications on small ncRNAs allow for dual regulation of RNA activity, at both the level of biogenesis and RNA‐mediated actions. RNA post‐transcriptional modifications act through structural alterations and specialized RNA‐binding proteins (RBPs) called writers, readers, and erasers. It is through SC‐context RBPs that the epitranscriptome coordinates specific functional roles. Small ncRNA post‐transcriptional modifications are today exploited by different mechanisms to facilitate SC translational studies. One mechanism readily being studied is identifying how SC‐specific RBPs of small ncRNAs regulate fate decisions. Another common practice of using the epitranscriptome for regenerative applications is using naturally occurring post‐transcriptional modifications on synthetic RNA to generate induced pluripotent SCs. Here, we review exciting insights into how small ncRNA post‐transcriptional modifications control SC fate decisions in development and disease. We hope, by illustrating how essential the epitranscriptome and their associated proteome are in SCs, they would be considered as novel tools to propagate SCs for regenerative medicine.
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Affiliation(s)
- James M W R McElhinney
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Ayesha Hasan
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Abdulrahim A Sajini
- Department of Biomedical Engineering, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
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34
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Effects of Lactobacillus casei Strain T2 (IBRC-M10783) on the Modulation of Th17/Treg and Evaluation of miR-155, miR-25, and IDO-1 Expression in a Cuprizone-Induced C57BL/6 Mouse Model of Demyelination. Inflammation 2020; 44:334-343. [PMID: 32914363 DOI: 10.1007/s10753-020-01339-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 08/19/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022]
Abstract
Multiple sclerosis (MS) is a complex inflammatory disease in which demyelination occurs in the central nervous system affecting approximately 2.5 million people worldwide. Recent reports have shown that the gut microbiome plays a crucial role in the functioning of the immune system in inflammatory diseases such as MS. In this study, the cuprizone-induced demyelination mouse model was used to investigate the effect of Lactobacillus casei strain T2 (IBRC-M10783) on the alleviation of these mice. Female C57BL/6 mice (8-10 weeks old) were divided into 6 groups: group 1, normal control; group 2, cuprizone control (oral administration of cuprizone 0.2% w/w for 4 weeks); group 3, probiotic control (oral administration of 1 × 109 CFU/ml probiotic for 4 weeks); group 4, treatment 1 (probiotic for 4 weeks then cuprizone for 4 weeks); group 5, treatment 2 (cuprizone for 4 weeks then probiotic for 4 weeks); and group 6, treatment 3 (cuprizone for 4 weeks then probiotic for 4 weeks with vitamin D3 at a dose of 20 IU/day). Then, TGF-β and IL-17 were measured by ELISA, and the expression of miR-155, miR-25, and IDO-1 was evaluated by real-time PCR. Among the measured microRNAs, the results showed that there was a significant decrease in miR-155 expression between the treatment 1 group and the cuprizone group. In the case of IL-17, the results also showed a significant reduction between the three treatment groups and the cuprizone group. These observations suggest that L. casei can reduce proinflammatory cytokines and reduce demyelinating symptoms in the mouse model.
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Bekric D, Neureiter D, Ritter M, Jakab M, Gaisberger M, Pichler M, Kiesslich T, Mayr C. Long Non-Coding RNAs in Biliary Tract Cancer-An Up-to-Date Review. J Clin Med 2020; 9:jcm9041200. [PMID: 32331331 PMCID: PMC7231154 DOI: 10.3390/jcm9041200] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
The term long non-coding RNA (lncRNA) describes non protein-coding transcripts with a length greater than 200 base pairs. The ongoing discovery, characterization and functional categorization of lncRNAs has led to a better understanding of the involvement of lncRNAs in diverse biological and pathological processes including cancer. Aberrant expression of specific lncRNA species was demonstrated in various cancer types and associated with unfavorable clinical characteristics. Recent studies suggest that lncRNAs are also involved in the development and progression of biliary tract cancer, a rare disease with high mortality and limited therapeutic options. In this review, we summarize current findings regarding the manifold roles of lncRNAs in biliary tract cancer and give an overview of the clinical and molecular consequences of aberrant lncRNA expression as well as of underlying regulatory functions of selected lncRNA species in the context of biliary tract cancer.
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Affiliation(s)
- Dino Bekric
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Markus Ritter
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Jakab
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
| | - Martin Gaisberger
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Paracelsus Medical University, 5020 Salzburg, Austria
- Gastein Research Institute, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Martin Pichler
- Research Unit of Non-Coding RNAs and Genome Editing, Division of Clinical Oncology, Department of Medicine, Comprehensive Cancer Center Graz, Medical University of Graz, 8036 Graz, Austria;
| | - Tobias Kiesslich
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
| | - Christian Mayr
- Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria; (D.B.); (M.R.); (M.J.); (M.G.); (T.K.)
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
- Correspondence:
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Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, Zhang G, Wang X, Dong Z, Chen F, Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5:8. [PMID: 32296030 PMCID: PMC7005297 DOI: 10.1038/s41392-020-0110-5] [Citation(s) in RCA: 1178] [Impact Index Per Article: 235.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 12/15/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022] Open
Abstract
Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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Affiliation(s)
- Liqun Yang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Pengfei Shi
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Gaichao Zhao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jie Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Wen Peng
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Jiayi Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Guanghui Zhang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Xiaowen Wang
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Zhen Dong
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China
| | - Fei Chen
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48201, USA
| | - Hongjuan Cui
- State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.
- Cancer Center, Medical Research Institute, Southwest University, 400716, Chongqing, China.
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Solé C, Lawrie CH. MicroRNAs and Metastasis. Cancers (Basel) 2019; 12:cancers12010096. [PMID: 31906022 PMCID: PMC7016783 DOI: 10.3390/cancers12010096] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/20/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Metastasis, the development of secondary malignant growths at a distance from the primary site of a cancer, is associated with almost 90% of all cancer deaths, and half of all cancer patients present with some form of metastasis at the time of diagnosis. Consequently, there is a clear clinical need for a better understanding of metastasis. The role of miRNAs in the metastatic process is beginning to be explored. However, much is still to be understood. In this review, we present the accumulating evidence for the importance of miRNAs in metastasis as key regulators of this hallmark of cancer.
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Affiliation(s)
- Carla Solé
- Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain;
| | - Charles H. Lawrie
- Molecular Oncology Group, Biodonostia Research Institute, 20014 San Sebastián, Spain;
- IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
- Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- Correspondence: or ; Tel.: +34-943-006138
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Heldin P, Kolliopoulos C, Lin CY, Heldin CH. Involvement of hyaluronan and CD44 in cancer and viral infections. Cell Signal 2019; 65:109427. [PMID: 31654718 DOI: 10.1016/j.cellsig.2019.109427] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/19/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
Hyaluronan and its major receptor CD44 are ubiquitously distributed. They have important structural as well as signaling roles, regulating tissue homeostasis, and their expression levels are tightly regulated. In addition to signaling initiated by the interaction of the intracellular domain of CD44 with cytoplasmic signaling molecules, CD44 has important roles as a co-receptor for different types of receptors of growth factors and cytokines. Dysregulation of hyaluronan-CD44 interactions is seen in diseases, such as inflammation and cancer. In the present communication, we discuss the mechanism of hyaluronan-induced signaling via CD44, as well as the involvement of hyaluronan-engaged CD44 in malignancies and in viral infections.
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Affiliation(s)
- Paraskevi Heldin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden.
| | - Constantinos Kolliopoulos
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden
| | - Chun-Yu Lin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden; Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Department of Surgery, Uppsala University, Sweden; Department of Surgical Sciences, Uppsala University, Akademiska Hospital, 751 85 Uppsala, Sweden
| | - Carl-Henrik Heldin
- Department of Medical Biochemistry and Microbiology, Box 582, Uppsala University, SE-751 23 Uppsala, Sweden.
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Wei C, Gao JJ. Downregulated miR-383-5p contributes to the proliferation and migration of gastric cancer cells and is associated with poor prognosis. PeerJ 2019; 7:e7882. [PMID: 31637133 PMCID: PMC6798866 DOI: 10.7717/peerj.7882] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/12/2019] [Indexed: 12/24/2022] Open
Abstract
Aim The study aims to identify differentially expressed microRNAs (DEMs) in gastric cancer (GC) and explore the expression, prognosis and downstream regulation role of miR-383-5p in GC. Methods The GC miRNA-Seq and clinical information were downloaded from Firebrowse which stores integrated data sourced from The Cancer Genome Atlas database. The DEMs were identified with limma package in R software at the cut-off criteria of P < 0.05 and |log2 fold change| > 1.0 (|log2FC| > 1.0). The expression of miR-383-5p in GC cell lines and 54 paired GC tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The overall survival curve of miR-383-5p and the association between its expression and clinicopathological features were explored. Wound healing and cell counting kit-8 assays were performed to investigate the capacity of miR-383-5p in cell proliferation and migration. The downstream target genes were predicted by bioinformatics tools (miRDB, TargetScan and starBase). The consensus target genes were selected for gene functional enrichment analysis by FunRich v3.0 software. The luciferase reporter assay was performed to verify the potential targeting sites of miR-383-5p on lactate dehydrogenase A (LDHA). Results A total of 21 down-regulated miRNAs (including miR-383-5p) and 202 up-regulated miRNAs were identified by analyzing GC miRNA-Seq data. Survival analysis found that patients with low miR-383-5p expression had a shorter survival time (median survival time 21.1 months) than those with high expression (46.9 months). The results of qRT-PCR indicated that miR-383-5p was downregulated in GC cell lines and tissues, which was consistent with miRNA-Seq data. The expression of miR-383-5p was significantly associated with tumor size and differentiation grade. Besides, overexpression of miR-383-5p suppressed GC cells proliferation and migration. A total of 49 common target genes of miR-383-5p were obtained by bioinformatics tools and gene functional enrichment analysis showed that these predicted genes participated in PI3K, mTOR, c-MYC, TGF-beta receptor, VEGF/VEGFR and E-cadherin signaling pathways. The data showed that expression of miR-383-5p was negatively correlated with target LDHA (r = −0.203). Luciferase reporter assay suggested that LDHA was a target of miR-383-5p. Conclusion The present study concluded that miR-383-5p was downregulated and may act as a tumor suppressor in GC. Furthermore, its target genes were involved in important signaling pathways. It could be a prognostic biomarker and play a vital role in exploring the molecular mechanism of GC.
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Affiliation(s)
- Chao Wei
- Department of General Surgery, The No.967 Hospital of PLA Joint Logistics Support Force, Postgraduate Culture Base of Jinzhou Medical University, Dalian, China
| | - Jian-Jun Gao
- Department of General Surgery, The No.967 Hospital of PLA Joint Logistics Support Force, Jinzhou Medical University, Dalian, China
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The Effects of TGF-β Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment. Int J Mol Sci 2019; 20:ijms20205117. [PMID: 31619018 PMCID: PMC6829436 DOI: 10.3390/ijms20205117] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 10/02/2019] [Accepted: 10/14/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) plays a key role in bone metastasis formation; we hypothesized the possible involvement of TGF-β in the induction of cancer stem cells (CSCs) in the bone microenvironment (micro-E), which may be responsible for chemo-resistance. METHODS Mouse mammary tumor cells were implanted under the dorsal skin flap over the calvaria and into a subcutaneous (subQ) lesions in female mice, generating tumors in the bone and subQ micro-Es. After implantation of the tumor cells, mice were treated with a TGF-β R1 kinase inhibitor (R1-Ki). RESULTS Treatment with R1-Ki decreased tumor volume and cell proliferation in the bone micro-E, but not in the subQ micro-E. R1-Ki treatment did not affect the induction of necrosis or apoptosis in either bone or subQ micro-E. The number of cells positive for the CSC markers, SOX2, and CD166 in the bone micro-E, were significantly higher than those in the subQ micro-E. R1-Ki treatment significantly decreased the number of CSC marker positive cells in the bone micro-E but not in the subQ micro-E. TGF-β activation of the MAPK/ERK and AKT pathways was the underlying mechanism of cell proliferation in the bone micro-E. BMP signaling did not play a role in cell proliferation in either micro-E. CONCLUSION Our results indicated that the bone micro-E is a key niche for CSC generation, and TGF-β signaling has important roles in generating CSCs and tumor cell proliferation in the bone micro-E. Therefore, it is critically important to evaluate responses to chemotherapeutic agents on both cancer stem cells and proliferating tumor cells in different tumor microenvironments in vivo.
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Khan AQ, Ahmed EI, Elareer NR, Junejo K, Steinhoff M, Uddin S. Role of miRNA-Regulated Cancer Stem Cells in the Pathogenesis of Human Malignancies. Cells 2019; 8:840. [PMID: 31530793 PMCID: PMC6721829 DOI: 10.3390/cells8080840] [Citation(s) in RCA: 207] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 07/28/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022] Open
Abstract
Recent biomedical discoveries have revolutionized the concept and understanding of carcinogenesis, a complex and multistep phenomenon which involves accretion of genetic, epigenetic, biochemical, and histological changes, with special reference to MicroRNAs (miRNAs) and cancer stem cells (CSCs). miRNAs are small noncoding molecules known to regulate expression of more than 60% of the human genes, and their aberrant expression has been associated with the pathogenesis of human cancers and the regulation of stemness features of CSCs. CSCs are the small population of cells present in human malignancies well-known for cancer resistance, relapse, tumorigenesis, and poor clinical outcome which compels the development of novel and effective therapeutic protocols for better clinical outcome. Interestingly, the role of miRNAs in maintaining and regulating the functioning of CSCs through targeting various oncogenic signaling pathways, such as Notch, wingless (WNT)/β-Catenin, janus kinases/ signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol 3-kinase/ protein kinase B (PI3/AKT), and nuclear factor kappa-light-chain-enhancer of activated B (NF-kB), is critical and poses a huge challenge to cancer treatment. Based on recent findings, here, we have documented the regulatory action or the underlying mechanisms of how miRNAs affect the signaling pathways attributed to stemness features of CSCs, such as self-renewal, differentiation, epithelial to mesenchymal transition (EMT), metastasis, resistance and recurrence etc., associated with the pathogenesis of various types of human malignancies including colorectal cancer, lung cancer, breast cancer, head and neck cancer, prostate cancer, liver cancer, etc. We also shed light on the fact that the targeted attenuation of deregulated functioning of miRNA related to stemness in human carcinogenesis could be a viable approach for cancer treatment.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Eiman I Ahmed
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Noor R Elareer
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Kulsoom Junejo
- General Surgery Department, Hamad General Hospital, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
- Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar
- Weill Cornell Medicine, Doha, P.O. Box 24811, Qatar
- Weill Cornell University, New York, NY 10065, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, P.O. Box 3050, Qatar.
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The Role of MicroRNAs in the Regulation of Gastric Cancer Stem Cells: A Meta-Analysis of the Current Status. J Clin Med 2019; 8:jcm8050639. [PMID: 31075910 PMCID: PMC6572052 DOI: 10.3390/jcm8050639] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 05/04/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the major causes of cancer-related mortality worldwide. As for other types of cancers, several limitations to the success of current therapeutic GC treatments may be due to cancer drug resistance that leads to tumor recurrence and metastasis. Increasing evidence suggests that cancer stem cells (CSCs) are among the major causative factors of cancer treatment failure. The research of molecular CSC mechanisms and the regulation of their properties have been intensively studied. To date, molecular gastric cancer stem cell (GCSC) characterization remains largely incomplete. Among the GCSC-targeting approaches to overcome tumor progression, recent studies have focused their attention on microRNA (miRNA). The miRNAs are short non-coding RNAs which play an important role in the regulation of numerous cellular processes through the modulation of their target gene expression. In this review, we summarize and discuss recent findings on the role of miRNAs in GCSC regulation. In addition, we perform a meta-analysis aimed to identify novel miRNAs involved in GCSC homeostasis.
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Zhang Z, Dong Y, Hua J, Xue H, Hu J, Jiang T, Shi L, Du J. A five-miRNA signature predicts survival in gastric cancer using bioinformatics analysis. Gene 2019; 699:125-134. [DOI: 10.1016/j.gene.2019.02.058] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/14/2019] [Accepted: 02/21/2019] [Indexed: 12/11/2022]
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Zhang B, Zhang G, Wei T, Yang Z, Tan W, Mo Z, Liu J, Li D, Wei Y, Zhang L, Webster KA, Wei J. MicroRNA-25 Protects Smooth Muscle Cells against Corticosterone-Induced Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:2691514. [PMID: 30992737 PMCID: PMC6434288 DOI: 10.1155/2019/2691514] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/17/2018] [Accepted: 01/01/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Vascular smooth muscle cells (VSMCs) are central components of atherosclerotic plaque. Loss of VSMCs through apoptotic cell death can cause fibrous cap thinning, necrotic core formation, and calcification that may destabilize plaque. Elevated glucocorticoid levels caused by psychological stress promote VSMC apoptosis and can exacerbate atherosclerosis in mice and humans. Changes in the levels of antiapoptosis microRNA-25 (miR-25) have been linked with heart disease, inflammation, VSMC phenotype, oxidative stress, and apoptosis. Here, we investigated the pathways and mechanisms of glucocorticoid-induced apoptosis of mouse VSMCs and the protective role of miR-25. METHODS Primary mouse VSMCs were cultured +/- corticosterone for 48 h. Apoptosis, ROS, apoptotic protein activities, miR-25, MOAP1, a miR-25 target, and p70S6 kinase were quantified at intervals. The roles of miR-25 were assessed by treating cells with lenti-pre-miR-25 and anti-miR-25. RESULTS VSMC apoptosis, caspase-3 activity, and Bax were increased by corticosterone, and cell death was paralleled by marked loss of miR-25. Protection was conferred by pre-miR-25 and exacerbated by anti-miR-25. Pre-miR-25 conferred reduced expression of the proapoptotic protein MOAP1, and the protective effects of pre-miR-25 were abrogated by overexpressing MOAP1. The antiapoptotic effects of miR-25 were paralleled by inhibition of the p70S6K pathway, a convergence target for the survival signaling pathways, and protection by pre-miR-25 was abrogated by the p70S6k inhibitor rapamycin. CONCLUSIONS MicroRNA-25 blocks corticosterone-induced VSMC apoptosis by targeting MOAP1 and the p70S6k pathway. Therapeutic manipulation of miR-25 may reduce atherosclerosis and unstable plaque formation associated with chronic stress.
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Affiliation(s)
- Bin Zhang
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Gaoxing Zhang
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Tianlu Wei
- Department of Medicine, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, China
| | - Zhen Yang
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
- Department of Cardiovascular, Sun Yat-Sen University, Guangzhou 510080, China
| | - Wenfeng Tan
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Ziqing Mo
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Jinxue Liu
- Department of Cardiovascular Disease, The Jiangmen Central Hospital, Jiangmen 529030, China
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
| | - Dong Li
- Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-Sen University, Jiangmen 529030, China
- Department of Intensive Care Unit, The Jiangmen Central Hospital, Jiangmen 529030, China
| | - Yidong Wei
- Youjiang Medical University for Nationalities, Chengxiang Rd, Baise, Guangxi 533000, China
| | - Lukun Zhang
- Department of Infection, Third People's Hospital of Shenzhen, 29 Bulan Road, Shenzhen 518112, China
| | - Keith A. Webster
- Department of Molecular and Cellular Pharmacology and the Vascular Biology Institute, Miller School of Medicine, University of Miami, FL 33136, USA
| | - Jianqin Wei
- Department of Medicine, Division of Cardiology, Miller School of Medicine, University of Miami, FL 33136, USA
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Tata P, Gondaliya P, Sunkaria A, Srivastava A, Kalia K. Modulation of CD44, EGFR and RAC Pathway Genes (WAVE Complex) in Epithelial Cancers. Curr Pharm Des 2019; 25:833-848. [PMID: 30799784 DOI: 10.2174/1381612825666190222143044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 02/13/2019] [Indexed: 12/12/2022]
Abstract
Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.
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Affiliation(s)
- Pranathi Tata
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Piyush Gondaliya
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Aditya Sunkaria
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Akshay Srivastava
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
| | - Kiran Kalia
- National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Palaj, Opposite Air Force Station, Gandhinagar, Gujarat-382355, India
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Li H, Yan W, Suo X, Peng H, Yang X, Li Z, Zhang J, Liu D. Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy. Biomaterials 2019; 200:1-14. [PMID: 30743049 DOI: 10.1016/j.biomaterials.2019.01.048] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 01/21/2019] [Accepted: 01/31/2019] [Indexed: 01/08/2023]
Abstract
Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy.
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Affiliation(s)
- Hongjuan Li
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Weixiao Yan
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Xiaomin Suo
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Haotong Peng
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Xinjian Yang
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Zhenhua Li
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China
| | - Jinchao Zhang
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China.
| | - Dandan Liu
- Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding 071002, People's Republic of China; College of Chemistry and Environmental Science, Chemical Biology Key Laboratory of Hebei Province, Hebei University, Baoding 071002, People's Republic of China.
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Liang C, Yang P, Han T, Wang RY, Xing XL, Si AF, Ma QY, Chen Z, Li HY, Zhang B. Long non-coding RNA DILC promotes the progression of gallbladder carcinoma. Gene 2019; 694:102-110. [PMID: 30716440 DOI: 10.1016/j.gene.2018.12.086] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/18/2018] [Accepted: 12/27/2018] [Indexed: 12/31/2022]
Abstract
Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) contribute to tumorigenesis, progression and recurrence of various malignancies including Gallbladder carcinoma (GBC). Lnc-DILC is reported to be the tumor suppressor gene to play an important role in liver cancer stem cells (CSCs). However, the role of lnc-DILC in GBC remains to be elucidated. Herein, we show that lnc-DILC is upregulated in gallbladder CSCs and GBC patients' tissues. Knockdown of lnc-DILC attenuates the self-renewal, tumorigenicity, proliferation and metastasis of gallbladder CSCs. Mechanistically, lnc-DILC promotes gallbladder CSCs expansion via Wnt/β-catenin pathway. Special Wnt/β-catenin inhibitor FH535 diminishes the discrepancy of self-renewal, growth and metastasis between lnc-DILC interference GBC cells and their control cells. In conclusion, lnc-DILC drives gallbladder CSCs self-renewal, tumorigenicity, proliferation and metastasis by activating Wnt/β-catenin signaling, and may therefore prove to be a potential therapeutic target for GBC patients.
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Affiliation(s)
- Chi Liang
- Department of General surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China; Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
| | - Pinghua Yang
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
| | - Tao Han
- Department of Oncology, Cancer Center of People's Liberation Army, General Hospital of Region, Shenyang 110001, China
| | - Ruo-Yu Wang
- Department of Hepatic Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
| | - Xiang-Lei Xing
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China
| | - An-Feng Si
- Department of Surgical Oncology, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Qian-Yun Ma
- Department of Urology Surgery, First Affiliated Hospital of Second Military Medical University, Shanghai, 200433, China
| | - Zhong Chen
- Department of General surgery, The Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, China.
| | - Heng-Yu Li
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Second Military Medical University, Shanghai, 200433, China.
| | - Baohua Zhang
- Department of Biliary Tract Surgery, Third Affiliated Hospital of Second Military Medical University, Shanghai 200438, China.
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48
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Lee SD, Yu D, Lee DY, Shin HS, Jo JH, Lee YC. Upregulated microRNA-193a-3p is responsible for cisplatin resistance in CD44(+) gastric cancer cells. Cancer Sci 2018; 110:662-673. [PMID: 30485589 PMCID: PMC6361556 DOI: 10.1111/cas.13894] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 12/17/2022] Open
Abstract
Cisplatin is a well‐known anticancer drug used to treat various cancers. However, development of cisplatin resistance has hindered the efficiency of this drug in cancer treatment. Development of chemoresistance is known to involve many signaling pathways. Recent attention has focused on microRNAs (miRNAs) as potentially important upstream regulators in the development of chemoresistance. CD44 is one of the gastric cancer stem cell markers and plays a role in regulating self‐renewal, tumor initiation, metastasis and chemoresistance. The purpose of the present study was to examine the mechanism of miRNA‐mediated chemoresistance to cisplatin in CD44‐positive gastric cancer stem cells. We sorted gastric cancer cells according to level of CD44 expression by FACS and analyzed their miRNA expression profiles by microarray analysis. We found that miR‐193a‐3p was significantly upregulated in CD44(+) cells compared with CD44(−) cells. Moreover, SRSF2 of miR‐193a‐3p target gene was downregulated in CD44(+) cells. We studied the modulation of Bcl‐X and caspase 9 mRNA splicing by SRSF2 and found that more pro‐apoptotic variants of these genes were generated. We also found that downstream anti‐apoptotic genes such as Bcl‐2 were upregulated, whereas pro‐apoptotic genes such as Bax and cytochrome C were downregulated in CD44(+) cells compared to CD44(−) cells. In addition, we found that an elevated level of miR‐193a‐3p triggered the development of cisplatin resistance in CD44(+) cells. Inhibition of miR‐193a‐3p in CD44(+) cells increased SRSF2 expression and also altered the levels of multiple apoptotic genes. Furthermore, inhibition of miR‐193a‐3p reduced cell viability and increased the number of apoptotic cells. Therefore, miR‐193a‐3p may be implicated in the development of cisplatin resistance through regulation of the mitochondrial apoptosis pathway. miR‐193a‐3p could be a promising target for cancer therapy in cisplatin‐resistant gastric cancer.
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Affiliation(s)
- So D Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Dayeon Yu
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Do Y Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyun-Soo Shin
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong-Hyeon Jo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Yong C Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Fu Y, Du P, Zhao J, Hu C, Qin Y, Huang G. Gastric Cancer Stem Cells: Mechanisms and Therapeutic Approaches. Yonsei Med J 2018; 59:1150-1158. [PMID: 30450848 PMCID: PMC6240570 DOI: 10.3349/ymj.2018.59.10.1150] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC stem-like cells (GCSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to the refractory features of GC and have gained increasing attention for their role in GC drug resistance, relapse, and metastasis. Therapies targeting GCSCs seem to be one of the most promising methods to improve the outcomes of GC patients. Extensive investigations have attempted to outline the regulatory mechanisms in GCSCs and to develop GCSCs-targeting therapies with which to diminish GC drug resistance, metastasis and relapse. To the best of our knowledge, there is a lack of reviews summarizing these studies. In this review, we systematically recapitulated findings regarding the regulatory mechanisms of GCSCs, as well as therapies that target GCSCs, hoping to support the development of prognostic biomarkers and GCSCs-targeting anticancer therapies in GC.
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Affiliation(s)
- Yan Fu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Peizhun Du
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Cheng'en Hu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunyun Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Guangjian Huang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
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50
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Bu W, Wang Y, Min X. MicroRNA-106b promotes the proliferation, migration and invasion of retinoblastoma cells by inhibiting the expression of ZBTB4 protein. Exp Ther Med 2018; 16:4537-4545. [PMID: 30542402 PMCID: PMC6257475 DOI: 10.3892/etm.2018.6811] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 12/06/2017] [Indexed: 12/18/2022] Open
Abstract
The present study investigated the function of microRNA (miR)-106b in the proliferation, migration and invasion of retinoblastoma (RB) cells, and aimed to elucidate the underlying mechanism. A total of 56 patients with RB were enrolled in the present study. The expression of miR-106b in RB tissues was measured by reverse transcription quantitative polymerase chain reaction. After transfection with miR-106b mimics or miR-106b inhibitor, a Cell-Counting kit-8 assay was used to determine the proliferation of WERI-Rb-1 cells and a Transwell assay was employed to measure the migration and invasion of the cells. Western blot analysis was performed to determine the expression of zinc finger and BTB domain containing 4 (ZBTB4) protein. By silencing or overexpression of ZBTB4 protein, the biological functions of ZBTB4 in WERI-Rb-1 cells were studied. A dual luciferase reporter assay was performed to test whether ZBTB4 was a target gene of miR-106b. The expression of miR-106b in RB tissues was elevated and closely associated with the severity of the disease. Overexpression of miR-106b increased but inhibition of miR-106b expression decreased the proliferation, migration and invasion abilities of WERI-Rb-1 cells. In addition, overexpression of miR-106b decreased but inhibition of miR-106b expression increased ZBTB4 protein expression in WERI-Rb-1 cells. Similarly, overexpression of ZBTB4 reduced but inhibition of ZBTB4 expression promoted the proliferation, migration and invasion of WERI-Rb-1 cells. Finally, miR-106b regulated the expression of ZBTB4 by binding to the 3'-untranslated region of the ZBTB4 gene. The present study demonstrated that increased expression of miR-106b in RB tissues is positively associated with the metastasis and differentiation of RB cells. As an oncogene, miR-106b promotes the proliferation, migration and invasion of WERI-Rb-1 cells by inhibiting the expression of ZBTB4 protein.
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Affiliation(s)
- Wenjuan Bu
- Department of Ophthalmology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Yanhui Wang
- Department of Fundus Surgery, Hebei Province Eye Hospital, Xingtai, Hebei 054000, P.R. China
| | - Xiangrong Min
- Department of Ophthalmology, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
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