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1
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Teo LTK, Juantuah-Kusi N, Subramanian G, Sampath P. Psoriasis Treatments: Emerging Roles and Future Prospects of MicroRNAs. Noncoding RNA 2025; 11:16. [PMID: 39997616 PMCID: PMC11858470 DOI: 10.3390/ncrna11010016] [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: 12/19/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 02/26/2025] Open
Abstract
Psoriasis, a widespread and chronic inflammatory skin disorder, is marked by its persistence and the lack of a definitive cure. The pathogenesis of psoriasis is increasingly understood, with ongoing research highlighting the intricate interplay of genetic, immunological, and environmental factors. Recent advancements have illuminated the pivotal role of microRNAs in orchestrating complex processes in psoriasis and other hyperproliferative skin diseases. This narrative review highlights the emerging significance of miRNAs as key regulators in psoriasis pathogenesis and examines their potential as therapeutic targets. We discuss current treatment approaches and the promising future of miRNAs as next-generation therapeutic agents for this condition.
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Affiliation(s)
- Li Tian Keane Teo
- Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London SW7 2AZ, UK
| | - Nerissa Juantuah-Kusi
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
| | - Gowtham Subramanian
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road #17-01 Clinical Sciences Building, Singapore 308232, Singapore
| | - Prabha Sampath
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road #17-01 Clinical Sciences Building, Singapore 308232, Singapore
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School 8 College Road, Singapore 169857, Singapore
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Martínez-Campa C, Álvarez-García V, Alonso-González C, González A, Cos S. Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer. Cancers (Basel) 2024; 16:956. [PMID: 38473317 DOI: 10.3390/cancers16050956] [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: 01/12/2024] [Revised: 02/13/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.
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Affiliation(s)
- Carlos Martínez-Campa
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Virginia Álvarez-García
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Carolina Alonso-González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alicia González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
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Szymański M, Bonowicz K, Antosik P, Jerka D, Głowacka M, Soroka M, Steinbrink K, Kleszczyński K, Gagat M. Role of Cyclins and Cytoskeletal Proteins in Endometriosis: Insights into Pathophysiology. Cancers (Basel) 2024; 16:836. [PMID: 38398227 PMCID: PMC10886501 DOI: 10.3390/cancers16040836] [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: 12/11/2023] [Revised: 01/21/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Endometriosis is a gynecological condition where endometrium-like tissue grows outside the uterus, posing challenges in understanding and treatment. This article delves into the deep cellular and molecular processes underlying endometriosis, with a focus on the crucial roles played by cyclins and cytoskeletal proteins in its pathogenesis, particularly in the context of Epithelial-Mesenchymal Transition (EMT). The investigation begins by examining the activities of cyclins, elucidating their diverse biological roles such as cell cycle control, proliferation, evasion of apoptosis, and angiogenesis among ectopic endometrial cells. A comprehensive analysis of cytoskeletal proteins follows, emphasizing their fundamental biological roles and their specific significance to endometriotic cell features. This review sheds light on the interconnected pathways through which cyclins and cytoskeletal proteins converge, contributing to the genesis and progression of endometriosis. Understanding these molecular complexities not only provides insight into the underlying causes of the disease but also holds promise for the development of specific therapeutic approaches, ushering in a new era in the management of this devastating disorder.
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Affiliation(s)
- Marcin Szymański
- Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland; (M.S.); (K.B.); (D.J.)
| | - Klaudia Bonowicz
- Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland; (M.S.); (K.B.); (D.J.)
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 08-110 Płock, Poland; (M.G.); (M.S.)
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland;
| | - Dominika Jerka
- Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland; (M.S.); (K.B.); (D.J.)
| | - Mariola Głowacka
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 08-110 Płock, Poland; (M.G.); (M.S.)
| | - Małgorzata Soroka
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 08-110 Płock, Poland; (M.G.); (M.S.)
| | - Kerstin Steinbrink
- Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany; (K.S.); (K.K.)
| | - Konrad Kleszczyński
- Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany; (K.S.); (K.K.)
| | - Maciej Gagat
- Department of Histology and Embryology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland; (M.S.); (K.B.); (D.J.)
- Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 08-110 Płock, Poland; (M.G.); (M.S.)
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Goncharov AP, Vashakidze N, Kharaishvili G. Epithelial-Mesenchymal Transition: A Fundamental Cellular and Microenvironmental Process in Benign and Malignant Prostate Pathologies. Biomedicines 2024; 12:418. [PMID: 38398019 PMCID: PMC10886988 DOI: 10.3390/biomedicines12020418] [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: 12/29/2023] [Revised: 02/01/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial and fundamental mechanism in many cellular processes, beginning with embryogenesis via tissue remodulation and wound healing, and plays a vital role in tumorigenesis and metastasis formation. EMT is a complex process that involves many transcription factors and genes that enable the tumor cell to leave the primary location, invade the basement membrane, and send metastasis to other tissues. Moreover, it may help the tumor avoid the immune system and establish radioresistance and chemoresistance. It may also change the normal microenvironment, thus promoting other key factors for tumor survival, such as hypoxia-induced factor-1 (HIF-1) and promoting neoangiogenesis. In this review, we will focus mainly on the role of EMT in benign prostate disease and especially in the process of establishment of malignant prostate tumors, their invasiveness, and aggressive behavior. We will discuss relevant study methods for EMT evaluation and possible clinical implications. We will also introduce clinical trials conducted according to CONSORT 2010 that try to harness EMT properties in the form of circulating tumor cells to predict aggressive patterns of prostate cancer. This review will provide the most up-to-date information to establish a keen understanding of the cellular and microenvironmental processes for developing novel treatment lines by modifying or blocking the pathways.
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Affiliation(s)
- Aviv Philip Goncharov
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
| | - Nino Vashakidze
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
| | - Gvantsa Kharaishvili
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
- Department of Human Morphology and Pathology, Medical Faculty, David Tvildiani Medical University, Tbilisi 0159, Georgia
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Pouliquen DL, Boissard A, Henry C, Coqueret O, Guette C. Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies. Front Pharmacol 2022; 13:934534. [PMID: 35873564 PMCID: PMC9304619 DOI: 10.3389/fphar.2022.934534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 11/21/2022] Open
Abstract
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
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Affiliation(s)
- Daniel L. Pouliquen
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
- *Correspondence: Daniel L. Pouliquen,
| | - Alice Boissard
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Cécile Henry
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Olivier Coqueret
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Catherine Guette
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
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Abstract
MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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Khordadmehr M, Shahbazi R, Baradaran B, Sadreddini S, Shanehbandi D, Hajiasgharzadeh K, Firouzamandi M. Mir-193a-5p Replacement Can Alter Metastasis Gene Expression in Breast Adenocarcinoma Cells In Vitro. PHARMACEUTICAL SCIENCES 2020. [DOI: 10.34172/ps.2020.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background: Recent evidence presented the significant role of the microRNA-193 (miR-193) family in biological processes by the contribution of specific targeting, which mainly display as a tumor suppressor in various cancers. In the present study, we evaluated the effect of miR-193a-5p replacement on some metastasis gene expression in metastatic breast cancer (BC) cells. Methods: For this purpose, firstly, the quantitative real-time polymerase chain reaction (qRTPCR) was used to detect the miR-193a-5p expression in the MDA-MB-231 BC cell line. Subsequently, miR-193a-5p was transfected into the cells, and the expression levels of ROCK1 (Rho‑associated, coiled‑coil containing protein kinase 1), CXCR4 (Chemokine Receptor-4), CD44, and vimentin genes were evaluated by qRT-PCR. Results: The expression level of miR-193a-5p strongly reduced in MDA-MB-231 cells. Interestingly, the ROCK1 (P < 0. 001), CD44 (P < 0.0001), CXCR4 (P < 0. 001) and vimentin (P < 0. 001) expression levels significantly decreased following miR-193a-5p transfection in MDA-MB-231 BC cells. Conclusion: To conclude, it seems that miR-193a-5p restoration can attenuate the metastatic behavior of BC cells in vitro through decreased expression level of metastasis-related genes and may constitute an effective novel therapeutic strategy in miRNA-replacement therapy and treatment of metastatic breast adenocarcinoma in the future.
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Affiliation(s)
- Monireh Khordadmehr
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - Roya Shahbazi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Sanam Sadreddini
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Khalil Hajiasgharzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, 51666-14761, Tabriz, Iran
| | - Masoumeh Firouzamandi
- Department of Pathology, Faculty of Veterinary Medicine, University of Tabriz, 51665-1647, Tabriz, Iran
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Sakuma H, Hagiwara S, Kantharidis P, Gohda T, Suzuki Y. Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs. Front Pharmacol 2020; 11:587689. [PMID: 33364960 PMCID: PMC7751689 DOI: 10.3389/fphar.2020.587689] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.
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Affiliation(s)
- Hiroko Sakuma
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Shinji Hagiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Kidney and Hypertension, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan
| | | | - Tomohito Gohda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Wang X, De Geyter C, Jia Z, Peng Y, Zhang H. HECTD1 regulates the expression of SNAIL: Implications for epithelial‑mesenchymal transition. Int J Oncol 2020; 56:1186-1198. [PMID: 32319576 PMCID: PMC7115742 DOI: 10.3892/ijo.2020.5002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 01/29/2020] [Indexed: 01/11/2023] Open
Abstract
As a transcription factor, SNAIL plays a crucial role in embryonic development and cancer progression by mediating epithelial‑mesenchymal transition (EMT); however, post‑translational modifications, such as ubiquitination, which control the degradation of SNAIL have been observed to affect its functional role in EMT. In a previous study by the authors, it was demonstrated that the HECT domain E3 ubiquitin ligase 1 (HECTD1) regulated the dynamic nature of adhesive structures. In the present study, HECTD1 was observed to interact with SNAIL and regulate its stability through ubiquitination, and the knockdown of HECTD1 increased the expression levels of SNAIL. HECTD1 was discovered to contain putative nuclear localization and export signals that facilitated its translocation between the cytoplasm and nucleus, a process regulated by epidermal growth factor (EGF). Treatment with leptomycin B resulted in the nuclear retention of HECTD1, which was associated with the loss of SNAIL expression. The knockdown of HECTD1 in HeLa cells increased cell migration and induced a mesenchymal phenotype, in addition to demonstrating sustained EGF signaling, which was observed through increased phosphorylated ERK expression levels. Under hypoxic conditions, HECTD1 expression levels were decreased by microRNA (miRNA or miR)‑210. Upon the observation of genetic abnormalities in the HECTD1 gene in cervical cancer specimens, it was observed that the decreased expression levels of HECTD1 were significantly associated with a poor patient survival. Thus, it was hypothesized that HECTD1 may regulate EMT through the hypoxia/hypoxia inducible factor 1α/miR‑210/HECTD1/SNAIL signaling pathway and the EGF/EGF receptor/HECTD1/ERK/SNAIL signaling pathway in cervical cancer. On the whole, the data of the present study indicated that HECTD1 serves as an E3 ubiquitin ligase to mediate the stability of SNAIL proteins.
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Affiliation(s)
- Xinggang Wang
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Christian De Geyter
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Zanhui Jia
- Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China
| | - Ya Peng
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
| | - Hong Zhang
- Department of Biomedicine (DBM), University Hospital, University of Basel, CH‑4031 Basel, Switzerland
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Fierro-Fernández M, Miguel V, Márquez-Expósito L, Nuevo-Tapioles C, Herrero JI, Blanco-Ruiz E, Tituaña J, Castillo C, Cannata P, Monsalve M, Ruiz-Ortega M, Ramos R, Lamas S. MiR-9-5p protects from kidney fibrosis by metabolic reprogramming. FASEB J 2019; 34:410-431. [PMID: 31914684 DOI: 10.1096/fj.201901599rr] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 10/04/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-β1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-β1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.
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Affiliation(s)
- Marta Fierro-Fernández
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Verónica Miguel
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | | | - Cristina Nuevo-Tapioles
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - J Ignacio Herrero
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Eva Blanco-Ruiz
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | - Jessica Tituaña
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
| | | | - Pablo Cannata
- Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (UAM), Madrid, Spain
| | - María Monsalve
- Instituto de Investigaciones Biomédicas "Alberto Sols", (CSIC-UAM), Madrid, Spain
| | - Marta Ruiz-Ortega
- Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (UAM), Madrid, Spain
| | - Ricardo Ramos
- Servicio de Genómica, Fundación Parque Científico de Madrid, Madrid, Spain
| | - Santiago Lamas
- Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain
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11
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Decreased expression of GPC1 in human skin keratinocytes and epidermis during ageing. Exp Gerontol 2019; 126:110693. [PMID: 31430521 DOI: 10.1016/j.exger.2019.110693] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 07/23/2019] [Accepted: 08/14/2019] [Indexed: 01/12/2023]
Abstract
BACKGROUND Glypicans (GPCs) are heparan sulfate cell membrane proteoglycans containing glycosylphosphatidylinositol (GPI) anchor. They play important role in cell behavior by activating/presenting numerous growth factors and cytokines. OBJECTIVES The expression of GPCs was investigated in primary culture of skin keratinocytes sampled from healthy donors of different age. MATERIALS AND METHODS Primary keratinocytes from healthy female donors aged from 20 to 89 years old (n = 30) were either isolated from breast or abdominal skin samples (n = 27) or purchased (n = 3). GPCs expression was examined by qPCR, immunohistochemistry and western blot. Its role in proliferation induced by fibroblast growth factor 2 (FGF2) was also studied. RESULTS Glypican 1 (GPC1) was the major expressed GPC in human keratinocytes. Its expression was up to two orders of magnitude higher than other GPCs and was significantly decreased with the age of the donors. It was localized at the cell surface and associated with intracellular granules. In skin sections, GPC1 was mainly localized in basal layer of epidermis. Shedding of GPCs decreased the proliferative effect of FGF2, confirming their role of modulator of growth factor effects on keratinocytes. These results established GPC1 as an important player in epidermis biology and skin ageing.
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12
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Curcumol inhibits colorectal cancer proliferation by targeting miR-21 and modulated PTEN/PI3K/Akt pathways. Life Sci 2019; 221:354-361. [PMID: 30811964 DOI: 10.1016/j.lfs.2019.02.049] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/23/2019] [Accepted: 02/23/2019] [Indexed: 01/19/2023]
Abstract
AIMS The purpose of this study was to demonstrate how curcumol affected the expression of miR-21 and whether its effects on miR-21 was associated with the activation of PTEN/PI3K/Akt pathways in CRC cells. MAIN METHODS MTT and xenograft assay were used to examine how curcumol inhibits colorectal cancer (CRC) cells' growth. Q-PCR and western blot analysis were employed to test the role of miR-21 in the inhibition of curcumol on proliferation and PTEN/PI3K/Akt pathways of CRC cells. KEY FINDINGS We found that curcumol effectively inhibited CRC cells from proliferating via the PTEN/PI3K/Akt pathways and reduced expression of miR-21 both in vitro and in vivo. miR-21 mimics were found to decrease the protein level of PTEN and increase the expression of PI3K, phospho-Akt (p-Akt) and NF-κB, while miR-21 sponge (miR-21-SP) enhanced the expression of PTEN and reduced the activity of PI3K, Akt and NF-κB. Furthermore, miR-21-SP strengthened the role of curcumol in up-regulating PTEN and inhibiting PI3K/Akt pathways, but miR-21 reversed the effect of curcumol on the PTEN/PI3K/Akt pathways. SIGNIFICANCE Our research demonstrated that curcumol reduced the proliferation of CRC cells through PTEN/PI3K/Akt by targeting miR-21 and miR-21 could be a target molecule of curcumol for CRC treatment.
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13
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Zhang X, Yang Z, Heng Y, Miao C. MicroRNA‑181 exerts an inhibitory role during renal fibrosis by targeting early growth response factor‑1 and attenuating the expression of profibrotic markers. Mol Med Rep 2019; 19:3305-3313. [PMID: 30816527 DOI: 10.3892/mmr.2019.9964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 02/07/2019] [Indexed: 11/06/2022] Open
Abstract
Progressive renal fibrosis is a common complication of chronic kidney disease that results in end‑stage renal disorder. It is well established that several microRNAs (miRs) function as critical regulators implicated in fibrotic diseases. However, the role of miR‑181 in the development and progression of renal fibrosis remains unclear, and the precise mechanism has not yet been fully defined. The present study identified the functional implications of miR‑181 expression during renal fibrosis. miR‑181 exhibited significantly reduced expression in the serum of renal fibrosis patients and in the kidneys of mice with unilateral ureteral obstruction (UUO). In addition, miR‑181 downregulated the expression of human α‑smooth muscle actin (α‑SMA) in response to angiotensin II stimulation. Transfection with miR‑181 mimics significantly suppressed the expression levels of α‑SMA, connective tissue growth factor, collagen type I α1 (COL1A1) and collagen type III α1 (COL3A1) in NRK49F cells. Notably, early growth response factor‑1 (Egr1) was identified as a direct target gene of miR‑181. Furthermore, in vivo experiments revealed that treatment with miR‑181 agonist strongly rescued kidney impairment induced by UUO, as supported by Masson's trichrome staining of kidney tissues and reverse transcription‑quantitative polymerase chain reaction analysis of COL1A1 and COL3A1 mRNA levels. Therefore, miR‑181 may be regarded as an important mediator in the control of profibrotic markers during renal fibrosis via binding to Egr1, and may be a promising new target in the diagnosis and therapy of renal fibrosis.
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Affiliation(s)
- Xiaoyan Zhang
- Department of Nephrology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Zhenning Yang
- School of Clinical Medicine, Norman Bethune Health Science Center of Jilin University, Changchun, Jilin 130022, P.R. China
| | - Yanyan Heng
- Department of Nephrology, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
| | - Congxiu Miao
- Department of Scientific Research, Changzhi Medical College, Changzhi, Shanxi 046000, P.R. China
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Ma L, Ma J, Ou HL. MicroRNA‑219 overexpression serves a protective role during liver fibrosis by targeting tumor growth factor β receptor 2. Mol Med Rep 2018; 19:1543-1550. [PMID: 30592264 PMCID: PMC6390038 DOI: 10.3892/mmr.2018.9787] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 11/05/2018] [Indexed: 12/11/2022] Open
Abstract
Progressive liver fibrosis is the primary cause of liver cirrhosis and hepatocellular carcinoma, and leads to considerable morbidity and mortality. Recent studies have demonstrated that microRNAs (miRNAs or miRs) are associated with fibrotic processes in liver disorders, although the exact role of miR-219 remains unclear and the relevant mechanisms remain to be completely understood. To the best of our knowledge, the present study was the first to demonstrate the functional implications of miR-219 expression during liver fibrosis. The present study reported that miR-219 exhibited significantly reduced expression in serum from patients and that its expression was negatively associated with clinical stage. It was also demonstrated that miR-219 attenuated angiotensin II-induced expression of pro-fibrotic markers, including α-smooth muscle actin, atlastin GTPase 1 and collagen. Additionally, a CCl4-induced mouse liver injury model was used to demonstrate that miR-219 strongly suppressed liver fibrosis in vivo. Furthermore, the present study identified tumor growth factor β receptor 2 (TGFBR2) as a direct target gene of miR-219. In conclusion, the results of the present study revealed that miR-219 may regulate pro-fibrotic markers by directly targeting the TGFBR2 gene and the miR-219/TGFBR2 signaling pathway may be a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Li Ma
- Department of Liver Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China
| | - Jian Ma
- Department of Endocrinology, The People's Hospital of Fenghua District, Ningbo, Zhejiang 315500, P.R. China
| | - Hong-Liang Ou
- Department of Liver Diseases, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China
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15
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Chen B. The miRNA-184 drives renal fibrosis by targeting HIF1AN in vitro and in vivo. Int Urol Nephrol 2018; 51:543-550. [PMID: 30536131 PMCID: PMC6424919 DOI: 10.1007/s11255-018-2025-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 11/03/2018] [Indexed: 11/10/2022]
Abstract
Progressive renal fibrosis is the last phase of chronic kidney disease and results in renal failure. Micro-RNA has been demonstrated as important agent to drive organ fibrosis. However, the precise mechanisms are not fully understood. Here, we found miRNA-184 as a critical mediator to promote the renal fibrosis by targeting HIF1AN. In Vivo, miRNA-184 expression levels remarkably increased both in patients’ serum and in unilateral ureteral obstruction kidneys, as well as induced the expression of COL1A1 and COL3A1. Furthermore, transfection of NRK49F cells with miRNA-184 mimics down-regulated HIF1AN, transfection of NRK49F cells with miRNA-184 inhibitor up-regulated HIF1AN, while the cells transfected with miRNA-184 inhibitor exerted the opposite effect. When the cells were co-transfected with miRNA-184 mimics and HIF1AN, the expression of α-SMA, GTGF, COL1A1, and COL3A1 at mRNA level was apparently decreased when compared with miRNA-184 mimic-transfected cells, which was strengthened when transfected with miRNA-184 inhibitor. Thus, miRNA-184 is an important agent to promote the fibrosis though binding to HIF1AN, and may be a promising novel target in treatment of renal fibrosis.
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Affiliation(s)
- Bin Chen
- Kidney Department, Zhenhai People's Hospital of Ningbo City (Ningbo No.7 Hospital), 718 Nanerxi Road, Luotuo Subdistrict, Zhenhai, Ningbo, People's Republic of China.
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16
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Wang W, Tang S, Li H, Liu R, Su Y, Shen L, Sun M, Ning B. MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma. Exp Cell Res 2018; 370:24-30. [PMID: 29883711 DOI: 10.1016/j.yexcr.2018.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 06/03/2018] [Accepted: 06/04/2018] [Indexed: 02/06/2023]
Abstract
Traumatic spinal cord injury (SCI) causes permanent disability to at least 180,000 people per year worldwide. Early regulation of spinal fibroblast proliferation may inhibit fibrotic scar formation, allowing the creation of a favorable environment for neuronal regeneration and thereby enhancing recovery from traumatic SCIs. In this study, we aimed to identify the role of microRNA-21a-5p (miR-21a-5p) in regulating spinal fibroblasts after mechanical trauma and to investigate the dysregulation of miR-21a-5p in the pathological process of spinal SCI. We investigated the differential expression of microRNAs in primary spinal fibroblasts after mechanical trauma and found that the expression of miR-21a-5p was higher in spinal fibroblasts after scratch damage (SD). In addition, mouse spinal fibroblasts were transfected with miR-21a-5p mimics/inhibitor, and the role of miR-21a-5p in spinal fibrogenic activation was analyzed. These experiments demonstrated that miR-21a-5p overexpression promoted fibrogenic activity in spinal fibroblasts after mechanical trauma, as well as enhancing proliferation and attenuating apoptosis in spinal fibroblasts. Finally, the potential role of miR-21a-5p in regulating the Smad signaling pathway was examined. MiR-21a-5p activated the Smad signaling pathway by enhancing Smad2/3 phosphorylation. These results suggest that miR-21a-5p promotes spinal fibrosis after mechanical trauma. Based on these findings, we propose a close relationship between miR-21a-5p and spinal fibrosis, providing a new potential therapeutic target for SCI.
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Affiliation(s)
- Wenzhao Wang
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Shi Tang
- Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hongfei Li
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Ronghan Liu
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Yanlin Su
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Lin Shen
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Mingjie Sun
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Bin Ning
- Department of Spinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China.
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17
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Hao Y, Huang J, Ma Y, Chen W, Fan Q, Sun X, Shao M, Cai H. Asiatic acid inhibits proliferation, migration and induces apoptosis by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway in human colon carcinoma cells. Oncol Lett 2018; 15:8223-8230. [PMID: 29805556 PMCID: PMC5950025 DOI: 10.3892/ol.2018.8417] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/25/2017] [Indexed: 12/15/2022] Open
Abstract
Previous studies have demonstrated that asiatic acid (AA), the major component of Centella asiatica, is able to meditate cytotoxic and anticancer effects on various types of carcinoma cells. In order to investigate the molecular mechanism that underlies the antitumor effect of AA, the present study investigated the effects of AA on proliferation, migration and apoptosis of SW480 and HCT116 colon cancer cells. Viability and changes in cell morphology in the cells were assessed by MTT assay and transmission electron microscopy, respectively. Colony formation analysis was used to observe proliferation of the single cell, and migratory ability of the cells was assessed by performing Transwell migration assay. Hoechst 33342 nuclear staining and flow cytometry were used to assess apoptosis in colon carcinoma cells. The expression of proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K signaling pathway and epithelial-mesenchymal transition (EMT) marker were analyzed by western blotting. The present study revealed that proliferation and migration of colon carcinoma cells were inhibited by AA in a dose-dependent and time-dependent manner. Numerous apoptotic bodies were observed, and G2/M and S phase progression were delayed in colon cancer cells treated with AA, but not in the control group. A number of phosphorylated proteins, including PI3K, Akt (Ser473), mTOR, ribosomal protein S6 kinase (p70S6K) downregulated, while the expression of Pdcd4 was upregulated following treatment with AA. Additionally, AA affects expression of EMT markers in a dose-dependent manner. On the basis of these results, it was concluded that AA inhibited proliferation, migration and induced apoptosis of colon cancer cells by regulating Pdcd4 via the PI3K/Akt/mTOR/p70S6K signaling pathway. These observations suggest that AA may be a potential therapeutic agent for the treatment of colon carcinoma.
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Affiliation(s)
- Yajuan Hao
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jiawei Huang
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yun Ma
- Department of Pharmacy, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Wancheng Chen
- Cancer Research Institute, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qin Fan
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xuegang Sun
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Meng Shao
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Hongbing Cai
- Department of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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18
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Tang WB, Zheng L, Yan R, Yang J, Ning J, Peng L, Zhou Q, Chen L. miR302a-3p May Modulate Renal Epithelial-Mesenchymal Transition in Diabetic Kidney Disease by Targeting ZEB1. Nephron Clin Pract 2017; 138:231-242. [PMID: 29227974 DOI: 10.1159/000481465] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2017] [Accepted: 09/04/2017] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Recent study found that microRNA (miRNA) are involved in diabetic kidney disease (DKD). The objective of this study is to determine the role of miR302a-3p in the process of renal epithelial-mesenchymal transition (EMT) in DKD. METHODS The miRNA expression profiling of the cell line stimulated by high glucose was performed by a microarray analysis. Then real-time polymerase chain reaction (PCR) were used to determine the expression of one of the miRNAs significantly upregulated in cell line stimulated by high glucose, miR302a-3p. miR302a-3p mimics and inhibitor were transfected to HK-2 cells following exposure to high glucose and normal glucose, respectively. The expressions of E-cadherin, vimentin, and Zinc finger E-box-binding protein 1 (ZEB-1) were determined by real-time PCR and Western blot. Finally, the levels of miR302a-3p in the plasma of DKD patients were detected by real-time PCR, and then the relationship of miR302a-3p and urinary albumin excretion (UAE) or estimated glomerular filtration rate (eGFR) was analyzed. RESULTS The expression of miR-302a-3p, 513a-5p, 1291 and the other 17 miRNA were increased significantly in HK-2 cell line after high glucose stimulation; on the other hand, miRNA490-3p, 638, 3203 and the other 19 miRNA were decreased significantly. In vitro, miR-302a-3p expression in HG group increased at 6 h and ascended to the highest level at 12 and 24 h and then gradually decreased from 48 to 72 h. More interesting, ZEB1 protein expression had an opposite change, which gradually decreased from 6 to 24 h and then gradually increased from 48 to 72 h. Moreover, overexpression of miR-302a-3p suppressed expression of ZEB1 in the post-transcriptional level and reversed high glucose-mediated downregulation of E-cadherin and upregulation of vimentin. Meanwhile, loss of miR-302a-3p expression can lead to EMT of HK-2 cells just as high glucose stimulation. Further study demonstrated that the expression of circulating miR-302a-3p was significantly increased in the diabetes mellitus (DM) with normoalbuminuria (DM group, n = 22) compared with control (healthy persons, n = 30) and then decreased in DM with microalbuminuria (DNE group, n = 20). Furthermore, its expression in DM with macroalbuminuria (DNC group, n = 18) was decreased significantly compared with DM group. Circulating miR-302a-3p had negative relevance with UAE in DNE group (r = -0.649, p = 0.002) and DNC group (r = -0.681, p = 0.006). Circulating miR-302a-3p had positive relevance with eGFR in DNC group (r = 0.486, p = 0.041). CONCLUSIONS These findings suggest that miR-302a-3p may play a protective role by targeting ZEB1 in renal EMT in DKD. In view of these findings, it is conceivable that miR-302a-3p may serve as a potential novel target in pre-EMT states for the amelioration renal fibrosis seen in DKD.
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Affiliation(s)
- Wen-Bin Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Linfeng Zheng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Renheng Yan
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Jiayi Yang
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, China
| | - Jianping Ning
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Linlin Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Qiaoling Zhou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Liping Chen
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
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19
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Ross K. Towards topical microRNA-directed therapy for epidermal disorders. J Control Release 2017; 269:136-147. [PMID: 29133119 DOI: 10.1016/j.jconrel.2017.11.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/08/2017] [Accepted: 11/09/2017] [Indexed: 01/09/2023]
Abstract
There remains an unmet dermatological need for innovative topical agents that achieve better longterm outcomes with fewer side effects. Modulation of the expression and activity of microRNA (miRNAs) represents an emerging translational framework for the development of such innovative therapies because changes in the expression of one miRNA can have wide-ranging effects on diverse cellular processes associated with disease. In this short review, the roles of miRNA in epidermal development, psoriasis, cutaneous squamous cell carcinoma and re-epithelisation are highlighted. Consideration is given to the delivery of oligonucleotides that mimic or inhibit miRNA function using vehicles such as cell penetrating peptides, spherical nucleic acids, deformable liposomes and liquid crystalline nanodispersions. Formulation of miRNA-directed oligonucleotides with such skin-penetrating epidermal agents will drive the development of RNA-based cutaneous therapeutics for deployment as primary or adjuvant therapies for epidermal disorders.
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Affiliation(s)
- Kehinde Ross
- School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, United Kingdom.
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20
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Wang J, Liu K, Wang XF, Sun DJ. Juglone reduces growth and migration of U251 glioblastoma cells and disrupts angiogenesis. Oncol Rep 2017; 38:1959-1966. [PMID: 28791366 PMCID: PMC5652942 DOI: 10.3892/or.2017.5878] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Accepted: 06/21/2017] [Indexed: 01/11/2023] Open
Abstract
Accumulating data show that prolylisomerase (Pin1) is overexpressed in human glioblastoma multiforme (GBM) specimens. Therefore, Pin1 inhibitors should be investigated as a new chemotherapeutic drug that may enhance the clinical management of human gliomas. Recently, juglone, a Pin1 inhibitor, was shown to exhibit potent anticancer activity in various tumor cells, but its role in human glioma cells remains unknown. In the present study, we determined if juglone exerts antitumor effects in the U251 human glioma cell line and investigated its potential underlying molecular mechanisms. Cell survival, apoptosis, migration, angiogenesis and molecular targets were identified with multiple detection techniques including the MTT cell proliferation assay, dual acridine orange/ethidium bromide staining, electron microscopy, Transwell migration assay, chick chorioallantoic membrane assay, quantitative real-time polymerase chain reaction and immunoblotting. The results showed that 5–20 µM juglone markedly suppressed cell proliferation, induced apoptosis, and enhanced caspase-3 activity in U251 cells in a dose- and time-dependent manner. Moreover, juglone inhibited cell migration and the formation of new blood vessels. At the molecular level, juglone markedly suppressed Pin1 levels in a time-dependent manner. TGF-β1/Smad signaling, a critical upstream regulator of miR-21, was also suppressed by juglone. Moreover, the transient overexpression of Pin1 reversed its antitumor effects in U251 cells and inhibited juglone-mediated changes to the TGF-β1/miR-21 signaling pathway. These findings suggest that juglone inhibits cell growth by causing apoptosis, thereby inhibiting the migration of U251 glioma cells and disrupting angiogenesis; and that Pin1 is a critical target for juglones antitumor activity. The present study provides evidence that juglone has in vitro efficacy against glioma. Therefore, additional studies are warranted to examine the clinical potential of juglone in human gliomas.
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Affiliation(s)
- Jian Wang
- Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
| | - Ke Liu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
| | - Xiao-Feng Wang
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
| | - Dian-Jun Sun
- Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province and Ministry of Health, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
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21
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Heery R, Finn SP, Cuffe S, Gray SG. Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells. Cancers (Basel) 2017; 9:cancers9040038. [PMID: 28430163 PMCID: PMC5406713 DOI: 10.3390/cancers9040038] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/14/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023] Open
Abstract
Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype.
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Affiliation(s)
- Richard Heery
- Thoracic Oncology Research Group, Rm 2.09, Trinity Translational Medical Institute, St. James's Hospital, Dublin D08 W9RT, Ireland.
- Masters in Translational Oncology Program, Department of Surgery, Trinity College Dublin, Trinity Translational Medical Institute, St. James's Hospital, Dublin D08 W9RT, Ireland.
| | - Stephen P Finn
- Department of Histopathology & Morbid Anatomy, Trinity College Dublin, Dublin D08 RX0X, Ireland.
| | - Sinead Cuffe
- HOPE Directorate, St. James's Hospital, Dublin D08 RT2X, Ireland.
| | - Steven G Gray
- Thoracic Oncology Research Group, Rm 2.09, Trinity Translational Medical Institute, St. James's Hospital, Dublin D08 W9RT, Ireland.
- HOPE Directorate, St. James's Hospital, Dublin D08 RT2X, Ireland.
- Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin D02 R590, Ireland.
- Labmed Directorate, St. James's Hospital, Dublin D08 K0Y5, Ireland.
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22
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Zhou P, Li B, Liu F, Zhang M, Wang Q, Liu Y, Yao Y, Li D. The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer. Mol Cancer 2017; 16:52. [PMID: 28245823 PMCID: PMC5331747 DOI: 10.1186/s12943-017-0624-9] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 02/23/2017] [Indexed: 02/08/2023] Open
Abstract
The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.
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Affiliation(s)
- Pingting Zhou
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bo Li
- Department of Bone Tumor Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Furao Liu
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Meichao Zhang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qian Wang
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yuanhua Liu
- Department of Chemotherapy, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu, China
| | - Yuan Yao
- Department of Radiation Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dong Li
- Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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23
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Hassan A, Mosley J, Singh S, Zinn PO. A Comprehensive Review of Genomics and Noncoding RNA in Gliomas. Top Magn Reson Imaging 2017; 26:3-14. [PMID: 28079712 DOI: 10.1097/rmr.0000000000000111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Glioblastoma (GBM) is the most malignant primary adult brain tumor. In spite of our greater understanding of the biology of GBMs, clinical outcome of GBM patients remains poor, as their median survival with best available treatment is 12 to 18 months. Recent efforts of The Cancer Genome Atlas (TCGA) have subgrouped patients into 4 molecular/transcriptional subgroups: proneural, neural, classical, and mesenchymal. Continuing efforts are underway to provide a comprehensive map of the heterogeneous makeup of GBM to include noncoding transcripts, genetic mutations, and their associations to clinical outcome. In this review, we introduce key molecular events (genetic and epigenetic) that have been deemed most relevant as per studies such as TCGA, with a specific focus on noncoding RNAs such as microRNAs (miRNA) and long noncoding RNAs (lncRNA). One of our main objectives is to illustrate how miRNAs and lncRNAs play a pivotal role in brain tumor biology to define tumor heterogeneity at molecular and cellular levels. Ultimately, we elaborate how radiogenomics-based predictive models can describe miRNA/lncRNA-driven networks to better define heterogeneity of GBM with clinical relevance.
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Affiliation(s)
- Ahmed Hassan
- *Department of Diagnostic Radiology †Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center ‡Department of Neurosurgery, Baylor College of Medicine, Houston, TX
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Diepenbruck M, Christofori G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 2016; 43:7-13. [PMID: 27371787 DOI: 10.1016/j.ceb.2016.06.002] [Citation(s) in RCA: 369] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 06/06/2016] [Accepted: 06/08/2016] [Indexed: 12/17/2022]
Abstract
An epithelial to mesenchymal transition (EMT) is a process of cell remodeling critical during embryonic development and organogenesis. During an EMT, epithelial cells lose their polarized organization and acquire migratory and invasive capabilities. While a plethora of experimental results have indicated that manipulating an EMT also affects cancer metastasis, its reverse process, a mesenchymal to epithelial transition (MET), seems to support metastatic outgrowth in distant organs. Moreover, recent reports investigating cancer cells circulating in the blood stream or employing genetic lineage-tracing have questioned a critical role of an EMT in metastasis formation. Hence, we need to better understand the molecular networks underlying the cell plasticity conferred by an EMT or a MET and its functional contribution to malignant tumor progression.
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Affiliation(s)
- Maren Diepenbruck
- Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
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Ye Z, Zhao L, Li J, Chen W, Li X. miR-30d Blocked Transforming Growth Factor β1-Induced Epithelial-Mesenchymal Transition by Targeting Snail in Ovarian Cancer Cells. Int J Gynecol Cancer 2015; 25:1574-81. [PMID: 26501435 DOI: 10.1097/igc.0000000000000546] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE MicroRNAs (miRs) are essential regulators of gene expression by suppressing translation or causing degradation of target mRNA. Growing evidence sheds light on the crucial roles of miR dysregulation in cancer development and progression. In this study, we focused on the role of miR-30d in transforming growth factor β1 (TGF-β1)-initiated epithelial-mesenchymal transition (EMT) in ovarian cancer cells. METHODS Transforming growth factor β1 (10 ng/mL) was used to initiate EMT in SKOV3 and 3AO cells. The expression of miR-30 family members was determined by quantitative real-time polymerase chain reaction. Messenger RNA and protein levels of E-cadherin, N-cadherin, vimentin, and Snail were detected by quantitative real-time polymerase chain reaction and Western blot, respectively. Cell migration and invasion capacities were evaluated by Transwell chamber assay. Luciferase activity assay was performed to verify the direct inhibition of Snail by miR-30d. RESULTS MiR-30b, MiR-30c, and MiR-30d were down-regulated during TGF-β1-induced EMT in SKOV3 and 3AO ovarian cancer cells. Restoration of miR-30d by miR-30d mimic reversed TGF-β1-induced EMT phenotypes including the morphological changes, expression pattern of molecular markers (E-cadherin, N-cadherin), and migratory and invasive capabilities in ovarian cancer cells. Furthermore, Snail was identified as the direct target of miR-30d. CONCLUSIONS Our results revealed that miR-30d functioned as a suppressor of ovarian cancer progression by decreasing Snail expression and thus blocking TGF-β1-induced EMT process, suggesting the potentiality of miR-30d analogs to be used as therapeutics for ovarian cancer.
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Affiliation(s)
- Zhongxue Ye
- Centers for *Translational Medicine and †Laboratory Medicine, the First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, People's Republic of China
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Abstract
Based on own translational research of the biochemical and hormonal effects of cow's milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal. This signaling system is highly conserved and tightly controlled by the lactation genome. Milk is sufficient to activate mTORC1, the crucial regulator of protein, lipid, and nucleotide synthesis orchestrating anabolism, cell growth and proliferation. To fulfill its mTORC1-activating function, milk delivers four key metabolic messengers: (1) essential branched-chain amino acids (BCAAs); (2) glutamine; (3) palmitic acid; and (4) bioactive exosomal microRNAs, which in a synergistical fashion promote mTORC1-dependent translation. In all mammals except Neolithic humans, postnatal activation of mTORC1 by milk intake is restricted to the postnatal lactation period. It is of critical concern that persistent hyperactivation of mTORC1 is associated with aging and the development of age-related disorders such as obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Persistent mTORC1 activation promotes endoplasmic reticulum (ER) stress and drives an aimless quasi-program, which promotes aging and age-related diseases.
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AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR-21/CDK5 axis. Cancer Lett 2015; 362:174-82. [PMID: 25827073 DOI: 10.1016/j.canlet.2015.03.038] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/24/2015] [Accepted: 03/24/2015] [Indexed: 12/21/2022]
Abstract
Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAK(ser732). A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including β-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application.
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TGFβ Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. JOURNAL OF ONCOLOGY 2015; 2015:587193. [PMID: 25883652 PMCID: PMC4389829 DOI: 10.1155/2015/587193] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 10/14/2014] [Indexed: 01/07/2023]
Abstract
Retaining the delicate balance in cell signaling activity is a prerequisite for the maintenance of physiological tissue homeostasis. Transforming growth factor-beta (TGFβ) signaling is an essential pathway that plays crucial roles during embryonic development as well as in adult tissues. Aberrant TGFβ signaling activity regulates tumor progression in a cancer cell-autonomous or non-cell-autonomous fashion and these effects may be tumor suppressing or tumor promoting depending on the cellular context. The fundamental role of this pathway in promoting cancer progression in multiple stages of the metastatic process, including epithelial-to-mesenchymal transition (EMT), is also becoming increasingly clear. In this review, we discuss the latest advances in the effort to unravel the inherent complexity of TGFβ signaling and its role in cancer progression and metastasis. These findings provide important insights into designing personalized therapeutic strategies against advanced cancers.
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Renart J, Carrasco-Ramírez P, Fernández-Muñoz B, Martín-Villar E, Montero L, Yurrita MM, Quintanilla M. New insights into the role of podoplanin in epithelial-mesenchymal transition. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2015; 317:185-239. [PMID: 26008786 DOI: 10.1016/bs.ircmb.2015.01.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Podoplanin is a small mucin-like transmembrane protein expressed in several adult tissues and with an important role during embryogenesis. It is needed for the proper development of kidneys and lungs as well as accurate formation of the lymphatic vascular system. In addition, it is involved in the physiology of the immune system. A wide variety of tumors express podoplanin, both in the malignant cells and in the stroma. Although there are exceptions, the presence of podoplanin results in poor prognosis. The main consequence of forced podoplanin expression in established and tumor-derived cell lines is an increase in cell migration and, eventually, the triggering of an epithelial-mesenchymal transition, whereby cells acquire a fibroblastoid phenotype and increased motility. We will examine the current status of the role of podoplanin in the induction of epithelial-mesenchymal transition as well as the different interactions that lead to this program.
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Affiliation(s)
- Jaime Renart
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | | | | | - Ester Martín-Villar
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Lucía Montero
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - María M Yurrita
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Miguel Quintanilla
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
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Abstract
MicroRNAs (miRNAs) are endogenous short non-coding RNAs that regulate most of important cellular processes by inhibiting gene expression through the post-transcriptional repression of their target mRNAs. In kidneys, miRNAs have been associated in renal development, homeostasis, and physiological functions. Results from clinical and experimental animal studies demonstrate that miRNAs play essential roles in the pathogenesis of various renal diseases. Chronic kidney diseases (CKD) is characterized by renal fibrosis. Transforming growth factor beta (TGF-β) is recognized as a major mediator of renal fibrosis because it is able to stimulate the accumulation of extracellular matrix (ECM) proteins to impair normal kidney function. Recently, emerging evidence demonstrate the relationship between TGF-β signaling and miRNAs expression during renal diseases. TGF-β regulates expression of several microRNAs, such as miR-21, miR-192, miR-200, miR-433, and miR-29. MiR-21, miR-192, and miR-433 which are positively induced by TGF-β signaling play a pathological role in kidney diseases. In contrast, members in both miR-29 and miR-200 families which are inhibited by TGF-β signaling protect kidneys from renal fibrosis by suppressing the deposition of ECM and preventing epithelial-to-mesenchymal transition, respectively. Clinically, the presence of miRNAs in blood and urine has been examined to be early biomarkers for detecting renal diseases. From experimental animal studies of CKD, targeting microRNAs also provides evidence about therapeutic potential of miRNAs during renal diseases. Now, it comes to the stage to examine the exact mechanisms of miRNAs during the initiation and progression of renal diseases. Therefore, determining the function of miRNAs in renal fibrosis may facilitate the development of both early diagnosis and treatment of renal diseases.
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Affiliation(s)
- Arthur C-K Chung
- Partner State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University Hong Kong, China ; HKBU Institute for Research and Continuing Education Shenzhen, China
| | - Hui Y Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Hong Kong, China
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Zhang S, Han L, Wei J, Shi Z, Pu P, Zhang J, Yuan X, Kang C. Combination treatment with doxorubicin and microRNA-21 inhibitor synergistically augments anticancer activity through upregulation of tumor suppressing genes. Int J Oncol 2015; 46:1589-600. [PMID: 25625875 DOI: 10.3892/ijo.2015.2841] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 11/04/2014] [Indexed: 11/05/2022] Open
Abstract
Doxorubicin (DOX) is a key chemotherapeutic drug for cancer treatment. The antitumor mechanism of DOX is its action as a topoisomerase II poison by preventing DNA replication. Our study shows that DOX can be involved in epigenetic regulation of gene transcription through downregulation of DNA methyltransferase 1 (DNMT1) then reactivation of DNA methylation-silenced tumor suppressor genes in glioblastoma (GBM). Recent evidence demonstrated that microRNA (miR or miRNA) can mediate expression of genes through post-transcriptional regulation and modulate sensitivity to anticancer drugs. As one of the first miRNAs detected in the human genome, miR-21 has been validated to be overexpressed in GBM. Combination treatment of a chemotherapeutic and miRNA showed synergistically increased anticancer activities which has been proven to be an effective strategy for tumor therapy. In our study, co-treatment of DOX and miR-21 inhibitor (miR-21i) resulted in remarkably increased expression of tumor suppressor genes compared with DOX or the miR-21i treatment alone. Moreover, we demonstrate that combining DOX and miR-21i significantly reduced tumor cell proliferation, invasion and migration in vitro. Our study concludes that combining DOX and miR-21i is a new strategy for the therapy of GBM.
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Affiliation(s)
- Shanshan Zhang
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin 300072, P.R. China
| | - Lei Han
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jianwei Wei
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Zhendong Shi
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Peiyu Pu
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Jianning Zhang
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
| | - Xubo Yuan
- Tianjin Key Laboratory of Composite and Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin 300072, P.R. China
| | - Chunsheng Kang
- Laboratory of Neuro-Oncology, Department of Neurosurgery, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, P.R. China
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Luo F, Ji J, Liu Y, Xu Y, Zheng G, Jing J, Wang B, Xu W, Shi L, Lu X, Liu Q. MicroRNA-21, up-regulated by arsenite, directs the epithelial-mesenchymal transition and enhances the invasive potential of transformed human bronchial epithelial cells by targeting PDCD4. Toxicol Lett 2014; 232:301-9. [PMID: 25445583 DOI: 10.1016/j.toxlet.2014.11.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 10/10/2014] [Accepted: 11/02/2014] [Indexed: 01/04/2023]
Abstract
Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) contributes to carcinogen-induced malignant transformation and subsequent tumor formation. We have found that, during the neoplastic transformation induced in human bronchial epithelial (HBE) cells by a low concentration (1.0μM) of arsenite, the cells undergo an EMT and show enhanced invasion and migration. With longer times for transformation of HBE cells, there was increased miR-21 expression. Further, during the transformation of HBE cells, inhibition of miR-21 with an miR-21 inhibitor increased levels of PDCD4, an inhibitor of neoplastic transformation; reduced Twist1, a transcription factor involved in cell differentiation; and inhibited cell invasion and migration. In addition, PDCD4 interacted with Twist1 and inhibited its expression function, which is involved in arsenite-induced EMT. Thus, miR-21, acting on PDCD4, which interacts with Twist1 and represses the expression of Twist1, contributes to the EMT induced by arsenite. These observations add to an understanding of the processes involved in arsenite-induced carcinogenesis.
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Affiliation(s)
- Fei Luo
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Jie Ji
- The First Clinic Medical College, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Yi Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Yuan Xu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Gang Zheng
- Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
| | - Jinfei Jing
- Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China
| | - Bairu Wang
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Wenchao Xu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Le Shi
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Xiaolin Lu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China
| | - Qizhan Liu
- Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
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Loewen G, Zhuo Y, Zhuang Y, Jayawickramarajah J, Shan B. lincRNA HOTAIR as a novel promoter of cancer progression. ACTA ACUST UNITED AC 2014; 3:134-140. [PMID: 25663954 DOI: 10.6000/1929-2279.2014.03.03.3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Large intergenic non-coding RNAs (lincRNA) regulate development and disease via interactions with their protein partners. Expression of the lincRNA HOX transcript antisense RNA (HOTAIR) is elevated in a variety of malignancies and linked to metastasis and poor prognosis. HOTAIR promotes proliferation, invasion, and metastasis in the preclinical studies of cancer through modulation of chromatin modifying complexes. In the current review we discuss the molecular mechanisms of HOTAIR-mediated aggressive phenotypes of cancer, HOTAIR's potential in cancer intervention, and challenges in exploration of HOTAIR in cancer biology.
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Affiliation(s)
- Gregory Loewen
- Providence Regional Cancer Center, 105 W. 8th Avenue, Spokane, WA 99204 USA
| | - Ying Zhuo
- Medical Oncology Associates, 6001 North Mayfair Street, Spokane, WA 99208 USA
| | - Yan Zhuang
- Department of Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA
| | | | - Bin Shan
- College of Medical Sciences, Washington State University Spokane, 412 E. Spokane Falls Boulevard, Spokane, WA 99202 USA
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Wang JY, Gao YB, Zhang N, Zou DW, Wang P, Zhu ZY, Li JY, Zhou SN, Wang SC, Wang YY, Yang JK. miR-21 overexpression enhances TGF-β1-induced epithelial-to-mesenchymal transition by target smad7 and aggravates renal damage in diabetic nephropathy. Mol Cell Endocrinol 2014; 392:163-72. [PMID: 24887517 DOI: 10.1016/j.mce.2014.05.018] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 04/24/2014] [Accepted: 05/20/2014] [Indexed: 01/13/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) plays an important role in renal interstitial fibrosis (RIF) with diabetic nephropathy (DN). Smad7 (a inhibitory smad), a downstream signaling molecules of TGF-β1, represses the EMT. The physiological function of miR-21 is closely linked to EMT and RIF. However, it remained unclear whether miR-21 over-expression affected TGF-β1-induced EMT by regulating smad7 in DN. In this study, real-time RT-PCR, cell transfection, luciferase reporter gene assays, western blot and confocal microscope were used, respectively. Here, we found that miR-21 expression was upregulated by TGF-β1 in time- and concentration -dependent manner. Moreover, miR-21 over-expression enhanced TGF-β1-induced EMT(upregulation of a-SMA and downregulation of E-cadherin) by directly down-regulating smad7/p-smad7 and indirectly up-regulating smad3/p-smad3, accompanied by the decrease of Ccr and the increase of col-IV, FN, the content of collagen fibers, RTBM, RTIAW and ACR. Meantime, the siRNA experiment showed that smad7 can directly regulate a-SMA and E-cadherin expression. More importantly, miR-21 inhibitor can not only inhibit EMT and fibrosis but also ameliorate renal structure and function. In conclusion, our results demonstrated that miR-21 overexpression can contribute to TGF-β1-induced EMT by inhibiting target smad7, and that targeting miR-21 may be a better alternative to directly suppress TGF-β1-mediated fibrosis in DN.
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Affiliation(s)
- Jin-Yang Wang
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Department of Endocrine and Metabolism, Capital Medical University, Beijing, China; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
| | - Yan-Bin Gao
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China; Department of Endocrine and Metabolism, Capital Medical University, Beijing, China.
| | - Na Zhang
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Da-Wei Zou
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Peng Wang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhi-Yao Zhu
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Jiao-Yang Li
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Sheng-Nan Zhou
- Metabolic Disease Center, School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Shao-Cheng Wang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Ying-Ying Wang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jin-Kui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China.
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Pinhal CS, Lopes A, Torres DB, Felisbino SL, Rocha Gontijo JA, Boer PA. Time-course morphological and functional disorders of the kidney induced by long-term high-fat diet intake in female rats. Nephrol Dial Transplant 2014; 28:2464-76. [PMID: 24078639 DOI: 10.1093/ndt/gft304] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Evidence is emerging that highlights the far-reaching consequences of a high-fat diet (HFD) on kidney morphology and function disorders. METHODS The present study was performed on 3-, 5-, 7- and 9-week-old HFD female rats compared with the appropriate gender and age-matched animals. We evaluated the kidney expression of angiotensin type II receptor and fibrotic and epithelial-to-mesenchymal transition (EMT) markers, by immunoblotting and immunohistochemical and histological techniques, in parallel with kidney function. RESULTS In the current study, the time-course HFD-treated group showed, by immunoblotting and immunohistochemical analysis, an early time-course increase in the expression of transforming growth factor β-1 (TGFβ-1) in the entire kidney of HFD-treated rats, compared with that observed in the control group. Simultaneously, the study shows a transient increase in the expression of ZEB2 in the HFD whole kidney accompanied by a fall in the E-cadherin expression and increased collagen and fibronectin deposition. A pronounced decrease in fractional urinary sodium excretion was also demonstrated in the long-term HFD-treated rats. The decreased FENa(+) was accompanied by a fall in FEPNa(+) and FEPPNa(+), which occurred in association with significantly decreased CCr and, certainly on the sodium-filtered load. The reduction in the glomerular filtration rate (GFR) occurred in parallel to proteinuria and glomerular desmin overexpression. CONCLUSIONS The results of the current study suggest that podocyte injury in parallel with observed proteinuria and evidence of EMT transformation are associated with long-term loss of kidney function and renal sodium and water retention.
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Affiliation(s)
- Carolina Staut Pinhal
- Renal Function Laboratory, Campinas State University, UNICAMP, Campinas, São Paulo, Brazil
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Vislovukh A, Vargas TR, Polesskaya A, Groisman I. Role of 3’-untranslated region translational control in cancer development, diagnostics and treatment. World J Biol Chem 2014; 5:40-57. [PMID: 24600513 PMCID: PMC3942541 DOI: 10.4331/wjbc.v5.i1.40] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 11/22/2013] [Accepted: 12/19/2013] [Indexed: 02/05/2023] Open
Abstract
The messenger RNA 3’-untranslated region (3’UTR) plays an important role in regulation of gene expression on the posttranscriptional level. The 3’UTR controls gene expression via orchestrated interaction between the structural components of mRNAs (cis-element) and the specific trans-acting factors (RNA binding proteins and non-coding RNAs). The crosstalk of these factors is based on the binding sequences and/or direct protein-protein interaction, or just functional interaction. Much new evidence that has accumulated supports the idea that several RNA binding factors can bind to common mRNA targets: to the non-overlapping binding sites or to common sites in a competitive fashion. Various factors capable of binding to the same RNA can cooperate or be antagonistic in their actions. The outcome of the collective function of all factors bound to the same mRNA 3’UTR depends on many circumstances, such as their expression levels, affinity to the binding sites, and localization in the cell, which can be controlled by various physiological conditions. Moreover, the functional and/or physical interactions of the factors binding to 3’UTR can change the character of their actions. These interactions vary during the cell cycle and in response to changing physiological conditions. Abnormal functioning of the factors can lead to disease. In this review we will discuss how alterations of these factors or their interaction can affect cancer development and promote or enhance the malignant phenotype of cancer cells. Understanding these alterations and their impact on 3’UTR-directed posttranscriptional gene regulation will uncover promising new targets for therapeutic intervention and diagnostics. We will also discuss emerging new tools in cancer diagnostics and therapy based on 3’UTR binding factors and approaches to improve them.
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Krstic J, Santibanez JF. Transforming growth factor-beta and matrix metalloproteinases: functional interactions in tumor stroma-infiltrating myeloid cells. ScientificWorldJournal 2014; 2014:521754. [PMID: 24578639 PMCID: PMC3918721 DOI: 10.1155/2014/521754] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 10/28/2013] [Indexed: 01/05/2023] Open
Abstract
Transforming growth factor-beta (TGF-β) is a pleiotropic factor with several different roles in health and disease. In tumorigenesis, it may act as a protumorigenic factor and have a profound impact on the regulation of the immune system response. Matrix metalloproteinases (MMPs) are a family that comprises more than 25 members, which have recently been proposed as important regulators acting in tumor stroma by regulating the response of noncellular and cellular microenvironment. Tumor stroma consists of several types of resident cells and infiltrating cells derived from bone marrow, which together play crucial roles in the promotion of tumor growth and metastasis. In cancer cells, TGF-β regulates MMPs expression, while MMPs, produced by either cancer cells or residents' stroma cells, activate latent TGF-β in the extracellular matrix, together facilitating the enhancement of tumor progression. In this review we will focus on the compartment of myeloid stroma cells, such as tumor-associated macrophages, neutrophils, and dendritic and mast cells, which are potently regulated by TGF-β and produce large amounts of MMPs. Their interplay and mutual implications in the generation of pro-tumorigenic cancer microenvironment will be analyzed.
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Affiliation(s)
- Jelena Krstic
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Dr Subotića 4, 11129 Belgrade, Serbia
| | - Juan F. Santibanez
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Dr Subotića 4, 11129 Belgrade, Serbia
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Son H, Moon A. Epithelial-mesenchymal Transition and Cell Invasion. Toxicol Res 2013; 26:245-52. [PMID: 24278531 PMCID: PMC3834497 DOI: 10.5487/tr.2010.26.4.245] [Citation(s) in RCA: 245] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 11/02/2010] [Accepted: 11/14/2010] [Indexed: 12/31/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF) -β, Wnt, and Notch signaling pathways, have been shown to induce EMT. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Mounting evidence shows that EMT is associated with cell invasion and tumor progression.In this review, we summarize the characteristic features of EMT, pathways leading to EMT, and the role of EMT in cell invasion. Three topics are addressed in this review: (1) Definition of EMT, (2) Signaling pathways leading to EMT, (3) Role of EMT in cell invasion. Understanding the role of EMT in cell invasion will provide valuable information for establishing strategies to develop anti-metastatic therapeutics which modulate malignant cellular processes mediated by EMT.
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Affiliation(s)
- Hwajin Son
- College of Pharmacy, Duksung Women's University, Seoul 132-714, Korea
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Wang X, Liu Y, Chen X, Zhang M, Xiao Z. Impact of MiR-21 on the expression of FasL in the presence of TGF-β1. Aesthet Surg J 2013; 33:1186-98. [PMID: 24335017 DOI: 10.1177/1090820x13511969] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Micro-ribonucleic acids (miR) are small, noncoding RNA molecules 19 to 25 nucleotides in length that typically function as negative regulators of expression for many target genes involved in cell proliferation, differentiation, and apoptosis. However, the effects of miR-21 on keloid fibroblasts are currently unknown. OBJECTIVES The authors investigate whether miR-21, a specific miR implicated in multiple aspects of keloid fibroblasts, affects the expression of Fas ligand (FasL) in the presence of transforming growth factor (TGF)-β1. METHODS The relationship between TGF-β1 and miR-21 expression was investigated by TaqMan quantitative real-time polymerase chain reaction (Life Technologies, Grand Island, New York). FasL protein was determined by Western blotting, and regulation of cell proliferation/migration/apoptosis ability by TGF-β1 inhibitor or plasmid was evaluated respectively by EdU incorporation, Transwell assay, and flow cytometry analysis. RESULTS Fibroblasts from keloid tissue were confirmed to express high levels of TGF-β1 and miR-21 compared with normal skin fibroblasts. Expression of TGF-β1 and miR-21 was positively correlated in fibroblasts. In addition, cells transfected with TGF-β1 inhibitor or miR-21 inhibitor showed significant increases in FasL protein levels and number of apoptotic cells compared with control cells, whereas cell growth and migration significantly decreased. The opposite results could also be confirmed when TGF-β1 was upregulated in normal skin fibroblasts. CONCLUSIONS TGF-β1 could effectively influence cell proliferation, apoptosis, and migration via its control of miR-21. These findings also identify a novel mechanism of interaction between TGF-β1 and miR-21 in the regulation of FasL protein, which is involved in keloid formation.
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Affiliation(s)
- Xiaoxue Wang
- Department of Plastic Surgery, the Second Affiliated Hospital of Harbin Medical University, Heilongjiang Province, China
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40
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Denby L, Ramdas V, Lu R, Conway BR, Grant JS, Dickinson B, Aurora AB, McClure JD, Kipgen D, Delles C, van Rooij E, Baker AH. MicroRNA-214 antagonism protects against renal fibrosis. J Am Soc Nephrol 2013; 25:65-80. [PMID: 24158985 DOI: 10.1681/asn.2013010072] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Renal tubulointerstitial fibrosis is the common end point of progressive renal disease. MicroRNA (miR)-214 and miR-21 are upregulated in models of renal injury, but the function of miR-214 in this setting and the effect of its manipulation remain unknown. We assessed the effect of inhibiting miR-214 in an animal model of renal fibrosis. In mice, genetic deletion of miR-214 significantly attenuated interstitial fibrosis induced by unilateral ureteral obstruction (UUO). Treatment of wild-type mice with an anti-miR directed against miR-214 (anti-miR-214) before UUO resulted in similar antifibrotic effects, and in vivo biodistribution studies demonstrated that anti-miR-214 accumulated at the highest levels in the kidney. Notably, in vivo inhibition of canonical TGF-β signaling did not alter the regulation of endogenous miR-214 or miR-21. Whereas miR-21 antagonism blocked Smad 2/3 activation, miR-214 antagonism did not, suggesting that miR-214 induces antifibrotic effects independent of Smad 2/3. Furthermore, TGF-β blockade combined with miR-214 deletion afforded additional renal protection. These phenotypic effects of miR-214 depletion were mediated through broad regulation of the transcriptional response to injury, as evidenced by microarray analysis. In human kidney tissue, miR-214 was detected in cells of the glomerulus and tubules as well as in infiltrating immune cells in diseased tissue. These studies demonstrate that miR-214 functions to promote fibrosis in renal injury independent of TGF-β signaling in vivo and that antagonism of miR-214 may represent a novel antifibrotic treatment in the kidney.
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Affiliation(s)
- Laura Denby
- BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
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Li M, Li J, Liu L, Li W, Yang Y, Yuan J. MicroRNA in Human Glioma. Cancers (Basel) 2013; 5:1306-31. [PMID: 24202447 PMCID: PMC3875941 DOI: 10.3390/cancers5041306] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Revised: 10/08/2013] [Accepted: 10/10/2013] [Indexed: 02/06/2023] Open
Abstract
Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy.
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Affiliation(s)
- Mengfeng Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +86-20-87332748; Fax: +86-20-87331209
| | - Jun Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Lei Liu
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Wei Li
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Yi Yang
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
| | - Jie Yuan
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080, China; E-Mails: (J.L.); (L.L.); (W.L.); (Y.Y.); (J.Y.)
- Key Laboratory of Functional Molecules from Oceanic Microorganisms (Sun Yat-sen University), Department of Education of Guangdong Province, Guangzhou 510080, China
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Non-coding RNAs: the "dark matter" of cardiovascular pathophysiology. Int J Mol Sci 2013; 14:19987-20018. [PMID: 24113581 PMCID: PMC3821599 DOI: 10.3390/ijms141019987] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 09/12/2013] [Accepted: 09/16/2013] [Indexed: 12/17/2022] Open
Abstract
Large-scale analyses of mammalian transcriptomes have identified a significant number of different RNA molecules that are not translated into protein. In fact, the use of new sequencing technologies has identified that most of the genome is transcribed, producing a heterogeneous population of RNAs which do not encode for proteins (ncRNAs). Emerging data suggest that these transcripts influence the development of cardiovascular disease. The best characterized non-coding RNA family is represented by short highly conserved RNA molecules, termed microRNAs (miRNAs), which mediate a process of mRNA silencing through transcript degradation or translational repression. These microRNAs (miRNAs) are expressed in cardiovascular tissues and play key roles in many cardiovascular pathologies, such as coronary artery disease (CAD) and heart failure (HF). Potential links between other ncRNAs, like long non-coding RNA, and cardiovascular disease are intriguing but the functions of these transcripts are largely unknown. Thus, the functional characterization of ncRNAs is essential to improve the overall understanding of cellular processes involved in cardiovascular diseases in order to define new therapeutic strategies. This review outlines the current knowledge of the different ncRNA classes and summarizes their role in cardiovascular development and disease.
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Abstract
Micro ribonucleic acids (miRNAs) are short noncoding RNAs that inhibit gene expression through the post-transcriptional repression of their target mRNAs. Increasing evidence shows that miRNAs have emerged as key players in diverse biologic processes. Aberrant miRNA expression is also closely related to various human diseases, including kidney diseases. From clinical and experimental animal studies, emerging evidence demonstrates a critical role for miRNAs in renal pathophysiology. Renal fibrosis is the hallmark of various chronic kidney diseases and transforming growth factor beta (TGF-β) is recognized as a vital mediator of renal fibrosis because it can induce production of extracellular matrix proteins resulting in dysfunction of the kidneys. The relationship between TGF-β signaling and miRNAs expression during renal diseases has been recently established. TGF-β positively or negatively regulates expression of several miRNAs, such as miR-21, miR-192, miR-200, and miR-29. Both miR-192 and miR-21 are positively regulated by TGF-β1/Smad3 signaling and play a pathological role in kidney diseases. Conversely, members of both miR-29 and miR-200 families are negatively regulated by TGF-β/Smad3 and play a protective role in renal fibrosis by inhibiting the deposition of extracellular matrix and preventing epithelial-to-mesenchymal transition, respectively. Clinically, levels of miRNAs in circulation and urine may be potential biomarkers for detecting early stages of renal diseases and targeting miRNAs also provides promising therapeutic effects in rodent models of chronic kidney disease. However, mechanisms and roles of miRNAs under disease conditions remain to be explored. Thus, understanding the function of miRNAs in the pathogenesis of kidney diseases may offer an innovative approach for both early diagnosis and treatment of renal diseases.
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Affiliation(s)
- Arthur Ck Chung
- Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People's Republic of China ; CUHK Shenzhen Research Institute, Shenzhen, People's Republic of China
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Chen C, Zimmermann M, Tinhofer I, Kaufmann AM, Albers AE. Epithelial-to-mesenchymal transition and cancer stem(-like) cells in head and neck squamous cell carcinoma. Cancer Lett 2013; 338:47-56. [DOI: 10.1016/j.canlet.2012.06.013] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2012] [Revised: 06/11/2012] [Accepted: 06/27/2012] [Indexed: 12/19/2022]
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Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats. PLoS One 2013; 8:e71310. [PMID: 23977013 PMCID: PMC3747155 DOI: 10.1371/journal.pone.0071310] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2013] [Accepted: 06/26/2013] [Indexed: 12/14/2022] Open
Abstract
Prior study shows that maternal protein-restricted (LP) 16-wk-old offspring have pronounced reduction of nephron number and arterial hypertension associated with unchanged glomerular filtration rate, besides enhanced glomerular area, which may be related to glomerular hyperfiltration/overflow and which accounts for the glomerular filtration barrier breakdown and early glomerulosclerosis. In the current study, LP rats showed heavy proteinuria associated with podocyte simplification and foot process effacement. TGF-β1 glomerular expression was significantly enhanced in LP. Isolated LP glomeruli show a reduced level of miR-200a, miR-141, miR-429 and ZEB2 mRNA and upregulated collagen 1α1/2 mRNA expression. By western blot analyzes of whole kidney tissue, we found significant reduction of both podocin and nephrin and enhanced expression of mesenchymal protein markers such as desmin, collagen type I and fibronectin. From our present knowledge, these are the first data showing renal miRNA modulation in the protein restriction model of fetal programming. The fetal-programmed adult offspring showed pronounced structural glomerular disorders with an accentuated and advanced stage of fibrosis, which led us to state that the glomerular miR-200 family would be downregulated by TGF-β1 action inducing ZEB 2 expression that may subsequently cause glomeruli epithelial-to-mesenchymal transition.
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46
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Li R, Chung ACK, Dong Y, Yang W, Zhong X, Lan HY. The microRNA miR-433 promotes renal fibrosis by amplifying the TGF-β/Smad3-Azin1 pathway. Kidney Int 2013; 84:1129-44. [PMID: 23868013 DOI: 10.1038/ki.2013.272] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Revised: 05/15/2013] [Accepted: 05/16/2013] [Indexed: 11/09/2022]
Abstract
The TGF-β/Smad3 pathway plays a major role in tissue fibrosis, but the precise mechanisms are not fully understood. Here we identified microRNA miR-433 as an important component of TGF-β/Smad3-driven renal fibrosis. The miR-433 was upregulated following unilateral ureteral obstruction, a model of aggressive renal fibrosis. In vitro, overexpression of miR-433 enhanced TGF-β1-induced fibrosis, whereas knockdown of miR-433 suppressed this response. Furthermore, Smad3, but not Smad2, bound to the miR-433 promoter to induce its expression. Delivery of an miR-433 knockdown plasmid to the kidney by ultrasound microbubble-mediated gene transfer suppressed the induction and progression of fibrosis in the obstruction model. The antizyme inhibitor Azin1, an important regulator of polyamine synthesis, was identified as a target of miR-433. Overexpression of miR-433 suppressed Azin1 expression, while, in turn, Azin1 overexpression suppressed TGF-β signaling and the fibrotic response. Thus, miR-433 is an important component of TGF-β/Smad3-induced renal fibrosis through the induction of a positive feedback loop to amplify TGF-β/Smad3 signaling, and may be a potential therapeutic target in tissue fibrosis.
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Affiliation(s)
- Rong Li
- 1] Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China [2] Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China [3] Department of Nephrology, First People's Hospital of Yunnan Province, Yunnan, China
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Shi Z, Zhang J, Qian X, Han L, Zhang K, Chen L, Liu J, Ren Y, Yang M, Zhang A, Pu P, Kang C. AC1MMYR2, an inhibitor of dicer-mediated biogenesis of Oncomir miR-21, reverses epithelial-mesenchymal transition and suppresses tumor growth and progression. Cancer Res 2013; 73:5519-31. [PMID: 23811941 DOI: 10.1158/0008-5472.can-13-0280] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The extensive involvement of miRNAs in cancer pathobiology has opened avenues for drug development based on oncomir inhibition. Dicer is the core enzyme in miRNA processing that cleaves the terminal loop of precursor microRNAs (pre-miRNAs) to generate mature miRNA duplexes. Using the three-dimensional structure of the Dicer binding site on the pre-miR-21 oncomir, we conducted an in silico high-throughput screen for small molecules that block miR-21 maturation. By this method, we identified a specific small-molecule inhibitor of miR-21, termed AC1MMYR2, which blocked the ability of Dicer to process pre-miR-21 to mature miR-21. AC1MMYR2 upregulated expression of PTEN, PDCD4, and RECK and reversed epithelial-mesenchymal transition via the induction of E-cadherin expression and the downregulation of mesenchymal markers, thereby suppressing proliferation, survival, and invasion in glioblastoma, breast cancer, and gastric cancer cells. As a single agent in vivo, AC1MMYR2 repressed tumor growth, invasiveness, and metastasis, increasing overall host survival with no observable tissue cytotoxicity in orthotopic models. Our results offer a novel, high-throughput method to screen for small-molecule inhibitors of miRNA maturation, presenting AC1MMYR2 as a broadly useful candidate antitumor drug.
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Affiliation(s)
- Zhendong Shi
- Tianjin Medical University General Hospital, 154, Anshan Road, Heping, Tianjin 300052, China
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Said NABM, Simpson KJ, Williams ED. Strategies and challenges for systematically mapping biologically significant molecular pathways regulating carcinoma epithelial-mesenchymal transition. Cells Tissues Organs 2013; 197:424-34. [PMID: 23774256 DOI: 10.1159/000351717] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2013] [Indexed: 11/19/2022] Open
Abstract
Enormous progress has been made towards understanding the role of specific factors in the process of epithelial-mesenchymal transition (EMT); however, the complex underlying pathways and the transient nature of the transition continues to present significant challenges. Targeting tumour cell plasticity underpinning EMT is an attractive strategy to combat metastasis. Global gene expression profiling and high-content analyses are among the strategies employed to identify novel EMT regulators. In this review, we highlight several approaches to systematically interrogate key pathways involved in EMT, with particular emphasis on the features of multiparametric, high-content imaging screening strategies that lend themselves to the systematic discovery of highly significant modulators of tumour cell plasticity.
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Cai ZG, Zhang SM, Zhang H, Zhou YY, Wu HB, Xu XP. Aberrant expression of microRNAs involved in epithelial-mesenchymal transition of HT-29 cell line. Cell Biol Int 2013; 37:669-74. [PMID: 23483606 DOI: 10.1002/cbin.10087] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 02/08/2013] [Indexed: 02/02/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is an essential step for cancer metastasis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate target-mRNAs post-transcriptionally. The expression and function of miRNAs in EMT of HT-29 colonic cells remain elusive. This study looks at expression of miRNAs in EMT and explores the effects of miRNAs on EMT in HT-29 cell line. HT-29 was treated with TGF β to establish an EMT model, in which a collection of miRNAs was dynamically regulated by real-time PCR (qPCR) analysis. Among them, miR-21 and miR-27 were significantly upregulated, while miR-22, miR-26, miR-30, miR-181, miR-200b, miR-200c and miR-214 were markedly downregulated. MiRNA-inhibitors were used to knockdown miRNAs in HT-29 and EMT markers were determined by qPCR to monitor the effects of miRNAs on EMT process. Results showed that miR-22 could not alter the expression of EMT markers, while knockdown of miR-200b could significantly increase that of epithelial markers, N-cadherin, Vimentin, α-Sma and Twist1 and decrease that of mesenchymal marker, E-cadherin. Bioinformatic analysis and Western blot showed that ZEB1 was directly suppressed by miR-200b. In conclusion, miRNAs are dynamically regulated in TGF β-induced EMT of HT-29 and miR-200b was essential for EMT by suppressing the expression of ZEB1 in HT-29.
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Affiliation(s)
- Zhi-Gang Cai
- Department of Cardio-Thoracic Surgery, Number 455 Hospital of The Chinese People's Liberation Army, Shanghai 200052, China.
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Potential role of human-specific genes, human-specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjögren's syndrome. Autoimmun Rev 2013; 12:1046-51. [PMID: 23684698 DOI: 10.1016/j.autrev.2013.04.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Accepted: 04/24/2013] [Indexed: 12/20/2022]
Abstract
The etiology and pathogenesis of human autoimmune diseases remain unknown despite intensive investigations. Although remarkable progress has been accomplished through genome wide association studies in the identification of genetic factors that may predispose to their occurrence or modify their clinical presentation to date no specific gene abnormalities have been conclusively demonstrated to be responsible for these diseases. The completion of the human and chimpanzee genome sequencing has opened up novel opportunities to examine the possible contribution of human specific genes and other regulatory elements unique to the human genome, such as microRNAs and non-coding RNAs, towards the pathogenesis of a variety of human disorders. Thus, it is likely that these human specific genes and non-coding regulatory elements may be involved in the development or the pathogenesis of various disorders that do not occur in non-human primates including certain autoimmune diseases such as Systemic Sclerosis and Primary Sjögren's Syndrome. Here, we discuss recent evidence supporting the notion that human specific genes or human specific microRNA and other non-coding RNA regulatory elements unique to the human genome may participate in the development or in the pathogenesis of Systemic Sclerosis and Primary Sjögren's Syndrome.
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