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1
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Xiong B, Zhang J, Si Y, Fu J. microRNA-875-5p-conjugated gold nanoparticles suppress breast cancer progression through the MTDH/PTEN/AKT signaling pathway. Discov Oncol 2024; 15:804. [PMID: 39692921 DOI: 10.1007/s12672-024-01626-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 11/25/2024] [Indexed: 12/19/2024] Open
Abstract
OBJECTIVE A lack of effective delivery methods has hampered the study of therapeutics targeting miR-875-5p for breast cancer (BC). METHODS The miR-875-5p mimic was conjugated to AuNPs to produce AuNP-miR-875-5p. Then, the effect of AuNP-miR-875-5p on the proliferative, migratory, invasive activities, and apoptosis of BC cells was detected, as well as on tumor growth in animals. The involvement of the MTDH/PTEN/AKT pathway in miR-875-5p-mediated BC progression was identified. RESULTS AuNP-miR-875-5p was delivered to BC cells and hampered cell malignancy. MTDH was targeted by miR-875-5p. MTDH expression was negatively correlated with miR-875-5p expression in BC tissues. The anti-tumor effect of AuNP-miR-875-5p in BC cells was counteracted by MTDH overexpression. AuNP-miR-875-5p enhanced PTEN protein expression, thereby inhibiting AKT activation by targeting MTDH. AuNP-miR-875-5p blocked MCF-7 tumor growth in vivo. CONCLUSION AuNPs can deliver miR-875-5p to BC cells, and AuNP-miR-875-5p has clinical potential for treating unresectable BC.
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Affiliation(s)
- Bin Xiong
- School of Clinical Medicine, Jining Medical University, Jining City, 272067, Shandong Province, China
| | - Junfeng Zhang
- School of Basic Medicine, Jining Medical University, No. 133 Hehua Road, Taibai Lake District, Jining City, 272067, Shandong Province, China
| | - Yanmei Si
- School of Forensic Medicine and Laboratory Medicine, Jining Medical University, Jining City, 272067, Shandong Province, China.
| | - Jia Fu
- School of Basic Medicine, Jining Medical University, No. 133 Hehua Road, Taibai Lake District, Jining City, 272067, Shandong Province, China.
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2
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Ortiz-Melo MT, Campos JE, Sánchez-Guzmán E, Herrera-Aguirre ME, Castro-Muñozledo F. Regulation of corneal epithelial differentiation: miR-141-3p promotes the arrest of cell proliferation and enhances the expression of terminal phenotype. PLoS One 2024; 19:e0315296. [PMID: 39642122 PMCID: PMC11623785 DOI: 10.1371/journal.pone.0315296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 11/22/2024] [Indexed: 12/08/2024] Open
Abstract
In recent years, different laboratories have provided evidence on the role of miRNAs in regulation of corneal epithelial metabolism, permeability and wound healing, as well as their alteration after surgery and in some ocular pathologies. We searched the available databases reporting miRNA expression in the human eye, looking for miRNAs highly expressed in central cornea, which could be crucial for maintenance of the epithelial phenotype. Using the rabbit RCE1(5T5) cell line as a model of corneal epithelial differentiation, we describe the participation of miR-141-3p as a possible negative regulator of the proliferative/migratory phenotype in corneal epithelial cells. The expression of miR-141-3p followed a time course similar to the differentiation-linked KRT3 cytokeratin, being delayed 24-48 hours relative to PAX6 expression; such result suggested that miR-141-3p only regulates the expression of terminal phenotype. Inhibition of miR-141-3p led to increased cell proliferation and motility, and induced the expression of molecular makers characteristic of an Epithelial Mesenchymal Transition (EMT). Comparison between the transcriptional profile of cells in which miR-141-3p was knocked down, and the transcriptomes from proliferative non-differentiated and differentiated stratified epithelia suggest that miR-141-3p is involved in the expression of terminal differentiation mediating the arrest of cell proliferation and inhibiting the EMT in highly motile early differentiating cells.
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Affiliation(s)
- María Teresa Ortiz-Melo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
- Unidad de Investigación en Biomedicina (UBIMED), Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
| | - Jorge E. Campos
- Unidad de Biotecnología y Prototipos (UBIPRO), Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, México
| | - Erika Sánchez-Guzmán
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - María Esther Herrera-Aguirre
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
| | - Federico Castro-Muñozledo
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México City, México
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3
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Jain P, Corbo S, Mohammad K, Sahoo S, Ranganathan S, George JT, Levine H, Taube J, Toneff M, Jolly MK. Epigenetic memory acquired during long-term EMT induction governs the recovery to the epithelial state. J R Soc Interface 2023; 20:20220627. [PMID: 36628532 PMCID: PMC9832289 DOI: 10.1098/rsif.2022.0627] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/16/2022] [Indexed: 01/12/2023] Open
Abstract
Epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) are critical during embryonic development, wound healing and cancer metastasis. While phenotypic changes during short-term EMT induction are reversible, long-term EMT induction has been often associated with irreversibility. Here, we show that phenotypic changes seen in MCF10A cells upon long-term EMT induction by TGFβ need not be irreversible, but have relatively longer time scales of reversibility than those seen in short-term induction. Next, using a phenomenological mathematical model to account for the chromatin-mediated epigenetic silencing of the miR-200 family by ZEB family, we highlight how the epigenetic memory gained during long-term EMT induction can slow the recovery to the epithelial state post-TGFβ withdrawal. Our results suggest that epigenetic modifiers can govern the extent and time scale of EMT reversibility and advise caution against labelling phenotypic changes seen in long-term EMT induction as 'irreversible'.
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Affiliation(s)
- Paras Jain
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Sophia Corbo
- Department of Biology, Widener University, Chester, PA 19013, USA
| | - Kulsoom Mohammad
- Department of Biology, Widener University, Chester, PA 19013, USA
| | - Sarthak Sahoo
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | | | - Jason T. George
- Department of Biomedical Engineering, Texas A&M University, College Station, TX 76798, USA
| | - Herbert Levine
- Center for Theoretical Biological Physics and Departments of Physics and Bioengineering, Northeastern University, Boston, MA 02115, USA
| | - Joseph Taube
- Department of Biology, Baylor University, Waco, TX 76706, USA
| | - Michael Toneff
- Department of Biology, Widener University, Chester, PA 19013, USA
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
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4
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Panda A, Mishra P, Mohanty A, Sundaragiri KS, Singh A, Jha K. Is Epithelial-Mesenchymal Transition a New Roadway in the Pathogenesis of Oral Submucous Fibrosis: A Comprehensive Review. Cureus 2022; 14:e29636. [PMID: 36321045 PMCID: PMC9606484 DOI: 10.7759/cureus.29636] [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] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) collectively refers to a series of episodes that reshape polarized, intact epithelial cells into discrete motile cells that can conquer the extracellular matrix (ECM). It performs a pivotal role in embryonic development, wound healing, and tissue repair. Surprisingly, the exact mechanism can also lead to the onset of malignancy and organ fibrosis contributing to scar formation and loss of function. transforming growth factor signaling, WNT signaling, Notch signaling, Hedgehog signaling, and receptor tyrosine kinase signaling, as well as non-transcriptional changes in response to extracellular cues, such as growth factors and cytokines, hypoxia, and contact with the surrounding ECM, are responsible for the initiation of EMT. Although the pathogenesis of oral submucous fibrosis (OSMF) is multifactorial, compelling evidence suggests that it results from collagen deregulation. EMT is one of the spotlight events in the pathogenesis of OSMF, with myofibroblasts and keratinocytes being the victim cells. EMT is an essential step in both physiological and pathological events. The importance of EMT in the malignant development of OSMF and the inflammatory reaction preceding fibrosis implies a new upcoming area of research. This review aims to focus on the EMT events that function as a double-edged sword between wound healing and fibrosis and further discuss the mechanisms along with the molecular pathways that direct changes in gene expression essential for the same in the oral cavity. As OSMF involves a risk of malignant transformation, understanding the cellular and molecular events will open more avenues for therapeutic breakthroughs targeting EMT.
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5
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Thomaidou AC, Batsaki P, Adamaki M, Goulielmaki M, Baxevanis CN, Zoumpourlis V, Fortis SP. Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs. Int J Mol Sci 2022; 23:ijms23158257. [PMID: 35897831 PMCID: PMC9367895 DOI: 10.3390/ijms23158257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/18/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023] Open
Abstract
Head and neck cancers (HNCs) comprise a heterogeneous group of tumors that extend from the oral cavity to the upper gastrointestinal tract. The principal etiologic factors for oral tumors include tobacco smoking and alcohol consumption, while human papillomavirus (HPV) infections have been accused of a high incidence of pharyngeal tumors. Accordingly, HPV detection has been extensively used to categorize carcinomas of the head and neck. The diverse nature of HNC highlights the necessity for novel, sensitive, and precise biomarkers for the prompt diagnosis of the disease, its successful monitoring, and the timely prognosis of patient clinical outcomes. In this context, the identification of certain microRNAs (miRNAs) and/or the detection of alterations in their expression patterns, in a variety of somatic fluids and tissues, could serve as valuable biomarkers for precision oncology. In the present review, we summarize some of the most frequently studied miRNAs (including miR-21, -375, -99, -34a, -200, -31, -125a/b, -196a/b, -9, -181a, -155, -146a, -23a, -16, -29, and let-7), their role as biomarkers, and their implication in HNC pathogenesis. Moreover, we designate the potential of given miRNAs and miRNA signatures as novel diagnostic and prognostic tools for successful patient stratification. Finally, we discuss the currently ongoing clinical trials that aim to identify the diagnostic, prognostic, or therapeutic utility of miRNAs in HNC.
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Affiliation(s)
- Arsinoe C. Thomaidou
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece; (A.C.T.); (M.A.)
| | - Panagiota Batsaki
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (P.B.); (M.G.); (C.N.B.)
| | - Maria Adamaki
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece; (A.C.T.); (M.A.)
| | - Maria Goulielmaki
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (P.B.); (M.G.); (C.N.B.)
| | - Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (P.B.); (M.G.); (C.N.B.)
| | - Vassilis Zoumpourlis
- Biomedical Applications Unit, Institute of Chemical Biology, National Hellenic Research Foundation (NHRF), 11635 Athens, Greece; (A.C.T.); (M.A.)
- Correspondence: (V.Z.); (S.P.F.); Tel.: +30-210-727-3730 (V.Z.); +30-210-640-9462 (S.P.F.)
| | - Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 11522 Athens, Greece; (P.B.); (M.G.); (C.N.B.)
- Correspondence: (V.Z.); (S.P.F.); Tel.: +30-210-727-3730 (V.Z.); +30-210-640-9462 (S.P.F.)
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6
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Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer. Biomolecules 2022; 12:biom12020284. [PMID: 35204785 PMCID: PMC8961659 DOI: 10.3390/biom12020284] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
Drug resistance in oral cancer is one of the major problems in oral cancer therapy because therapeutic failure directly results in tumor recurrence and eventually in metastasis. Accumulating evidence has demonstrated the involvement of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in processes related to the development of drug resistance. A number of studies have shown that ncRNAs modulate gene expression at the transcriptional or translational level and regulate biological processes, such as epithelial-to-mesenchymal transition, apoptosis, DNA repair and drug efflux, which are tightly associated with drug resistance acquisition in many types of cancer. Interestingly, these ncRNAs are commonly detected in extracellular vesicles (EVs) and are known to be delivered into surrounding cells. This intercellular communication via EVs is currently considered to be important for acquired drug resistance. Here, we review the recent advances in the study of drug resistance in oral cancer by mainly focusing on the function of ncRNAs, since an increasing number of studies have suggested that ncRNAs could be therapeutic targets as well as biomarkers for cancer diagnosis.
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7
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Greco L, Rubbino F, Morelli A, Gaiani F, Grizzi F, de’Angelis GL, Malesci A, Laghi L. Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers. Int J Mol Sci 2021; 22:11469. [PMID: 34768901 PMCID: PMC8584071 DOI: 10.3390/ijms222111469] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Alessandra Morelli
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Fabio Grizzi
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
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8
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Kolanska K, Bendifallah S, Canlorbe G, Mekinian A, Touboul C, Aractingi S, Chabbert-Buffet N, Daraï E. Role of miRNAs in Normal Endometrium and in Endometrial Disorders: Comprehensive Review. J Clin Med 2021; 10:jcm10163457. [PMID: 34441754 PMCID: PMC8396961 DOI: 10.3390/jcm10163457] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/15/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
The molecular responses to hormonal stimuli in the endometrium are modulated at the transcriptional and post-transcriptional stages. Any imbalance in cellular and molecular endometrial homeostasis may lead to gynecological disorders. MicroRNAs (miRNAs) are involved in a wide variety of physiological mechanisms and their expression patterns in the endometrium are currently attracting a lot of interest. miRNA regulation could be hormone dependent. Conversely, miRNAs could regulate the action of sexual hormones. Modifications to miRNA expression in pathological situations could either be a cause or a result of the existing pathology. The complexity of miRNA actions and the diversity of signaling pathways controlled by numerous miRNAs require rigorous analysis and findings need to be interpreted with caution. Alteration of miRNA expression in women with endometriosis has been reported. Thus, a potential diagnostic test supported by a specific miRNA signature could contribute to early diagnosis and a change in the therapeutic paradigm. Similarly, specific miRNA profile signatures are expected for RIF and endometrial cancer, with direct implications for associated therapies for RIF and adjuvant therapies for endometrial cancer. Advances in targeted therapies based on the regulation of miRNA expression are under evaluation.
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Affiliation(s)
- Kamila Kolanska
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
- Correspondence:
| | - Sofiane Bendifallah
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Geoffroy Canlorbe
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Service de Chirurgie et Cancérologie Gynécologique et Mammaire, Hôpitaux Universitaires Pitié-Salpêtrière, Charles-Foix, Sorbonne Université, 47/83, Boulevard de l’Hôpital, 75013 Paris, France
| | - Arsène Mekinian
- Service de Médecine Interne, Hôpital Saint Antoine, AP-HP, 184 Rue du Faubourg Saint Antoine, Sorbonne Université, 75012 Paris, France;
| | - Cyril Touboul
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Selim Aractingi
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Faculté de Médecine Paris 5 Descartes, 12 Rue de l’Ecole de Médecine, 75006 Paris, France
| | - Nathalie Chabbert-Buffet
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
| | - Emile Daraï
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, Hôpital Tenon, AP-HP, Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France; (S.B.); (C.T.); (N.C.-B.); (E.D.)
- INSERM UMRS 938, Sorbonne Université, Site Saint-Antoine, 27 Rue Chaligny, CEDEX 12, 75571 Paris, France; (G.C.); (S.A.)
- Centre Expert En Endométriose (C3E), Groupe de Recherche Clinique en Endométriose (GRC6), Sorbonne Université, 4 Rue de la Chine, 75020 Paris, France
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Vahabi M, Blandino G, Di Agostino S. MicroRNAs in head and neck squamous cell carcinoma: a possible challenge as biomarkers, determinants for the choice of therapy and targets for personalized molecular therapies. Transl Cancer Res 2021; 10:3090-3110. [PMID: 35116619 PMCID: PMC8797920 DOI: 10.21037/tcr-20-2530] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) are referred to a group of heterogeneous cancers that include structures of aerodigestive tract such as oral and nasal cavity, salivary glands, oropharynx, pharynx, larynx, paranasal sinuses, and local lymph nodes. HNSCC is characterized by frequent alterations of several genes such as TP53, PIK3CA, CDKN2A, NOTCH1, and MET as well as copy number increase in EGFR, CCND1, and PIK3CA. These genomic alterations play a role in terms of resistance to chemotherapy, molecular targeted therapy, and prediction of patient outcome. MicroRNAs (miRNAs) are small single-stranded noncoding RNAs which are about 19-25 nucleotides. They are involved in the tumorigenesis of HNSCC including dysregulation of cell survival, proliferation, cellular differentiation, adhesion, and invasion. The discovery of the stable presence of the miRNAs in all human body made them attractive biomarkers for diagnosis and prognosis or as targets for novel therapeutic ways, enabling personalized treatment for HNSCC. In recent times the number of papers concerning the characterization of miRNAs in the HNSCC tumorigenesis has grown a lot. In this review, we discuss the very recent studies on different aspects of miRNA dysregulation with their clinical significance and we apologize for the many past and most recent works that have not been mentioned. We also discuss miRNA-based therapy that are being tested on patients by clinical trials.
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Affiliation(s)
- Mahrou Vahabi
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Giovanni Blandino
- IRCCS Regina Elena National Cancer Institute, Oncogenomic and Epigenetic Laboratory, via Elio Chianesi, Rome, Italy
| | - Silvia Di Agostino
- Department of Health Sciences, University “Magna Graecia” of Catanzaro, viale Europa, Catanzaro, Italy
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10
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Matsuzaki S, Klar M, Matsuzaki S, Roman LD, Sood AK, Matsuo K. Uterine carcinosarcoma: Contemporary clinical summary, molecular updates, and future research opportunity. Gynecol Oncol 2020; 160:586-601. [PMID: 33183764 DOI: 10.1016/j.ygyno.2020.10.043] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/31/2020] [Indexed: 12/16/2022]
Abstract
Uterine carcinosarcoma (UCS) is a biphasic aggressive high-grade endometrial cancer in which the sarcoma element has de-differentiated from the carcinoma element. UCS is considered a rare tumor, but its incidence has gradually increased in recent years (annual percent change from 2000 to 2016 1.7%, 95% confidence interval 1.2-2.2) as has the proportion of UCS among endometrial cancer, exceeding 5% in recent years. UCS typically affects the elderly, but in recent decades patients became younger. Notably, a stage-shift has occurred in recent years with increasing nodal metastasis and decreasing distant metastasis. The concept of sarcoma dominance may be new in UCS, and a sarcomatous element >50% of the uterine tumor is associated with decreased survival. Multimodal treatment is the mainstay of UCS. Lymphadenectomy, chemotherapy, and brachytherapy have increased in the past few decades, but survival outcomes remain dismal: the median survival is less than two years, and the 5-year overall survival rate has not changed in decades (31.9% in 1975 to 33.8% in 2012). Carboplatin/paclitaxel adjuvant chemotherapy improves progression-free survival compared with ifosfamide/paclitaxel, particularly in stages III-IV disease (GOG-261 trial). Twenty-six clinical trials previously examined therapeutic effectiveness in recurrent/metastatic UCS. The median response rate and progression-free survival were 37.5% and 5.9 months, respectively, after first-line therapy, but after later therapies, the outcomes were far worse (5.5% and 1.8 months, respectively). One significant discovery was that epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of sarcomatous dedifferentiation in UCS and that heterologous sarcoma is associated with a higher EMT signature compared with homologous sarcoma. Furthermore, next-generation sequencing has revealed that UCS tumors are serous-like and that common somatic mutations include those in TP53, PIK3CA, FBXW7, PTEN, and ARID1A. This contemporary review highlights recent clinical and molecular updates in UCS. A possible therapeutic target of EMT in UCS is also discussed.
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Affiliation(s)
- Shinya Matsuzaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan
| | - Maximilian Klar
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Satoko Matsuzaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan
| | - Lynda D Roman
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, MD-Anderson Cancer Center, Houston, TX, USA
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
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11
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Leskela S, Pérez-Mies B, Rosa-Rosa JM, Cristobal E, Biscuola M, Palacios-Berraquero ML, Ong S, Matias-Guiu Guia X, Palacios J. Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma. Cancers (Basel) 2019; 11:cancers11070964. [PMID: 31324031 PMCID: PMC6678708 DOI: 10.3390/cancers11070964] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/28/2019] [Accepted: 07/02/2019] [Indexed: 02/08/2023] Open
Abstract
Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response.
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Affiliation(s)
- Susanna Leskela
- Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain.
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Belen Pérez-Mies
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Pathology, Hospital Ramón y Cajal, 28034 Madrid, Spain
| | - Juan Manuel Rosa-Rosa
- Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Eva Cristobal
- Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain
| | - Michele Biscuola
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Pathology, Instituto de Biomedicina de Sevilla (IBiS), 41013 Seville, Spain
- Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
| | | | - SuFey Ong
- NanoString Technologies, Inc, Seattle, WA 98109, USA
| | - Xavier Matias-Guiu Guia
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Department of Pathology, Hospital U Arnau de Vilanova, 25198 Lleida, Spain
- Department of Pathology, Hospital U de Bellvitge, L'Hospitalet de Llobregat, 08907 Barcelona, Spain
- IRBLLEIDA, IDIBELL, University of Lleida, 25003 Lleida, Spain
| | - José Palacios
- Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain.
- CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain.
- Faculty of Medicine, University of Alcalá de Henares, Alcalá de Henares, 28801 Madrid, Spain.
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12
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Franceschi T, Durieux E, Morel AP, de Saint Hilaire P, Ray-Coquard I, Puisieux A, Devouassoux-Shisheboran M. Role of epithelial–mesenchymal transition factors in the histogenesis of uterine carcinomas. Virchows Arch 2019; 475:85-94. [DOI: 10.1007/s00428-019-02532-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/18/2019] [Accepted: 01/21/2019] [Indexed: 02/06/2023]
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13
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Osakabe M, Fukagawa D, Sato C, Sugimoto R, Uesugi N, Ishida K, Itamochi H, Sugiyama T, Sugai T. Immunohistochemical analysis of the epithelial to mesenchymal transition in uterine carcinosarcoma. Int J Gynecol Cancer 2019; 29:277-281. [PMID: 30636710 DOI: 10.1136/ijgc-2018-000038] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 08/25/2018] [Accepted: 08/31/2018] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Uterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS. METHODS UCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells. RESULTS The expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected. CONCLUSION These results suggest that the EMT plays an essential role in the pathogenesis of UCS.
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Affiliation(s)
- Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Daisuke Fukagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Chie Sato
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiroaki Itamochi
- Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Toru Sugiyama
- Department of Obstetrics and Gynecology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
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14
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Maleki S, Cottrill KA, Poujade FA, Bhattachariya A, Bergman O, Gådin JR, Simon N, Lundströmer K, Franco-Cereceda A, Björck HM, Chan SY, Eriksson P. The mir-200 family regulates key pathogenic events in ascending aortas of individuals with bicuspid aortic valves. J Intern Med 2019; 285:102-114. [PMID: 30280445 PMCID: PMC6488227 DOI: 10.1111/joim.12833] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND An individual with a bicuspid aortic valve (BAV) runs a substantially higher risk of developing aneurysm in the ascending aorta compared to the normal population with tricuspid aortic valves (TAV). Aneurysm formation in patients with BAV and TAV is known to be distinct at the molecular level but the underlying mechanisms are undefined. Here, we investigated the still incompletely described role of microRNAs (miRNAs), important post-transcriptional regulators of gene expression, in such aortic disease of patients with BAV as compared with TAV. METHODS AND RESULTS Using a system biology approach, based on data obtained from proteomic analysis of non-dilated aortas from BAV and TAV patients, we constructed a gene-interaction network of regulatory microRNAs associated with the observed differential protein signature. The miR-200 family was the highest ranked miRNA, hence potentially having the strongest effect on the signalling network associated with BAV. Further, qRT-PCR and ChIP analyses showed lower expression of miR-200c, higher expression of miR-200 target genes, ZEB1/ZEB2 transcription factors, and higher chromatin occupancy of the miR-200c promoter by ZEB1/ZEB2 in BAV patients, indicating a miR-200c/ZEBs negative feedback loop and induction of endothelial/epithelial mesenchymal transition (EndMT/EMT). CONCLUSION We propose that a miR-200-dependent process of EndMT/EMT is a plausible biological mechanism rendering the BAV ascending aorta more prone to aneurysm development. Although initially supported by a miR-200c/ZEB feedback loop, this process is most probably advanced by cooperation of other miRNAs.
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Affiliation(s)
- S Maleki
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - K A Cottrill
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - F-A Poujade
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - A Bhattachariya
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - O Bergman
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - J R Gådin
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - N Simon
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - K Lundströmer
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - A Franco-Cereceda
- Karolinska University Hospital, Solna, Sweden.,Department of Molecular Medicine and Surgery, Cardiothoracic Surgery Unit, Karolinska Institutet, Stockholm, Sweden
| | - H M Björck
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
| | - S Y Chan
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - P Eriksson
- Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Sweden
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15
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Chen L, He X, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y. Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells. Sci Rep 2018; 8:15543. [PMID: 30341388 PMCID: PMC6195555 DOI: 10.1038/s41598-018-33913-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 10/08/2018] [Indexed: 12/11/2022] Open
Abstract
Dysregulation of microRNAs (miRNAs) contributes to epithelial-mesenchymal transition (EMT) of cancer, but the pathological roles of miRNAs in airway EMT of lung diseases remains largely unknown. We performed sequencing and real-time PCR analysis of the miRNA expression profile of human airway epithelial cells undergoing EMT, and revealed miR-133a to be one of the most common up-regulated miRNAs. MiR-133a was previously reported to be persistently up-regulated in airway epithelial cells of smokers. We found that mice exposed to cigarette smoke (CS) showed airway hyper-responsiveness, a typical symptom occurring in CS-related lung diseases, up-regulation of miR-133a and EMT marker protein N-cadherin in airway epithelium. Importantly, miR-133a overexpression induces airway epithelial cells to undergo spontaneous EMT via down-regulation of grainyhead-like 2 (GRHL2), an epithelial specific transcriptional factor. Loss of GRHL2 causes down-regulation of epithelial splicing regulatory protein 1 (ESRP1), a central coordinator of alternative splicing processes that are critical in the regulation of EMT. Down-regulation of ESRP1 induces isoform switching of adherens junction-associated protein p120-catenin, and leads to the loss of E-cadherin. Our study is the first to demonstrate that up-regulated miR-133a orchestrates airway EMT via alternative splicing processes, which points to novel therapeutic possibilities for the treatment of CS-related lung disease.
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Affiliation(s)
- Linjie Chen
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Xiaobai He
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Yan Xie
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Yapei Huang
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Dennis W Wolff
- Kansas City University of Medicine and Biosciences-Joplin, Joplin, MO, USA
| | - Peter W Abel
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Yaping Tu
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA.
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16
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Mehta SJ, Lewis A, Nijhuis A, Jeffery R, Biancheri P, Di Sabatino A, Feakins R, Silver A, Lindsay JO. Epithelial down-regulation of the miR-200 family in fibrostenosing Crohn's disease is associated with features of epithelial to mesenchymal transition. J Cell Mol Med 2018; 22:5617-5628. [PMID: 30188001 PMCID: PMC6201355 DOI: 10.1111/jcmm.13836] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Revised: 06/11/2018] [Accepted: 07/12/2018] [Indexed: 12/27/2022] Open
Abstract
Intestinal mesenchymal cells deposit extracellular matrix in fibrotic Crohn's disease (CD). The contribution of epithelial to mesenchymal transition (EMT) to the mesenchymal cell pool in CD fibrosis remains obscure. The miR‐200 family regulates fibrosis‐related EMT in organs other than the gut. E‐cadherin, cytokeratin‐18 and vimentin expression was assessed using immunohistochemistry on paired strictured (SCD) and non‐strictured (NSCD) ileal CD resections and correlated with fibrosis grade. MiR‐200 expression was measured in paired SCD and NSCD tissue compartments using laser capture microdissection and RT‐qPCR. Serum miR‐200 expression was also measured in healthy controls and CD patients with stricturing and non‐stricturing phenotypes. Extra‐epithelial cytokeratin‐18 staining and vimentin‐positive epithelial staining were significantly greater in SCD samples (P = 0.04 and P = 0.03, respectively). Cytokeratin‐18 staining correlated positively with subserosal fibrosis (P < 0.001). Four miR‐200 family members were down‐regulated in fresh SCD samples (miR‐141, P = 0.002; miR‐200a, P = 0.002; miR‐200c, P = 0.001; miR‐429; P = 0.004); miR‐200 down‐regulation in SCD tissue was localised to the epithelium (P = 0.001‐0.015). The miR‐200 target ZEB1 was up‐regulated in SCD samples (P = 0.035). No difference in serum expression between patient groups was observed. Together, these observations suggest the presence of EMT in CD strictures and implicate the miR‐200 family as regulators. Functional studies to prove this relationship are now warranted.
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Affiliation(s)
- Shameer J Mehta
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| | - Amy Lewis
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| | - Anke Nijhuis
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| | - Rosemary Jeffery
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| | - Paolo Biancheri
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK.,Norwich Medical School, University of East Anglia, Norwich, UK
| | - Antonio Di Sabatino
- Department of Internal Medicine, San Matteo Hospital, University of Pavia, Pavia, Italy
| | - Roger Feakins
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK.,Department of Histopathology, The Royal London Hospital, London, UK
| | - Andrew Silver
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
| | - James Oliver Lindsay
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK.,Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, UK
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17
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Xie L, Yao Z, Zhang Y, Li D, Hu F, Liao Y, Zhou L, Zhou Y, Huang Z, He Z, Han L, Yang Y, Yang Z. Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis. Cell Death Dis 2018; 9:772. [PMID: 29991755 PMCID: PMC6039476 DOI: 10.1038/s41419-018-0813-5] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 05/23/2018] [Accepted: 05/25/2018] [Indexed: 02/06/2023]
Abstract
Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n = 3), pulmonary metastatic OS (n = 3), and normal controls (n = 3) was conducted and differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs), and mRNAs (DEmRNAs) between primary OS and normal controls as well as pulmonary metastatic and primary OS were identified. A total of 65 DEmiRNAs, 233 DElncRNAs, and 1405 DEmRNAs were obtained between primary OS and normal controls; 48 DEmiRNAs, 50 DElncRNAs, and 307 DEmRNAs were obtained between pulmonary metastatic and primary OS. Then, the target DEmRNAs and DElncRNAs regulated by the same DEmiRNAs were searched and the OS tumorigenesis-related and OS pulmonary metastasis-related competing endogenous RNA (ceRNA) networks were constructed, respectively. Based on these ceRNA networks and Venn diagram analysis, we obtained 3 DEmiRNAs, 15 DElncRNAs, and 100 DEmRNAs, and eight target pairs including miR-223-5p/(CLSTN2, AC009951.1, LINC01705, AC090673.1), miR-378b/(ALX4, IGSF3, SULF1), and miR-323b-3p/TGFBR3 were involved in both tumorigenesis and pulmonary metastasis of OS. The TGF-β superfamily co-receptor TGFBR3, which is regulated by miR-323b-3p, acts as a tumor suppressor in OS tumorigenesis and acts as a tumor promoter in pulmonary metastatic OS via activation of the epithelial-mesenchymal transition (EMT) program.In conclusion, the OS transcriptome (miRNA, lncRNA, and mRNA) is dynamically regulated. These analyses might provide new clues to uncover the molecular mechanisms and signaling networks that contribute to OS progression, toward patient-tailored and novel-targeted treatments.
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MESH Headings
- Adolescent
- Adult
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinogenesis/genetics
- Carcinogenesis/metabolism
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Computational Biology
- Female
- Gene Expression Regulation, Neoplastic/genetics
- Gene Expression Regulation, Neoplastic/physiology
- High-Throughput Nucleotide Sequencing/methods
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Male
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Osteosarcoma/genetics
- Osteosarcoma/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Sequence Analysis, RNA/methods
- Young Adult
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Affiliation(s)
- Lin Xie
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zhihong Yao
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Ya Zhang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Dongqi Li
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Fengdi Hu
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yedan Liao
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Ling Zhou
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yonghong Zhou
- Department of Medical Oncology, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zeyong Huang
- Medical School, Kunming University of Science and Technology, Kunming, 650504, Yunnan, China
| | - Zewei He
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Lei Han
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Yihao Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China
| | - Zuozhang Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province), Kunming, 650118, Yunnan, China.
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18
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Sahabi K, Selvarajah GT, Abdullah R, Cheah YK, Tan GC. Comparative aspects of microRNA expression in canine and human cancers. J Vet Sci 2018; 19:162-171. [PMID: 28927253 PMCID: PMC5879064 DOI: 10.4142/jvs.2018.19.2.162] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 05/19/2017] [Accepted: 07/14/2017] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) have important roles in all biological pathways in multicellular organisms. Over 1,400 human miRNAs have been identified, and many are conserved among vertebrates and invertebrates. Regulation of miRNA is the most common mode of post-transcriptional gene regulation. The miRNAs that are involved in the initiation and progression of cancers are termed oncomiRs and several of them have been identified in canine and human cancers. Similarly, several miRNAs have been reported to be down-regulated in cancers of the two species. In this review, current information on the expression and roles of miRNAs in oncogenesis and progression of human and canine cancers, as well the roles miRNAs have in cancer stem cell biology, are highlighted. The potential for the use of miRNAs as therapeutic targets in personalized cancer therapy in domestic dogs and their possible application in human cancer counterparts are also discussed.
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Affiliation(s)
- Kabiru Sahabi
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Gayathri T Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Rasedee Abdullah
- Department of Veterinary Laboratory Diagnostics, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Sciences, Faculty of Medicine and Biomedical Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
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19
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EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells. Oncotarget 2018; 7:84453-84467. [PMID: 27563817 PMCID: PMC5356672 DOI: 10.18632/oncotarget.11497] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/09/2016] [Indexed: 02/07/2023] Open
Abstract
Cancer cells acquire essential characteristics for metastatic dissemination through the process of epithelial-to-mesenchymal transition (EMT), which is regulated by gene expression and chromatin remodeling changes. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) to repress gene transcription. Here we report the functional roles of EZH2-catalyzed H3K27me3 during EMT in ovarian cancer (OC) cells. TGF-β-induced EMT in SKOV3 OC cells was associated with decreased levels of EZH2 and H3K27me3 (P<0.05). These effects were delayed (~72 h relative to EMT initiation) and coincided with increased (>15-fold) expression of EMT-associated transcription factors ZEB2 and SNAI2. EZH2 knockdown (using siRNA) or enzymatic inhibition (by GSK126) induced EMT-like changes in OC cells. The EMT regulator ZEB2 was upregulated in cells treated with either approach. Furthermore, TGF-β enhanced expression of ZEB2 in EZH2 siRNA- or GSK126-treated cells (P<0.01), suggesting that H3K27me3 plays a role in TGF-β-stimulated ZEB2 induction. Chromatin immunoprecipitation assays confirmed that TGF-β treatment decreased binding of EZH2 and H3K27me3 to the ZEB2 promoter (P<0.05). In all, these results demonstrate that EZH2, by repressing ZEB2, is required for the maintenance of an epithelial phenotype in OC cells.
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20
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Pourteimoor V, Paryan M, Mohammadi‐Yeganeh S. microRNA as a systemic intervention in the specific breast cancer subtypes with C‐MYC impacts; introducing subtype‐based appraisal tool. J Cell Physiol 2018; 233:5655-5669. [DOI: 10.1002/jcp.26399] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/11/2017] [Indexed: 12/18/2022]
Affiliation(s)
| | - Mahdi Paryan
- Department of Research and Development, Production and Research ComplexPasteur Institute of IranTehranIran
| | - Samira Mohammadi‐Yeganeh
- Cellular and Molecular Biology Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Biotechnology, School of Advanced Technologies in MedicineShahid Beheshti University of Medical SciencesTehranIran
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21
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Hu Y, Guo X, Wang J, Liu Y, Gao H, Fan H, Nong X, Yang X, Liu M, Li S, Tang H. A novel microRNA identified in hepatocellular carcinomas is responsive to LEF1 and facilitates proliferation and epithelial-mesenchymal transition via targeting of NFIX. Oncogenesis 2018; 7:22. [PMID: 29472529 PMCID: PMC5833431 DOI: 10.1038/s41389-017-0010-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 10/27/2017] [Accepted: 11/08/2017] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers. It has been demonstrated that various cellular microRNAs (miRNAs) play an important role in HCC development. Here, we analyzed the miRNA profile in HCC tissues by Solexa sequencing, and we identified a novel microRNA, miR-HCC1, which is upregulated in HCC tissues. Further experiments showed that miR-HCC1 promoted HCC cell proliferation in vivo and in vitro, and migration and invasion resulting from the epithelial-mesenchymal transition (EMT) process. Nuclear factor I/X (NFIX), which inhibited cell proliferation, migration and invasion in HCC cells, was identified as a direct and functional target of miR-HCC1. Furthermore, lymphoid enhancer binding factor 1 (LEF1), a transcription factor, was shown to bind the promoter of miR-HCC1 and activate its expression. Collectively, these results indicate that LEF1-upregulated miR-HCC1 functions as an oncogene through the negative regulation of NFIX expression, which links the LEF1/miR-HCC1/NFIX axis to contribute to cell proliferation, migration and invasion of HCC cells and could provide novel insights into miRNA function and hepatocarcinogenesis and potential biomarkers for HCC.
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Affiliation(s)
- Yaqi Hu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Xu Guo
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Jinxia Wang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Yankun Liu
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.,The Cancer Institute, Tangshan People's Hospital, 063001, Tangshan, China
| | - Huijie Gao
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | - Hongxia Fan
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China
| | | | | | | | - Shengping Li
- Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, 510060, Guangzhou, China
| | - Hua Tang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
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22
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Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT. Oncotarget 2018; 7:40252-40265. [PMID: 27259233 PMCID: PMC5130006 DOI: 10.18632/oncotarget.9730] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 05/10/2016] [Indexed: 12/13/2022] Open
Abstract
The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.
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23
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Zhang T, Cai X, Li Q, Xue P, Chen Z, Dong X, Xue Y. Hsa-miR-875-5p exerts tumor suppressor function through down-regulation of EGFR in colorectal carcinoma (CRC). Oncotarget 2018; 7:42225-42240. [PMID: 27302926 PMCID: PMC5173130 DOI: 10.18632/oncotarget.9944] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 04/09/2016] [Indexed: 12/29/2022] Open
Abstract
Hsa-miRNA-875-5p (miR-875-5p) has recently been discovered to have anticancer efficacy in different organs. However, the role of miR-875-5p on colorectal carcinoma (CRC) is still ambiguous. In this study, we investigated the role of miR-875-5p on the development of CRC. The results indicated that miR-875-5p was significantly down-regulated in primary tumor tissues and very low levels were found in CRC cell lines. Ectopic expression of miR-875-5p in CRC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-875-5p induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-875-5p inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene EGFR was revealed to be a putative target of miR-875-5p, which was inversely correlated with miR-875-5p expression in CRC. Taken together, our results demonstrated that miR-875-5p played a pivotal role on CRC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic EGFR.
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Affiliation(s)
- Tiening Zhang
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Xun Cai
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Qi Li
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Peng Xue
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Zhixiao Chen
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Xiao Dong
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
| | - Ying Xue
- Oncology Center, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, P. R. China
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24
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Wu LY, Ma XP, Shi Y, Bao CH, Jin XM, Lu Y, Zhao JM, Zhou CL, Chen D, Liu HR. Alterations in microRNA expression profiles in inflamed and noninflamed ascending colon mucosae of patients with active Crohn's disease. J Gastroenterol Hepatol 2017; 32:1706-1715. [PMID: 28261881 DOI: 10.1111/jgh.13778] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/30/2017] [Accepted: 02/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIM The microRNA (miRNA) expression profiles of the terminal ileum, sigmoid colon, and rectal mucosa of adult patients with active Crohn's disease (CD) have been previously reported. The purpose of this study was to identify dysregulated miRNAs in the mucosa of the ascending colon. METHODS Biopsy tissue samples were taken from the mucosae of inflammatory (iCD) or noninflammatory (niCD) areas of the ascending colons of adult patients with active CD. miRNA and mRNA expression profiles were detected using microarray analyses. miRNAs and messenger RNAs (mRNAs) demonstrating significant differences were validated via quantitative real-time polymerase chain reaction. Luciferase reporter genes were used to measure two miRNAs inhibition of potential target genes in human 293T cells in vitro. RESULTS Compared with the healthy control group, the ascending colon miRNA expression profiles revealed that 43 miRNAs were significantly upregulated and 35 were downregulated in the iCD group. The mRNA expression profiles indicated that 3370 transcripts were significantly differentially expressed in the ascending colon, with 2169 upregulated and 1201 downregulated mRNAs in the iCD group, and only 20 miRNAs demonstrated significant differential expression in the niCD group. In contrast, nearly 100 miRNAs significantly varied between the iCD and niCD groups. Finally, luciferase reporter gene assays showed that hsa-miR-16-1 directly regulated the human C10orf54 gene and that they were negatively correlated. CONCLUSIONS Our results indicated that the differentially expressed miRNAs and mRNAs were related to immune inflammation and intestinal flora. The data provide preliminary evidence that the occurrence of CD involves the inhibition of C10orf54 expression by hsa-miR-16-1.
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Affiliation(s)
- Lu Yi Wu
- Qigong Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao Peng Ma
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yin Shi
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chun Hui Bao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao Ming Jin
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yuan Lu
- Department of Mechanics and Engineering Science, Fudan University, Shanghai, China
| | - Ji Meng Zhao
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ci Li Zhou
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dai Chen
- Novel Bioinformatics Company, Ltd., Shanghai, China
| | - Hui Rong Liu
- Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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25
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Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity. Trends Genet 2017; 33:943-959. [PMID: 28919019 DOI: 10.1016/j.tig.2017.08.004] [Citation(s) in RCA: 179] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 06/20/2017] [Accepted: 08/10/2017] [Indexed: 12/11/2022]
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process in which epithelial cells lose their junctions and polarity to gain a motile mesenchymal phenotype. EMT is essential during embryogenesis and adult physiological processes like wound healing, but is aberrantly activated in pathological conditions like fibrosis and cancer. A series of transcription factors (EMT-inducing transcription factor; EMT-TF) regulate the induction of EMT by repressing the transcription of epithelial genes while activating mesenchymal genes through mechanisms still debated. The nuclear interaction of EMT-TFs with larger protein complexes involved in epigenetic genome modulation has attracted recent attention to explain functions of EMT-TFs during reprogramming and cellular differentiation. In this review, we discuss recent advances in understanding the interplay between epigenetic regulators and EMT transcription factors and how these findings could be used to establish new therapeutic approaches to tackle EMT-related diseases.
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Affiliation(s)
- Nicolas Skrypek
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; These authors contributed equally
| | - Steven Goossens
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Centre for Medical Genetics, Ghent University and University Hospital, Ghent, Belgium; These authors contributed equally
| | - Eva De Smedt
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Niels Vandamme
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Inflammation Research Center (IRC), VIB, Ghent, Belgium
| | - Geert Berx
- Molecular and Cellular Oncology Laboratory, Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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26
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Epithelial-to-Mesenchymal Transition and MicroRNAs in Lung Cancer. Cancers (Basel) 2017; 9:cancers9080101. [PMID: 28771186 PMCID: PMC5575604 DOI: 10.3390/cancers9080101] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 07/17/2017] [Accepted: 07/26/2017] [Indexed: 12/13/2022] Open
Abstract
Despite major advances, non-small cell lung cancer (NSCLC) remains the major cause of cancer-related death in developed countries. Metastasis and drug resistance are the main factors contributing to relapse and death. Epithelial-to-mesenchymal transition (EMT) is a complex molecular and cellular process involved in tissue remodelling that was extensively studied as an actor of tumour progression, metastasis and drug resistance in many cancer types and in lung cancers. Here we described with an emphasis on NSCLC how the changes in signalling pathways, transcription factors expression or microRNAs that occur in cancer promote EMT. Understanding the biology of EMT will help to define reversing process and treatment strategies. We will see that this complex mechanism is related to inflammation, cell mobility and stem cell features and that it is a dynamic process. The existence of intermediate phenotypes and tumour heterogeneity may be debated in the literature concerning EMT markers, EMT signatures and clinical consequences in NSCLC. However, given the role of EMT in metastasis and in drug resistance the development of EMT inhibitors is an interesting approach to counteract tumour progression and drug resistance. This review describes EMT involvement in cancer with an emphasis on NSCLC and microRNA regulation.
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27
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Zidar N, Boštjančič E, Malgaj M, Gale N, Dovšak T, Didanovič V. The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity. Virchows Arch 2017; 472:237-245. [PMID: 28699108 DOI: 10.1007/s00428-017-2192-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 06/23/2017] [Accepted: 06/28/2017] [Indexed: 01/06/2023]
Abstract
Epithelial-mesenchymal transition (EMT) has emerged as a possible mechanism of cancer metastasizing, but strong evidence for EMT involvement in human cancer is lacking. Our aim was to compare oral spindle cell carcinoma (SpCC) as an example of EMT with oral conventional squamous cell carcinoma (SCC) with and without nodal metastases to test the hypothesis that EMT contributes to metastasizing in oral SCC. Thirty cases of oral SCC with and without nodal metastasis and 15 cases of SpCC were included. Epithelial (cytokeratin, E-cadherin), mesenchymal (vimentin, N-cadherin), and stem cell markers (ALDH-1, CD44, Nanog, Sox-2) and transcription repressors (Snail, Slug, Twist) were analyzed immunohistochemically. We also analyzed the expression of microRNAs miR-141, miR-200 family, miR-205, and miR-429. SpCC exhibited loss of epithelial markers and expression of mesenchymal markers or coexpression of both up-regulation of transcription repressors and down-regulation of the investigated microRNAs. SCC showed only occasional focal expression of mesenchymal markers at the invasive front. No other differences were observed between SCC with and without nodal metastases except for a higher expression of ALDH-1 in SCC with metastases. Our results suggest that SpCC is an example of true EMT but do not support the hypothesis that EMT is involved in metastasizing of conventional SCC. Regarding oral SCC progression and metastasizing, we have been facing a shift from the initial enthusiasm for the EMT concept towards a more critical approach with "EMT-like" and "partial EMT" concepts. The real question, though, is, is there no EMT at all?
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Affiliation(s)
- Nina Zidar
- University of Ljubljana, Institute of Pathology, Faculty of Medicine, Korytkova 2, 1000, Ljubljana, Slovenia.
| | - Emanuela Boštjančič
- University of Ljubljana, Institute of Pathology, Faculty of Medicine, Korytkova 2, 1000, Ljubljana, Slovenia
| | - Marija Malgaj
- Department of Nephrology, University Clinical Center, Zaloška 7, Ljubljana, Slovenia
| | - Nina Gale
- University of Ljubljana, Institute of Pathology, Faculty of Medicine, Korytkova 2, 1000, Ljubljana, Slovenia
| | - Tadej Dovšak
- Department of Maxillofacial and Oral Surgery, University Clinical Center, Zaloška 7, Ljubljana, Slovenia
| | - Vojko Didanovič
- Department of Maxillofacial and Oral Surgery, University Clinical Center, Zaloška 7, Ljubljana, Slovenia
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28
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Santamaria PG, Moreno‐Bueno G, Portillo F, Cano A. EMT: Present and future in clinical oncology. Mol Oncol 2017; 11:718-738. [PMID: 28590039 PMCID: PMC5496494 DOI: 10.1002/1878-0261.12091] [Citation(s) in RCA: 177] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/31/2017] [Accepted: 06/02/2017] [Indexed: 12/12/2022] Open
Abstract
Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting.
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Affiliation(s)
- Patricia G. Santamaria
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Gema Moreno‐Bueno
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
- Fundación MD Anderson InternationalMadridSpain
| | - Francisco Portillo
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
| | - Amparo Cano
- Departamento de BioquímicaInstituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM)Universidad Autónoma de Madrid (UAM)IdiPAZCIBERONCMadridSpain
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29
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miR-200c-driven Mesenchymal-To-Epithelial Transition is a Therapeutic Target in Uterine Carcinosarcomas. Sci Rep 2017; 7:3614. [PMID: 28620240 PMCID: PMC5472620 DOI: 10.1038/s41598-017-03972-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 05/09/2017] [Indexed: 12/12/2022] Open
Abstract
Uterine carcinosarcomas (UCSs) are highly aggressive malignancies associated with poor prognoses and limited treatment options. These tumors are hypothesized to develop from the endometrial adenocarcinoma (EAC) through epithelial-mesenchymal transition (EMT). We test this long-standing hypothesis by depleting miR-200, a family of microRNAs critical for EMT, in EAC cell lines. Our data suggest that UCSs do not develop from EACs via EMT. Clinically more relevant, we show that miR-200 expression in UCS cells induces a robust mesenchymal-epithelial transition (MET). Using in vitro and murine xenograft models, we demonstrate decreased growth and aggressiveness of miR-200-overexpressing UCS cell lines. Whole transcriptome analysis confirmed changes consistent with an MET and also revealed changes in angiogenic genes expression. Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities. These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS.
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30
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Integrated genomic and molecular characterization of cervical cancer. Nature 2017; 543:378-384. [PMID: 28112728 PMCID: PMC5354998 DOI: 10.1038/nature21386] [Citation(s) in RCA: 1107] [Impact Index Per Article: 138.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 01/14/2017] [Indexed: 02/06/2023]
Abstract
Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Reported here is an extensive molecular characterization of 228 primary cervical cancers, the largest comprehensive genomic study of cervical cancer to date. We observed striking APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered novel amplifications in immune targets CD274/PD-L1 and PDCD1LG2/PD-L2, and the BCAR4 lncRNA that has been associated with response to lapatinib. HPV integration was observed in all HPV18-related cases and 76% of HPV16-related cases, and was associated with structural aberrations and increased target gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumors with high frequencies of KRAS, ARID1A, and PTEN mutations. Integrative clustering of 178 samples identified Keratin-low Squamous, Keratin-high Squamous, and Adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers.
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Whole-Genome DNA Methylation Profiling Identifies Epigenetic Signatures of Uterine Carcinosarcoma. Neoplasia 2017; 19:100-111. [PMID: 28088687 PMCID: PMC5237802 DOI: 10.1016/j.neo.2016.12.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/07/2016] [Accepted: 12/12/2016] [Indexed: 02/08/2023] Open
Abstract
Uterine carcinosarcoma (UCS) is a form of endometrial cancer simultaneously exhibiting carcinomatous and sarcomatous elements, but the underlying molecular and epigenetic basis of this disease is poorly understood. We generated complete DNA methylomes for both the carcinomatous and the sarcomatous components of three UCS samples separated by laser capture microdissection and compared DNA methylomes of UCS with those of normal endometrium as well as methylomes derived from endometrioid carcinoma, serous endometrial carcinoma, and endometrial stromal sarcoma. We identified epigenetic lesions specific to carcinosarcoma and specific to its two components. Hallmarks of DNA methylation abnormalities in UCS included global hypomethylation, especially in repetitive elements, and hypermethylation of tumor suppressor gene promoters. Among these, aberrant DNA methylation of MIR200 genes is a key feature of UCS. The carcinoma component of UCS was characterized by hypermethylation of promoters of EMILIN1, NEFM, and CLEC14A, genes that are associated with tumor vascularization. In contrast, DNA methylation changes of PKP3, FAM83F, and TCP11 were more characteristic of the sarcoma components. Our findings highlight the epigenetic signatures that distinguish the two components of UCS, providing a valuable resource for investigation of this disease.
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Entangling Relation of Micro RNA-let7, miRNA-200 and miRNA-125 with Various Cancers. Pathol Oncol Res 2017; 23:707-715. [DOI: 10.1007/s12253-016-0184-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/29/2016] [Indexed: 12/18/2022]
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Sun C, Huang C, Li S, Yang C, Xi Y, Wang L, Zhang F, Fu Y, Li D. Hsa-miR-326 targets CCND1 and inhibits non-small cell lung cancer development. Oncotarget 2016; 7:8341-59. [PMID: 26840018 PMCID: PMC4884997 DOI: 10.18632/oncotarget.7071] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 01/13/2016] [Indexed: 12/12/2022] Open
Abstract
Hsa-miRNA-326 (miR-326) has recently been discovered having anticancer efficacy in different organs. However, the role of miR-326 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-326 on the development of NSCLC. The results indicated that miR-326 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-326 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-326 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-326 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-326, which was inversely correlated with miR-326 expression in NSCLC. Taken together, our results demonstrated that miR-326 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1.
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Affiliation(s)
- Chengcao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Chuanfeng Huang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China.,Department of Pharmacology, Basic Medical School, Nanyang Medical College, 473003 Nanyang, P.R.China
| | - Shujun Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China.,Wuhan Hospital for The Prevention and Treatment of Occupational Diseases, 430071 Wuhan, P.R.China
| | - Cuili Yang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Yongyong Xi
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Liang Wang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Feng Zhang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
| | - Yunfeng Fu
- The Third Xiang-Ya Hospital, Central South University, 410013 Changsha, P.R.China
| | - Dejia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P.R.China
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34
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The Novel miR-9600 Suppresses Tumor Progression and Promotes Paclitaxel Sensitivity in Non-small-cell Lung Cancer Through Altering STAT3 Expression. MOLECULAR THERAPY. NUCLEIC ACIDS 2016; 5:e387. [PMID: 27845771 PMCID: PMC5155328 DOI: 10.1038/mtna.2016.96] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/26/2016] [Indexed: 12/23/2022]
Abstract
MicroRNAs have been identified to be involved in center stage of cancer biology. They accommodate cell proliferation and migration by negatively regulate gene expression either by hampering the translation of targeted mRNAs or by promoting their degradation. We characterized and identified the novel miR-9600 and its target in human non-small-cell lung cancer (NSCLC). Our results demonstrated that the miR-9600 were downregulated in NSCLC tissues and cells. It is confirmed that signal transducer and activator of transcription 3 (STAT3), a putative target gene, is directly inhibited by miR-9600. The miR-9600 markedly suppressed the protein expression of STAT3, but with no significant influence in corresponding mRNA levels, and the direct combination of miR-9600 and STAT3 was confirmed by a luciferase reporter assay. miR-9600 inhibited cell growth, hampered expression of cell cycle-related proteins and inhibited cell migration and invasion in human NSCLC cell lines. Further, miR-9600 significantly suppressed tumor growth in nude mice. Similarly, miR-9600 impeded tumorigenesis and metastasis through directly targeting STAT3. Furthermore, we identified that miR-9600 augmented paclitaxel and cisplatin sensitivity by downregulating STAT3 and promoting chemotherapy-induced apoptosis. These data demonstrate that miR-9600 might be a useful and novel therapeutic target for NSCLC.
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35
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Damiano V, Brisotto G, Borgna S, di Gennaro A, Armellin M, Perin T, Guardascione M, Maestro R, Santarosa M. Epigenetic silencing of miR-200c in breast cancer is associated with aggressiveness and is modulated by ZEB1. Genes Chromosomes Cancer 2016; 56:147-158. [PMID: 27717206 DOI: 10.1002/gcc.22422] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 09/19/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023] Open
Abstract
Loss of expression of miR-200 family members has been implicated in cellular plasticity, a phenomenon that accounts for epithelial-to-mesenchymal transition (EMT) and stem-like features of many carcinomas and is considered a major cause of tumor aggressiveness and drug resistance. Nevertheless, the mechanisms of miR-200 downregulation in breast cancer are still largely unknown. Here we show that miR-200c expression inversely correlates with miR-200c/miR-141 locus methylation in triple-negative breast tumors (TNBC). Importantly, low levels of miR-200c expression and high levels of miR-200c/miR-141 locus methylation associated with lymph node metastasis. Moreover, miR-200c/miR-141 locus methylation was significantly related to high expression of ZEB1 in two independent TNBC series. Silencing of ZEB1 in vitro reduced miR-200c/miR-141 DNA methylation and, concurrently, decreased histone H3K9 trimethylation. This chromatin modifications were paralleled by an increase in the expression of both miR-200c and E-cadherin. Similar effects were achieved by treatment with a demethylating agent. Our data suggest that gene methylation is an important element in the regulation of the miR-200c/ZEB1 axis and that chromatin remodeling of the miR-200c/miR-141 locus is affected by ZEB1 and, thus, contributes to ZEB1-induced cellular plasticity. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Valentina Damiano
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Giulia Brisotto
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Silvia Borgna
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Alessandra di Gennaro
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Michela Armellin
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Tiziana Perin
- Pathology, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Michela Guardascione
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy.,Medical Oncology Department, Gastrointestinal Unit, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Roberta Maestro
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
| | - Manuela Santarosa
- Functional Onco-Genomics and Genetics, CRO Aviano National Cancer Institute, via F. Gallini 2, Aviano, PN, 33081, Italy
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36
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Sun CC, Li SJ, Yuan ZP, Li DJ. MicroRNA-346 facilitates cell growth and metastasis, and suppresses cell apoptosis in human non-small cell lung cancer by regulation of XPC/ERK/Snail/E-cadherin pathway. Aging (Albany NY) 2016; 8:2509-2524. [PMID: 27777383 PMCID: PMC5115903 DOI: 10.18632/aging.101080] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 10/04/2016] [Indexed: 01/02/2023]
Abstract
Determinants of growth and metastasis in cancer remain of great interest to define. MicroRNAs (miRNAs) have frequently emerged as tumor metastatic regulator by acting on multiple signaling pathways. Here we report the definition of miR-346 as a novel oncogenic microRNA that facilitates non-small cell lung cancer (NSCLC) cell growth and metastasis. XPC, an important DNA damage recognition factor in nucleotide excision repair was defined as a target for down-regulation by miR-346, functioning through direct interaction with the 3'-UTR of XPC mRNA. Blocking miR-346 by an antagomiR was sufficient to inhibit NSCLC cell growth and metastasis, an effect that could be phenol-copied by RNAi-mediated silencing of XPC. In vivo studies established that miR-346 overexpression was sufficient to promote tumor growth by A549 cells in xenografts mice, relative to control cells. Overall, our results defined miR-346 as an oncogenic miRNA in NSCLC, the levels of which contributed to tumor growth and invasive aggressiveness.
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Affiliation(s)
- Cheng-Cao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P. R. China
| | - Shu-Jun Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P. R. China
- Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, 430071 Wuhan, P. R. China
| | - Zhan-Peng Yuan
- Department of Toxicology, School of Public Health, Wuhan University, 430071 Wuhan, P. R. China
| | - De-Jia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, 430071 Wuhan, P. R. China
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37
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Przybyla L, Muncie JM, Weaver VM. Mechanical Control of Epithelial-to-Mesenchymal Transitions in Development and Cancer. Annu Rev Cell Dev Biol 2016; 32:527-554. [DOI: 10.1146/annurev-cellbio-111315-125150] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Laralynne Przybyla
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143;
| | - Jonathon M. Muncie
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143;
- Joint Graduate Group in Bioengineering (University of California, San Francisco, and University of California, Berkeley), San Francisco, California 94143
| | - Valerie M. Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, California 94143;
- Departments of Anatomy, Bioengineering, and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143
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38
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Sun KY, Peng T, Chen Z, Huang J, Zhou XH. MicroRNA-1275 suppresses cell growth, and retards G1/S transition in human nasopharyngeal carcinoma by down-regulation of HOXB5. J Cell Commun Signal 2016; 10:305-314. [PMID: 27644407 DOI: 10.1007/s12079-016-0351-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 08/24/2016] [Indexed: 12/20/2022] Open
Abstract
Through analysis of a reported microarray-based high-throughput examination, we found that miR-1275 was significantly down-regulated in nasopharyngeal carcinoma (NPC). While its role and mechanism participated in NPC progression are still little known. Here, we explored the effect of miR-1275 on the progression of NPC. Results demonstrated that miR-1275 was markedly down-regulated in NPC tissues and cell lines. MiR-1275 markedly repressed cell growth as confirmed by CCK8 and colony formation assay, via inhibition of HOXB5 in NPC cell lines. Moreover, miR-1275 suppressed G1/S transition via inhibition of HOXB5. Further, oncogene HOXB5 was evidenced to be a potential target of miR-1275, and its expression was conversely correlated with miR-1275 expression in NPC. Collectively, our study indicated that miR-1275, a tumor suppressor, played a critical effect on NPC progression via inhibition of cell growth, and suppression of G1/S transition by targeting oncogenic HOXB5.
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Affiliation(s)
- Kai-Yu Sun
- Department of Otorhinolaryngology-Head and Neck Surgery, ZhongNan Hospital, Wuhan University, No.169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Tao Peng
- Department of Otorhinolaryngology-Head and Neck Surgery, ZhongNan Hospital, Wuhan University, No.169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Zhe Chen
- Department of Otorhinolaryngology-Head and Neck Surgery, ZhongNan Hospital, Wuhan University, No.169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Jing Huang
- Department of Otorhinolaryngology-Head and Neck Surgery, ZhongNan Hospital, Wuhan University, No.169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Xu-Hong Zhou
- Department of Otorhinolaryngology-Head and Neck Surgery, ZhongNan Hospital, Wuhan University, No.169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China.
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Holzner S, Senfter D, Stadler S, Staribacher A, Nguyen CH, Gaggl A, Geleff S, Huttary N, Krieger S, Jäger W, Dolznig H, Mader RM, Krupitza G. Colorectal cancer cell-derived microRNA200 modulates the resistance of adjacent blood endothelial barriers in vitro. Oncol Rep 2016; 36:3065-3071. [PMID: 27666412 DOI: 10.3892/or.2016.5114] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 09/02/2016] [Indexed: 11/06/2022] Open
Abstract
Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three‑dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)‑barrier breaching to study mechanisms of intra‑/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5‑fluorouracil (5‑FU)‑resistant CRC CCL227 cells. The 3D model enabled quantifying effects of tumour‑derived microRNA200 (miR200) miR200a, miR200b, miR200c, miR141 and miR429 regarding the induction of so-called 'circular chemorepellent‑induced defects' (CCIDs) within the BEC‑barrier, which resemble gates for tumour transmigration. For this, miR200 precursors were individually transfected and furthermore, the modulation of ZEB family expression was analysed by western blotting. miR200c, miR141 and miR429, which are contained in exosomes from naïve CCL227 cells, downregulated the expression of ZEB2, SNAI and TWIST in BECs. The exosomes of 5‑FU‑resistant CCL227‑RH cells, which are devoid of miR200, accelerated CCID formation in BEC monolayers as compared to exosomes from naïve CCL227 cells. This confirmed the reported role of ZEB2 and SNAI in CRC metastasis and highlighted the active contribution of the stroma in the metastatic process. CCL227 spheroids affected the integrity of BEC and LEC barriers alike, which was in agreement with the observation that CRC metastasizes via blood stream (into the liver) as well as via lymphatics (into lymph nodes and lungs). This further validated the CRC/LEC and CRC/BEC in vitro model to study mechanisms of CRC spreading through vascular systems. Treatment of CCL227‑RH cells with the HDAC inhibitors mocetinostat and sulforaphane reduced CCID formation to the level triggered by naïve CCL227 spheroids, however, without significantly influencing miR200 expression in CCL227-RH cells.
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Affiliation(s)
- Silvio Holzner
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Daniel Senfter
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Serena Stadler
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Anna Staribacher
- Department of Medicine I, Comprehensive Cancer Centre, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Chi Huu Nguyen
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Anna Gaggl
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Silvana Geleff
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Nicole Huttary
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Sigurd Krieger
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Walter Jäger
- Department of Clinical Pharmacy and Diagnostics, University of Vienna, A‑1090 Vienna, Austria
| | - Helmut Dolznig
- Institute of Medical Genetics, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Robert M Mader
- Department of Medicine I, Comprehensive Cancer Centre, Medical University of Vienna, A‑1090 Vienna, Austria
| | - Georg Krupitza
- Clinical Institute of Pathology, Medical University of Vienna, A‑1090 Vienna, Austria
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40
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Tkatchenko AV, Luo X, Tkatchenko TV, Vaz C, Tanavde VM, Maurer-Stroh S, Zauscher S, Gonzalez P, Young TL. Large-Scale microRNA Expression Profiling Identifies Putative Retinal miRNA-mRNA Signaling Pathways Underlying Form-Deprivation Myopia in Mice. PLoS One 2016; 11:e0162541. [PMID: 27622715 PMCID: PMC5021328 DOI: 10.1371/journal.pone.0162541] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/24/2016] [Indexed: 12/16/2022] Open
Abstract
Development of myopia is associated with large-scale changes in ocular tissue gene expression. Although differential expression of coding genes underlying development of myopia has been a subject of intense investigation, the role of non-coding genes such as microRNAs in the development of myopia is largely unknown. In this study, we explored myopia-associated miRNA expression profiles in the retina and sclera of C57Bl/6J mice with experimentally induced myopia using microarray technology. We found a total of 53 differentially expressed miRNAs in the retina and no differences in miRNA expression in the sclera of C57BL/6J mice after 10 days of visual form deprivation, which induced -6.93 ± 2.44 D (p < 0.000001, n = 12) of myopia. We also identified their putative mRNA targets among mRNAs found to be differentially expressed in myopic retina and potential signaling pathways involved in the development of form-deprivation myopia using miRNA-mRNA interaction network analysis. Analysis of myopia-associated signaling pathways revealed that myopic response to visual form deprivation in the retina is regulated by a small number of highly integrated signaling pathways. Our findings highlighted that changes in microRNA expression are involved in the regulation of refractive eye development and predicted how they may be involved in the development of myopia by regulating retinal gene expression.
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Affiliation(s)
- Andrei V. Tkatchenko
- Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
- * E-mail: (AVT); (TLY)
| | - Xiaoyan Luo
- Department of Ophthalmology, School of Medicine, Duke University, Durham, North Carolina, United States of America
- Center for Human Genetics, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Tatiana V. Tkatchenko
- Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
| | - Candida Vaz
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
| | - Vivek M. Tanavde
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
- Institute for Medical Biology, A*STAR, Singapore, Singapore
| | - Sebastian Maurer-Stroh
- Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore
| | - Stefan Zauscher
- Department of Mechanical Engineering and Materials Science, Pratt School of Engineering, Duke University, Durham, North Carolina, United States of America
| | - Pedro Gonzalez
- Department of Ophthalmology, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Terri L. Young
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, United States of America
- * E-mail: (AVT); (TLY)
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Behbahani GD, Ghahhari NM, Javidi MA, Molan AF, Feizi N, Babashah S. MicroRNA-Mediated Post-Transcriptional Regulation of Epithelial to Mesenchymal Transition in Cancer. Pathol Oncol Res 2016; 23:1-12. [DOI: 10.1007/s12253-016-0101-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 08/24/2016] [Indexed: 02/06/2023]
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42
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Hudcova K, Raudenska M, Gumulec J, Binkova H, Horakova Z, Kostrica R, Babula P, Adam V, Masarik M. Expression profiles of miR-29c, miR-200b and miR-375 in tumour and tumour-adjacent tissues of head and neck cancers. Tumour Biol 2016; 37:12627-12633. [PMID: 27440205 DOI: 10.1007/s13277-016-5147-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 07/11/2016] [Indexed: 01/15/2023] Open
Abstract
Altered expression of microRNAs (miRNAs) has been shown in many types of malignancies including the head and neck squamous cell carcinoma (HNSCC). Although there are many new and innovative approaches in the treatment of HNSCC, a clear marker of this disease is still missing. Three candidate miRNAs (miR-29c-3p, miR-200b-5p and miR-375-3p) were studied in connection with HNSCC using quantitative real-time PCR expression levels in 42 tissue samples of HNSCC patients and histologically normal tumour-adjacent tissue samples of these patients. Primary HNSCC carcinoma tissues can be distinguished from histologically normal-matched noncancerous tumour-adjacent tissues based on hsa-miR-375-3p expression (sensitivity 87.5 %, specificity 65 %). Additionally, a significant decrease of hsa-miR-200b-5p expression was revealed in tumour-adjacent tissue samples of patients with node positivity. Lower expression of hsa-miR-200b-5p and hsa-miR-29c-3p in HNSCC tumour tissue was associated with higher tumour grade. Consequently, survival analysis was performed. Lower expression of hsa-miR-29c-3p in tumour-adjacent tissue was associated with worse overall and disease-specific survivals. Lower expression of miR-29c-3p in tumourous tissue was associated with worse relapse-free survival. hsa-miR-375-3p seems to be a relatively promising diagnostic marker in HNSCC but is not suitable for prognosis of patients. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in HNSCC progress (significant decrease of hsa-miR-200b-5p expression in tumour-adjacent tissue of patients with node positivity and low expression of hsa-miR-29c-3p in HNSCC tumour-adjacent tissue associated with worse prognosis).
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Affiliation(s)
- Kristyna Hudcova
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic
| | - Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic
| | - Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic
| | - Hana Binkova
- Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne's Faculty Hospital, Pekarska 53, CZ-656 91, Brno, Czech Republic
| | - Zuzana Horakova
- Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne's Faculty Hospital, Pekarska 53, CZ-656 91, Brno, Czech Republic
| | - Rom Kostrica
- Department of Otorhinolaryngology and Head and Neck Surgery, St. Anne's Faculty Hospital, Pekarska 53, CZ-656 91, Brno, Czech Republic
| | - Petr Babula
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic
| | - Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic.
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic.
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00, Brno, Czech Republic.
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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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Sun CC, Li SJ, Li DJ. Hsa-miR-134 suppresses non-small cell lung cancer (NSCLC) development through down-regulation of CCND1. Oncotarget 2016; 7:35960-35978. [PMID: 27166267 PMCID: PMC5094975 DOI: 10.18632/oncotarget.8482] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 04/18/2016] [Indexed: 12/20/2022] Open
Abstract
Hsa-miRNA-134 (miR-134) has recently been discovered to have anticancer efficacy in different organs. However, the role of miR-134 on non-small cell lung cancer (NSCLC) is still ambiguous. In this study, we investigated the role of miR-134 on the development of NSCLC. The results indicated that miR-134 was significantly down-regulated in primary tumor tissues and very low levels were found in NSCLC cell lines. Ectopic expression of miR-134 in NSCLC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1). In addition, miR-134 induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2. Moreover, miR-134 inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9. Further, oncogene CCND1 was revealed to be a putative target of miR-134, which was inversely correlated with miR-134 expression in NSCLC. Taken together, our results demonstrated that miR-134 played a pivotal role on NSCLC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic CCND1.
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Affiliation(s)
- Cheng-Cao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
| | - Shu-Jun Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
- Wuhan Hospital for The Prevention and Treatment of Occupational Diseases, Wuhan, P. R. China
| | - De-Jia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, P. R. China
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Abstract
AXIN2, an important regulator in Wnt/β-catenin signaling pathway, takes part in regulating cell proliferation, cytometaplasia, migration, apoptosis and other important functions, has showed close relations with the development of liver cancer, colon cancer, lung cancer, breast cancer and so on. The epigenetic regulation provides new insights for further exploring the pathogenesis of tumor. In this paper, the roles of AXIN2 in tumorigenesis, AXIN2 methylation, ubiquitination and siRNA/RNA regulation will be reviewed.
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46
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Sun C, Li S, Yang C, Xi Y, Wang L, Zhang F, Li D. MicroRNA-187-3p mitigates non-small cell lung cancer (NSCLC) development through down-regulation of BCL6. Biochem Biophys Res Commun 2016; 471:82-8. [DOI: 10.1016/j.bbrc.2016.01.175] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 01/18/2016] [Accepted: 01/28/2016] [Indexed: 12/31/2022]
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Abba ML, Patil N, Leupold JH, Allgayer H. MicroRNA Regulation of Epithelial to Mesenchymal Transition. J Clin Med 2016; 5:jcm5010008. [PMID: 26784241 PMCID: PMC4730133 DOI: 10.3390/jcm5010008] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 12/18/2015] [Accepted: 01/05/2016] [Indexed: 02/07/2023] Open
Abstract
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors.
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Affiliation(s)
- Mohammed L Abba
- Department of Experimental Surgery, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karl University of Heidelberg, Ludolf-Krehl-Str. 6, 68135 Mannheim, Germany.
| | - Nitin Patil
- Department of Experimental Surgery, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karl University of Heidelberg, Ludolf-Krehl-Str. 6, 68135 Mannheim, Germany.
| | - Jörg Hendrik Leupold
- Department of Experimental Surgery, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karl University of Heidelberg, Ludolf-Krehl-Str. 6, 68135 Mannheim, Germany.
| | - Heike Allgayer
- Department of Experimental Surgery, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karl University of Heidelberg, Ludolf-Krehl-Str. 6, 68135 Mannheim, Germany.
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48
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Shukla P, Vogl C, Wallner B, Rigler D, Müller M, Macho-Maschler S. High-throughput mRNA and miRNA profiling of epithelial-mesenchymal transition in MDCK cells. BMC Genomics 2015; 16:944. [PMID: 26572553 PMCID: PMC4647640 DOI: 10.1186/s12864-015-2036-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 10/08/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, especially during gastrulation and organ formation. Furthermore EMT is widely observed in pathological conditions, e.g., fibrosis, tumor progression and metastasis. Madin-Darby Canine Kidney (MDCK) cells are widely used for studies of EMT and epithelial plasticity. MDCK cells show an epithelial phenotype, while oncogenic Ras-transformed MDCK (MDCK-Ras) cells undergo EMT and show a mesenchymal phenotype. METHODS RNA-Seq and miRNA-Seq analyses were performed on MDCK and MDCK-Ras cells. Data were validated by qRT-PCR. Gene signature analyses were carried out to identify pathways and gene ontology terms. For selected miRNAs target prediction was performed. RESULTS With RNA-Seq, mRNAs of approximately half of the genes known for dog were detected. These were screened for differential regulation during Ras-induced EMT. We went further and performed gene signature analyses and found Gene Ontology (GO) terms and pathways important for epithelial polarity and implicated in EMT. Among the identified pathways, TGFβ1 emerged as a central signaling factor in many EMT related pathways and biological processes. With miRNA-Seq, approximately half of the known canine miRNAs were found expressed in MDCK and MDCK-Ras cells. Furthermore, among differentially expressed miRNAs, miRNAs that are known to be important regulators of EMT were detected and new candidates were predicted. New dog miRNAs were discovered after aligning our reads to that of other species in miRBase. Importantly, we could identify 25 completely novel miRNAs with a stable hairpin structure. Two of these novel miRNAs were differentially expressed. We validated the two novel miRNAs with the highest read counts by RT-qPCR. Target prediction of a particular novel miRNA highly expressed in mesenchymal MDCK-Ras cells revealed that it targets components of epithelial cell junctional complexes. Combining target prediction for the most upregulated miRNAs and validation of the targets in MDCK-Ras cells with pathway analysis allowed us to identify two novel pathways, e.g., JAK/STAT signaling and pancreatic cancer pathways. These pathways could not be detected solely by gene set enrichment analyses of RNA-Seq data. CONCLUSION With deep sequencing data of mRNAs and miRNAs of MDCK cells and of Ras-induced EMT in MDCK cells, differentially regulated mRNAs and miRNAs are identified. Many of the identified genes are within pathways known to be involved in EMT. Novel differentially upregulated genes in MDCK cells are interferon stimulated genes and genes involved in Slit and Netrin signaling. New pathways not yet linked to these processes were identified. A central pathway in Ras induced EMT is TGFβ signaling, which leads to differential regulation of many target genes, including miRNAs. With miRNA-Seq we identified miRNAs involved in either epithelial cell biology or EMT. Finally, we describe completely novel miRNAs and their target genes.
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Affiliation(s)
- Priyank Shukla
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Claus Vogl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Barbara Wallner
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Doris Rigler
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Mathias Müller
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Sabine Macho-Maschler
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
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Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma. J Pathol 2015; 236:505-16. [DOI: 10.1002/path.4550] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 04/20/2015] [Accepted: 04/25/2015] [Indexed: 11/07/2022]
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50
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Intestinal fibrosis in Crohn's disease: role of microRNAs as fibrogenic modulators, serum biomarkers, and therapeutic targets. Inflamm Bowel Dis 2015; 21:1141-50. [PMID: 25636122 DOI: 10.1097/mib.0000000000000298] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammation often precedes fibrosis and stricture formation in patients with Crohn's disease. Established medical therapies reduce inflammation, but there are currently no specific therapies to prevent fibrosis or treat established fibrosis. Our understanding of the pathogenic processes underpinning fibrogenesis is limited compared with our knowledge of the events initiating and propagating inflammation. There are several biomarkers for intestinal inflammation, but there are none that reflect the development of fibrosis. MicroRNAs (miRNAs) are regulators of cellular activities including inflammation and fibrosis and may serve as biomarkers of disease processes. Differential serum and mucosal miRNA expression profiles have been identified between patients with inflammatory bowel disease with active and inactive inflammatory disease. In contrast, studies in patients with fibrotic phenotypes are comparatively few, although specific miRNAs have defined roles in the development of fibrosis in other organ systems. Here, we discuss the most recent research on miRNA and fibrogenesis with a particular emphasis on Crohn's disease. We also anticipate the potential of miRNAs in fulfilling current unmet translational needs in this patient group by focusing on the role of miRNAs as modulators of fibrogenesis and on their potential value as serum biomarkers and therapeutic targets in the management of fibrosis.
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