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Vishnubalaji R, Shaath H, Al-Alwan M, Abdelalim EM, Alajez NM. Reciprocal interplays between MicroRNAs and pluripotency transcription factors in dictating stemness features in human cancers. Semin Cancer Biol 2022; 87:1-16. [PMID: 36354097 DOI: 10.1016/j.semcancer.2022.10.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
The interplay between microRNAs (miRNAs) and pluripotency transcription factors (TFs) orchestrates the acquisition of cancer stem cell (CSC) features during the course of malignant transformation, rendering them essential cancer cell dependencies and therapeutic vulnerabilities. In this review, we discuss emerging themes in tumor heterogeneity, including the clonal evolution and the CSC models and their implications in resistance to cancer therapies, and then provide thorough coverage on the roles played by key TFs in maintaining normal and malignant stem cell pluripotency and plasticity. In addition, we discuss the reciprocal interactions between miRNAs and MYC, OCT4, NANOG, SOX2, and KLF4 pluripotency TFs and their contributions to tumorigenesis. We provide our view on the potential to interfere with key miRNA-TF networks through the use of RNA-based therapeutics as single agents or in combination with other therapeutic strategies, to abrogate the CSC state and render tumor cells more responsive to standard and targeted therapies.
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Affiliation(s)
- Radhakrishnan Vishnubalaji
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Hibah Shaath
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Monther Al-Alwan
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia
| | - Essam M Abdelalim
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar; College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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Liang C, Huang M, Li T, Li L, Sussman H, Dai Y, Siemann DW, Xie M, Tang X. Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces. SOFT MATTER 2022; 18:1112-1148. [PMID: 35089300 DOI: 10.1039/d1sm01618k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
An increasing number of studies have demonstrated the significant roles of the interplay between microenvironmental mechanics in tissues and biochemical-genetic activities in resident tumor cells at different stages of tumor progression. Mediated by molecular mechano-sensors or -transducers, biomechanical cues in tissue microenvironments are transmitted into the tumor cells and regulate biochemical responses and gene expression through mechanotransduction processes. However, the molecular interplay between the mechanotransduction processes and intracellular biochemical signaling pathways remains elusive. This paper reviews the recent advances in understanding the crosstalk between biomechanical cues and three critical biochemical effectors during tumor progression: calcium ions (Ca2+), yes-associated protein (YAP), and microRNAs (miRNAs). We address the molecular mechanisms underpinning the interplay between the mechanotransduction pathways and each of the three effectors. Furthermore, we discuss the functional interactions among the three effectors in the context of soft matter and mechanobiology. We conclude by proposing future directions on studying the tumor mechanobiology that can employ Ca2+, YAP, and miRNAs as novel strategies for cancer mechanotheraputics. This framework has the potential to bring insights into the development of novel next-generation cancer therapies to suppress and treat tumors.
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Affiliation(s)
- Chenyu Liang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
| | - Miao Huang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
| | - Tianqi Li
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
| | - Lu Li
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
| | - Hayley Sussman
- Department of Radiation Oncology, COM, Gainesville, FL, 32611, USA
| | - Yao Dai
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- UF Genetics Institute (UFGI), University of Florida (UF), Gainesville, FL, 32611, USA
| | - Dietmar W Siemann
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- UF Genetics Institute (UFGI), University of Florida (UF), Gainesville, FL, 32611, USA
| | - Mingyi Xie
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
- Department of Biomedical Engineering, College of Engineering (COE), University of Delaware (UD), Newark, DE, 19716, USA
| | - Xin Tang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
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Perumal N, Kanchan RK, Doss D, Bastola N, Atri P, Chirravuri-Venkata R, Thapa I, Vengoji R, Maurya SK, Klinkebiel D, Talmon GA, Nasser MW, Batra SK, Mahapatra S. MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB). Acta Neuropathol Commun 2021; 9:195. [PMID: 34922631 PMCID: PMC8684142 DOI: 10.1186/s40478-021-01299-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022] Open
Abstract
Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.
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Affiliation(s)
- Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Doss
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 68124, USA
| | - Noah Bastola
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Shailendra K Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Klinkebiel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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The Role of Non-Coding RNAs in the Regulation of the Proto-Oncogene MYC in Different Types of Cancer. Biomedicines 2021; 9:biomedicines9080921. [PMID: 34440124 PMCID: PMC8389562 DOI: 10.3390/biomedicines9080921] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/25/2021] [Accepted: 07/28/2021] [Indexed: 01/17/2023] Open
Abstract
Alterations in the expression level of the MYC gene are often found in the cells of various malignant tumors. Overexpressed MYC has been shown to stimulate the main processes of oncogenesis: uncontrolled growth, unlimited cell divisions, avoidance of apoptosis and immune response, changes in cellular metabolism, genomic instability, metastasis, and angiogenesis. Thus, controlling the expression of MYC is considered as an approach for targeted cancer treatment. Since c-Myc is also a crucial regulator of many cellular processes in healthy cells, it is necessary to find ways for selective regulation of MYC expression in tumor cells. Many recent studies have demonstrated that non-coding RNAs play an important role in the regulation of the transcription and translation of this gene and some RNAs directly interact with the c-Myc protein, affecting its stability. In this review, we summarize current data on the regulation of MYC by various non-coding RNAs that can potentially be targeted in specific tumor types.
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Anauate AC, Leal MF, Calcagno DQ, Gigek CO, Karia BTR, Wisnieski F, dos Santos LC, Chen ES, Burbano RR, Smith MAC. The Complex Network between MYC Oncogene and microRNAs in Gastric Cancer: An Overview. Int J Mol Sci 2020; 21:ijms21051782. [PMID: 32150871 PMCID: PMC7084225 DOI: 10.3390/ijms21051782] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 12/24/2022] Open
Abstract
Despite the advancements in cancer treatments, gastric cancer is still one of the leading causes of death worldwide. In this context, it is of great interest to discover new and more effective ways of treating this disease. Accumulated evidences have demonstrated the amplification of 8q24.21 region in gastric tumors. Furthermore, this is the region where the widely known MYC oncogene and different microRNAs are located. MYC deregulation is key in tumorigenesis in various types of tissues, once it is associated with cell proliferation, survival, and drug resistance. microRNAs are a class of noncoding RNAs that negatively regulate the protein translation, and which deregulation is related with gastric cancer development. However, little is understood about the interactions between microRNAs and MYC. Here, we overview the MYC role and its relationship with the microRNAs network in gastric cancer aiming to identify potential targets useful to be used in clinic, not only as biomarkers, but also as molecules for development of promising therapies.
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Affiliation(s)
- Ana Carolina Anauate
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
- Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil
| | - Mariana Ferreira Leal
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
| | - Danielle Queiroz Calcagno
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém PA 66075-110, Brazil; (D.Q.C.); (R.R.B.)
| | - Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
- Departamento de Patologia, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil
| | - Bruno Takao Real Karia
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
| | - Fernanda Wisnieski
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
- Disciplina de Gastroenterologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil
| | - Leonardo Caires dos Santos
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
| | - Elizabeth Suchi Chen
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
| | - Rommel Rodríguez Burbano
- Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Universidade Federal do Pará, Belém PA 66075-110, Brazil; (D.Q.C.); (R.R.B.)
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém PA 66075-110, Brazil
- Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém PA 66063-240, Brazil
| | - Marília Arruda Cardoso Smith
- Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo SP 04023-062, Brazil; (A.C.A.); (M.F.L.); (C.O.G.); (B.T.R.K.); (F.W.); (L.C.d.S.); (E.S.C.)
- Correspondence: ; Tel.: +55-11-5576-4848
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Li YS, Zou Y, Dai DQ. MicroRNA-320a suppresses tumor progression by targeting PBX3 in gastric cancer and is downregulated by DNA methylation. World J Gastrointest Oncol 2019; 11:842-856. [PMID: 31662823 PMCID: PMC6815930 DOI: 10.4251/wjgo.v11.i10.842] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/19/2019] [Accepted: 07/28/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Ectopic expression of miRNAs promotes tumor development and progression. miRNA (miR)-320a is downregulated in many cancers, including gastric cancer (GC). However, the mechanism underlying its downregulation and the role of miR-320a in GC are unknown.
AIM To determine expression and biological functions of miR-320a in GC and investigate the underlying molecular mechanisms.
METHODS Quantitative real-time polymerase chain reaction (PCR) was used to determine expression of miR-320a in GC cell lines and tissues. TargetScanHuman7.1, miRDB, and microRNA.org were used to predict the possible targets of miR-320a, and a dual luciferase assay was used to confirm the findings. Western blotting was used to detect the protein levels of pre-B-cell leukemia homeobox 3 (PBX3) in GC cells and tissue samples. Cell Counting Kit-8 proliferation, Transwell, wound healing, and apoptosis assays were performed to analyze the biological functions of miR-320a in GC cells. Methylation-specific PCR was used to analyze the methylation level of the miR-320a promoter CpG islands. 5-Aza-2’-deoxycytidine (5-Aza-CdR) and trichostatin A (TSA) were used to treat GC cells.
RESULTS miR-320a expression was lower in GC cell lines and tissues than in the normal gastric mucosa cell line GES-1 and matched adjacent normal tissues. miR-320a overexpression suppressed GC cell proliferation, invasion and migration, and induced apoptosis. PBX3 was a target of miR-320a in GC. The methylation level of the miR-320a promoter CpG islands was elevated and this was partly reversed by 5-Aza-CdR and TSA.
CONCLUSION miR-320a acts as a tumor suppressor and inhibits malignant behavior of GC cells, partly by targeting PBX3. DNA methylation is an important mechanism associated with low expression of miR-320a.
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Affiliation(s)
- Yong-Shuang Li
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Ying Zou
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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Chen X, Lin ZF, Xi WJ, Wang W, Zhang D, Yang F, Li YF, Huo Y, Zhang TZ, Jiang YH, Qin WW, Yang AG, Wang T. DNA methylation-regulated and tumor-suppressive roles of miR-487b in colorectal cancer via targeting MYC, SUZ12, and KRAS. Cancer Med 2019; 8:1694-1709. [PMID: 30791232 PMCID: PMC6488202 DOI: 10.1002/cam4.2032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 01/22/2019] [Accepted: 01/29/2019] [Indexed: 12/13/2022] Open
Abstract
Human colorectal cancer (CRC), characterized by its high morbidity and lethality, seriously threatens human health and lives. MicroRNA‐487b (miR‐487b) is currently reported to be aberrantly expressed in several tumors, but the detailed functions and underlying mechanisms of miR‐487b in CRC remain unclear. Here, we found that miR‐487b is downregulated in CRC cell lines and is markedly decreased in tumor specimens derived from CRC patients. MiR‐487b inhibits cell proliferation, migration and invasion and promotes the apoptosis of CRC cells in vitro. Statistical analysis of clinical samples indicates that miR‐487b may serve as a biomarker for early CRC diagnosis. Inverse correlations between the expression levels of MYC, SUZ12, and KRAS and that of miR‐487b exist in vitro and in CRC patient tissue specimens. Further experiments demonstrated the regulatory effects of miR‐487b on MYC, SUZ12, and KRAS, and the disruption of these genes partially restores the miR‐487b inhibitor‐induced phenotype. Additionally, miR‐487b promoter region is in a DNA hypermethylated condition and the DNA methyltransferase inhibitor 5‐aza‐2’‐deoxycytidine (5‐Aza) increases the levels of miR‐487b but suppresses the expression of MYC, SUZ12, and KRAS in a time‐ and concentration‐dependent manner in CRC cells. Collectively, miR‐487b is regulated by DNA methylation and it functions as a tumor suppressor in CRC mainly through targeting MYC, SUZ12, and KRAS. Our study provides insight into the regulatory network in CRC cells, offering a new target for treating CRC patients.
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Affiliation(s)
- Xu Chen
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Zhi-Feng Lin
- Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Wen-Jin Xi
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Wei Wang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Dan Zhang
- Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Fan Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Yu-Fang Li
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Yi Huo
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Tian-Ze Zhang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Yi-Hong Jiang
- Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Wei-Wei Qin
- Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - An-Gang Yang
- State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
| | - Tao Wang
- Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China
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He X, Fan S. hsa-miR-212 modulates the radiosensitivity of glioma cells by targeting BRCA1. Oncol Rep 2018; 39:977-984. [PMID: 29286157 PMCID: PMC5802039 DOI: 10.3892/or.2017.6156] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 12/12/2017] [Indexed: 01/06/2023] Open
Abstract
Radioresistance remains a major challenge in the treatment of glioma, and the response of patients to radio-therapy varies considerably. MicroRNAs (miRNAs) are involved in various biological processes. The purpose of the present study was to investigate miRNAs involved in the response to radiation in glioma cell lines. Total RNA was isolated from human glioma U251 cells 30 min after γ-ray exposure and hybridized to an miRNA chip array. miRNA expression profiles were analyzed by quantitative real-time PCR. pcDNA3/EGFP-miR-212 mimic transfection was used to verify the function of miR-212 in colony formation tests, and the effect of miR-212 overexpression on U251 cells was examined by western blot analysis of apoptosis-related proteins (Bcl-2, Bax, caspase-3 and cytochrome c). The target genes of miR-212 were predicted using bioinformatic tools including miRNA databases, and breast cancer susceptibility gene 1 (BRCA1) was selected for further confirmation by EGFP fluorescence reporter and loss- and gain-of-function assays. Of the 16 candidate miRNAs showing altered expression, five were assessed by real-time PCR; miR-212 was identified as contributing to the radioresistance of glioma cells and was shown to attenuate radiation-induced apoptosis. miR-212 negatively regulated BRCA1 expression by interacting with its 3'-untranslated region, suggesting a correlation between BRCA1 expression and radiosensitivity in glioma cells. U-118MG and SHG-44 cell lines were used to confirm these observations. The response of glioma cells to radiation involves the miR-212-mediated modulation of BRCA1 gene expression, suggesting that the miR-212/BRCA1 axis may play a potential role in the radiotherapy of gliomas.
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Affiliation(s)
- Xin He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
| | - Saijun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin 300192, P.R. China
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9
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Xu L, Dai W, Li J, He L, Wang F, Xia Y, Chen K, Li S, Liu T, Lu J, Zhou Y, Wang Y, Guo C. Methylation-regulated miR-124-1 suppresses tumorigenesis in hepatocellular carcinoma by targeting CASC3. Oncotarget 2018; 7:26027-41. [PMID: 27029030 PMCID: PMC5041962 DOI: 10.18632/oncotarget.8266] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Accepted: 03/08/2016] [Indexed: 12/27/2022] Open
Abstract
This study was to investigate the roles and mechanisms of miR-124-1 in hepatocellular carcinoma (HCC). We analyzed the expression of miR-124-1 in human HCC tissues and cell lines. Luciferase reporter assays were used to analyze the target of miR-124-1. Human HCC cell lines were transduced with lentiviruses expressing miR-124-1, and proliferation and colony formation were analyzed. The growth of human HCC cells overexpressing miR-124-1 was assessed in nude mice. The expression of p38-MAPK, JNK, ERK and related signaling molecules was detected by western blotting and immunohistochemistry. Our results showed that miR-124-1 levels were reduced in HCC tissues and cell lines compared with those in adjacent non-cancer tissues and normal liver cell lines respectively. Downregulation of miR-124-1 in HCC cell lines were attributed to hypermethylation of its promoter region. Overexpression of miR-124-1 inhibited HCC cell proliferation in vitro, whereas miR-124-1 was correlated with clinicopathological parameters of HCC patients. HCC cell-mediated overexpression of miR-124-1 in nude mice suppressed tumor growth. Cancer susceptibility candidate 3 (CASC3) was identified as a direct target of miR-124-1 by computational analysis and experimental assays. MiR-124-1-mediated downregulation of CASC3 resulted in the inactivation of p38-MAPK, JNK and ERK. Our findings provide potential new targets for the prevention or treatment of HCC.
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Affiliation(s)
- Ling Xu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.,Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - JingJing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Lei He
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Sainan Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Tong Liu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Yugang Wang
- Department of Gastroenterology, Shanghai Tongren Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
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10
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Kaehler M, Ruemenapp J, Gonnermann D, Nagel I, Bruhn O, Haenisch S, Ammerpohl O, Wesch D, Cascorbi I, Bruckmueller H. MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells. Oncotarget 2017; 8:92018-92031. [PMID: 29190894 PMCID: PMC5696160 DOI: 10.18632/oncotarget.21272] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Accepted: 09/08/2017] [Indexed: 12/27/2022] Open
Abstract
BCR-ABL-independent resistance against tyrosine kinase inhibitor is an emerging problem in therapy of chronic myeloid leukemia. Such drug resistance can be linked to dysregulation of ATP-binding cassette (ABC)-transporters leading to increased tyrosine kinase inhibitor efflux, potentially caused by changes in microRNA expression or DNA-methylation. In an in vitro-imatinib-resistance model using K-562 cells, microRNA-212 was found to be dysregulated and inversely correlated to ABC-transporter ABCG2 expression, targeting its 3'-UTR. However, the functional impact on drug sensitivity remained unknown. Therefore, we performed transfection experiments using microRNA-mimics and -inhibitors and investigated their effect on imatinib-susceptibility in sensitive and resistant leukemic cell lines. Under imatinib-treatment, miR-212 inhibition led to enhanced cell viability (p = 0.01), reduced apoptosis (p = 0.01) and cytotoxicity (p = 0.03). These effects were limited to treatment-naïve cells and were not observed in cells, which were resistant to various imatinib-concentrations (0.1 μM to 2 μM). Further analysis in treatment-naïve cells revealed that miR-212 inhibition resulted in ABCG2 upregulation and increased ABCG2-dependent efflux. Furthermore, we observed miR-212 promoter hypermethylation in 0.5 and 2 μM IM-resistant sublines, whereas ABCG2 methylation status was not altered. Taken together, the miR-212/ABCG2-axis influences imatinib-susceptibility contributing to development of imatinib-resistance. Our data reveal new insights into mechanisms initiating imatinib-resistance in leukemic cells.
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Affiliation(s)
- Meike Kaehler
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Johanna Ruemenapp
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Daniel Gonnermann
- Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Inga Nagel
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Oliver Bruhn
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sierk Haenisch
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Ole Ammerpohl
- Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Daniela Wesch
- Institute of Immunology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Henrike Bruckmueller
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
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11
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Wu Z, Zhou L, Ding G, Cao L. Overexpressions of miR-212 are associated with poor prognosis of patients with pancreatic ductal adenocarcinoma. Cancer Biomark 2017; 18:35-39. [PMID: 27814273 DOI: 10.3233/cbm-160671] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The miR-212 was among the top differentially expressed miRNAs in pancreatic ductal adenocarcinoma (PDAC). OBJECTIVE The aim of this study was to investigate the expression of miR-212 in PDAC and evaluate its correlation with major clinicopathologic features and patients' survival. METHODS Fluorescence in situ hybridization (FISH) was adopted to examine miRNA expression in 45 pancreatic cancer and 20 normal pancreatic tissues. The relationship of miR-212 expression with clinicopathologic parameters and clinical outcome was evaluated. RESULTS miR-212 was confirmed to have significantly higher expression in PDAC compared with normal pancreatic tissues (51.1% vs 10%, p< 0.01). High expression of miR-212 was significantly associated with tumor size (p = 0.048) and tumor stage (p = 0.023). Moreover, in univariant analysis, patients with high expression of miR-212 demonstrate significantly poorer overall survival (p= 0.02). CONCLUSIONS High expression of miR-212 in PDAC is associated with shorter overall survival. It may be not only a potential prognostic marker, but also a possible therapeutic target in PDAC.
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12
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Epigenetic basis of cancer health disparities: Looking beyond genetic differences. Biochim Biophys Acta Rev Cancer 2017; 1868:16-28. [PMID: 28108348 DOI: 10.1016/j.bbcan.2017.01.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/07/2017] [Accepted: 01/16/2017] [Indexed: 12/18/2022]
Abstract
Despite efforts at various levels, racial health disparities still exist in cancer patients. These inequalities in incidence and/or clinical outcome can only be explained by a multitude of factors, with genetic basis being one of them. Several investigations have provided convincing evidence to support epigenetic regulation of cancer-associated genes, which results in the differential transcriptome and proteome, and may be linked to a pre-disposition of individuals of certain race/ethnicity to early or more aggressive cancers. Recent technological advancements and the ability to quickly analyze whole genome have aided in these efforts, and owing to their relatively easy detection, methylation events are much well-characterized, than the acetylation events, across human populations. The early trend of investigating a pre-determined set of genes for differential epigenetic regulation is paving way for more unbiased screening. This review summarizes our current understanding of the epigenetic events that have been tied to the racial differences in cancer incidence and mortality. A better understanding of the epigenetics of racial diversity holds promise for the design and execution of novel strategies targeting the human epigenome for reducing the disparity gaps.
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13
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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14
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Lin L, Wang Z, Jin H, Shi H, Lu Z, Qi Z. MiR-212/132 is epigenetically downregulated by SOX4/EZH2-H3K27me3 feedback loop in ovarian cancer cells. Tumour Biol 2016; 37:15719–15727. [PMID: 27812929 DOI: 10.1007/s13277-016-5339-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 09/06/2016] [Indexed: 11/25/2022] Open
Abstract
Both miR-212 and miR-132 are usually downregulated in ovarian cancer and act as tumor suppressors. However, the mechanism of their downregulation in ovarian cancer is not clear. In this study, we investigated the regulative effects of miR-212 and miR-132 on SOX4 expression in ovarian cancer cells and also studied whether there is a feedback regulation between miR-212/miR-132 and SOX4 via an epigenetic mechanism. The results showed that both EZH2 and SOX4 overexpressions significantly repressed miR-212 and miR-132 expressions in SKOV3 and OV2008 cells. Immunoprecipitation assay showed that there are interactions among SOX4, EZH2, and H3K27me3, and ChIP assay confirmed significant enrichment of EZH2 and H3K27me3 in the promoter region of miR-212/132. Both pri-miR-212 and pri-miR-132 expressions decreased after enforced EZH2 or SOX4 expression. Western blot and dual-luciferase assay confirmed that miR-212 and miR-132 can target the same sites in the 3'UTR of SOX4 mRNA and suppress its expression in ovarian cancer cells. MiR-132 or miR-212 overexpression or knockdown of endogenous SOX4 reduced epithelial-mesenchymal transition (EMT)-like properties. Therefore, we infer that the SOX4/EZH2 complex can silence miR-212 and miR-132 expressions via binding to the promoter region and promoting H3K27me3, while miR-212 and miR-132 can directly bind to the 3'UTR of SOX4 and suppress its expression. This forms a MiR-132/212-SOX4/EZH2-H3K27me3 feedback loop in ovarian cancer cells. Functionally, SOX4 is a downstream effector of miR-212/132 modulating EMT of ovarian cancer cells.
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Affiliation(s)
- Lin Lin
- Department of Reproductive Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
| | - Zhiwen Wang
- Department of Gynaecology and Obstetrics, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China.
| | - Haihong Jin
- Department of Gynaecology and Obstetrics, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
| | - Hongzhen Shi
- Department of Reproductive Medicine, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
| | - Zhihong Lu
- Department of Infectious Disease, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
| | - Zhenqin Qi
- B-ultrasound Room, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, China
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15
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Liu J, Chen B, Yue B, Yang J. MicroRNA-212 suppresses the proliferation and migration of osteosarcoma cells by targeting forkhead box protein A1. Exp Ther Med 2016; 12:4135-4141. [PMID: 28101191 DOI: 10.3892/etm.2016.3880] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/06/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that function as critical gene regulators by targeting the 3' untranslated region (UTR) of mRNA, causing translational repression or mRNA degradation. Deregulation of specific miRNAs, including miR-212, has been identified in patients with osteosarcoma. However, the underlying mechanism is yet to be fully elucidated. The present study aimed to reveal the regulatory mechanism of miR-212 in osteosarcoma cell viability and migration. Quantitative polymerase chain reaction data revealed that miR-212 was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. miR-212 was also downregulated in osteosarcoma cell lines compared with normal osteoblast cell lines. Overexpression of miR-212 significantly suppressed the viability and migration of human osteosarcoma MG-63 and Saos-2 cell lines. In addition, forkhead box protein A1 (FOXA1), an oncogene in osteosarcoma, was predicted to be a putative target of miR-212 by bioinformatical analysis. Furthermore, luciferase reporter assay data confirmed that miR-212 could directly bind to the seed sequences within the 3'UTR of FOXA1 mRNA, and miR-212 negatively mediated the protein levels of FOXA1 in osteosarcoma MG-63 and Saos-2 cells. Moreover, knockdown of FOXA1 also led to a significant decrease in the viability and migration of osteosarcoma MG-63 and Saos-2 cells and the expression levels of FOXA1 were significantly upregulated in osteosarcoma tissues and cell lines. These data suggest that miR-212 inhibits the viability and migration of osteosarcoma cells by targeting FOXA1. Accordingly, miR-212 may become a potential candidate for osteosarcoma therapy.
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Affiliation(s)
- Jian Liu
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Bohua Chen
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Bin Yue
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Junde Yang
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
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16
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Ding G, Zhou L, Qian Y, Fu M, Chen J, Chen J, Xiang J, Wu Z, Jiang G, Cao L. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget 2016; 6:29877-88. [PMID: 26337469 PMCID: PMC4745769 DOI: 10.18632/oncotarget.4924] [Citation(s) in RCA: 218] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Accepted: 08/03/2015] [Indexed: 12/21/2022] Open
Abstract
It has been reported tumor-derived exosomes can transfer miRNAs to recipient cells in the tumor microenvironment, promoting tumor invasion and metastasis. The present research aimed to explore how pancreatic cancer (PC) derived exosomal miRNAs inhibited mRNA expression of dendritic cells and induced immune tolerance. Our study revealed that 9 PC-related miRNAs were increased and 208 mRNAs were inhibited in exosome-stimulated dendritic cells (exo-iDCs) compared to immature dendritic cells (iDCs). A target prediction between the 9 miRNAs and 208 mRNAs was performed by bioinformatics database analysis. From the target prediction, it was predicted and validated that regulatory factor X-associated protein (RFXAP), an important transcription factor for MHC II, was inhibited by miR-212-3p transferred from PC-secreted exosomes, resulting in decreased MHC II expression. Moreover, a clinical study showed a negative correlation between miR-212-3p and RFXAP in PC tissue. From these data, we concluded that PC-related miRNAs can be transferred to dendritic cells via exosome and inhibit target mRNA expression. More importantly, PC-derived exosomes inhibit RFXAP expression via miR-212-3p, which decrease MHC II expression and induce immune tolerance of dendritic cells. RFXAP deficiency has never been reported in solid tumors. The functions and mechanisms of RFXAP in tumors deserve future explorations.
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Affiliation(s)
- Guoping Ding
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liangjing Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yingming Qian
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Mingnian Fu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jian Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jionghuang Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianyang Xiang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengrong Wu
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guixing Jiang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Liping Cao
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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17
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Wang H, Guo Q, Yang P, Long G. Restoration of microRNA-212 causes a G0/G1 cell cycle arrest and apoptosis in adult T-cell leukemia/lymphoma cells by repressing CCND3 expression. J Investig Med 2016; 65:82-87. [DOI: 10.1136/jim-2016-000233] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2016] [Indexed: 12/22/2022]
Abstract
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR-212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S-phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR-212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL.
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Yang Q, Zhang RW, Sui PC, He HT, Ding L. Dysregulation of non-coding RNAs in gastric cancer. World J Gastroenterol 2015; 21:10956-10981. [PMID: 26494954 PMCID: PMC4607897 DOI: 10.3748/wjg.v21.i39.10956] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 08/28/2015] [Accepted: 09/15/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer (GC) is one of the most common cancers in the world and a significant threat to the health of patients, especially those from China and Japan. The prognosis for patients with late stage GC receiving the standard of care treatment, including surgery, chemotherapy and radiotherapy, remains poor. Developing novel treatment strategies, identifying new molecules for targeted therapy, and devising screening techniques to detect this cancer in its early stages are needed for GC patients. The discovery of non-coding RNAs (ncRNAs), primarily microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), helped to elucidate the mechanisms of tumorigenesis, diagnosis and treatment of GC. Recently, significant research has been conducted on non-coding RNAs and how the regulatory dysfunction of these RNAs impacts the tumorigenesis of GC. In this study, we review papers published in the last five years concerning the dysregulation of non-coding RNAs, especially miRNAs and lncRNAs, in GC. We summarize instances of aberrant expression of the ncRNAs in GC and their effect on survival-related events, including cell cycle regulation, AKT signaling, apoptosis and drug resistance. Additionally, we evaluate how ncRNA dysregulation affects the metastatic process, including the epithelial-mesenchymal transition, stem cells, transcription factor activity, and oncogene and tumor suppressor expression. Lastly, we determine how ncRNAs affect angiogenesis in the microenvironment of GC. We further discuss the use of ncRNAs as potential biomarkers for use in clinical screening, early diagnosis and prognosis of GC. At present, no ideal ncRNAs have been identified as targets for the treatment of GC.
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19
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Yu X, Li Z. The role of microRNAs expression in laryngeal cancer. Oncotarget 2015; 6:23297-305. [PMID: 26079642 PMCID: PMC4695119 DOI: 10.18632/oncotarget.4195] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 05/23/2015] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRs, miRs) is a class of small non-coding RNAs, which posttranscriptionally regulate gene expression. Deregulated miRs are frequently obseved in patients with laryngeal cancer. In addition, numerous studies have showed miRs play significant roles in the pathogenesis of laryngeal cancer through regulating tumor cell proliferation, metastasis, invasion and apoptosis. miR can play either an oncogenic or tumor suppressive role in laryngeal cancer. In our review, we summarize the recent researches on laryngeal cancer-associated miRs, focusing on their role in the pathogenesis of laryngeal cancer. As changes in the levels of specific miRs in tissues or serum associate with diagnosis and prognosis of patients, we will also discuss the potential use of miRs in laryngeal cancer diagnosis and prognosis. Furthermore, supplementation of oncomiRs or inhibition of tumor suppressive miRs in vivo may be future therapeutic strategy for laryngeal cancer.
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Affiliation(s)
- Xin Yu
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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20
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Tu H, Wei G, Cai Q, Chen X, Sun Z, Cheng C, Zhang L, Feng Y, Zhou H, Zhou B, Zeng T. MicroRNA-212 inhibits hepatocellular carcinoma cell proliferation and induces apoptosis by targeting FOXA1. Onco Targets Ther 2015; 8:2227-35. [PMID: 26347321 PMCID: PMC4556035 DOI: 10.2147/ott.s87976] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
MircroRNA-212 (miR-212) is proposed as a novel tumor-related miRNA and has been found to be significantly deregulated in human cancers. In this study, the miR-212 expression was found to be obviously downregulated in hepatocellular carcinoma (HCC) tissues as compared with adjacent nontumor tissues. Clinical association analysis indicated that low expression of miR-212 was prominently correlated with poor prognostic features of HCC, including high AFP level, large tumor size, high Edmondson-Steiner grading, and advanced tumor-node-metastasis tumor stage. Furthermore, the miR-212 expression was an independent prognostic marker for predicting both 5-year overall survival and disease-free survival of HCC patients. Our in vitro studies showed that upregulation of miR-212 inhibited cell proliferation and induced apoptosis in HepG2 cells. On the contrary, downregulation of miR-212 promoted cell proliferation and suppressed apoptosis in Huh7 cells. Interestingly, we found that upregulation of miR-212 decreased FOXA1 expression in HepG2 cells. Significantly, FOXA1 was identified as a direct target of miR-212 in HCC. FOXA1 was downregulated in HCC tissues as compared with noncancerous tissues. An inverse correlation between FOXA1 and miR-212 expression was observed in HCC tissues. Notably, FOXA1 knockdown inhibited cell proliferation and induced apoptosis in HepG2 cells. In conclusion, miR-212 is a potent prognostic marker and may suppress HCC tumor growth by inhibiting FOXA1 expression.
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Affiliation(s)
- Huahua Tu
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Gang Wei
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Qinghe Cai
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Xianxiang Chen
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Zequn Sun
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Caitao Cheng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Linfei Zhang
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Yong Feng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Huadong Zhou
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Bo Zhou
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
| | - Tiancai Zeng
- Department of Hepatobiliary Surgery, Hubei University of Medicine, Shiyan, People's Republic of China
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Zhang QH, Yao YL, Wu XY, Wu JH, Gu T, Chen L, Gu JH, Liu Y, Xu L. Anti-miR-362-3p Inhibits Migration and Invasion of Human Gastric Cancer Cells by Its Target CD82. Dig Dis Sci 2015; 60:1967-76. [PMID: 25652145 DOI: 10.1007/s10620-015-3563-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/27/2015] [Indexed: 02/06/2023]
Abstract
AIM This study was to investigate the effects and mechanisms of miR-362-3p on regulation of gastric cancer (GC) cell metastasis potential. METHODS We detected miR-362-3p level in GC and adjacent normal tissues and investigated the relationship with clinicopathological factors. Next, we analyzed the level of miR-362-3p expression and CD82 in different differentiated GC cells compared with a normal gastric mucosa cell by RT-PCR and Western blot. Dual-luciferase reporter assay and Western blot confirmed a direct interaction between miR-362-3p and CD82 3'UTR. After miR-362-3p and CD82 were silenced in GC cells, we compared the transfected GC cells migration and invasion capacity by transwell assay. In addition, we detected the effects on cells angiogenesis by tube formation assay. Western blot was used to detect the impact of CD82 and miR-362-3p on epithelial-to-mesenchymal transition markers in treated GC cells. RESULTS Level of miR-362-3p expression was much higher in GC cells than in normal gastric mucosa cell, and miR-362-3p expression negatively correlated with CD82 mRNA expression in these cell lines. Furthermore, miR-362-3p expression induced [corrected] GC cell metastasis capacity by suppression of CD82 expression. Level of miR-362-3p may mediate E-cadherin, N-cadherin, and vimentin expression in GC cells. CONCLUSION This study illuminated that downregulation of miR-362-3p along with the upregulation of CD82 in GC cells resulted in the inhibition of GC migration and invasion. Thus, our results suggested that miR-362-3p or CD82 can be exploited as a new potential target for control of GC in the future.
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Affiliation(s)
- Qing-Hui Zhang
- Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, 215300, Jiangsu, China
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Jiang C, Chen X, Alattar M, Wei J, Liu H. MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer. Cancer Gene Ther 2015; 22:291-301. [DOI: 10.1038/cgt.2015.19] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 03/15/2015] [Accepted: 03/16/2015] [Indexed: 02/07/2023]
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23
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MiR-212-3p inhibits glioblastoma cell proliferation by targeting SGK3. J Neurooncol 2015; 122:431-9. [DOI: 10.1007/s11060-015-1736-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 02/01/2015] [Indexed: 10/23/2022]
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Loginov VI, Rykov SV, Fridman MV, Braga EA. Methylation of miRNA genes and oncogenesis. BIOCHEMISTRY (MOSCOW) 2015; 80:145-62. [DOI: 10.1134/s0006297915020029] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Guo X, Xia J, Yan J. Promoter methylated microRNAs: potential therapeutic targets in gastric cancer. Mol Med Rep 2014; 11:759-65. [PMID: 25351138 PMCID: PMC4262514 DOI: 10.3892/mmr.2014.2780] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Accepted: 09/09/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth most commonly diagnosed type of cancer worldwide and has the second highest mortality rate of all cancer types. Classical genetics alone does not fully explain how GC occurs; however, epigenetics provides a partial explanation with regard to the cause of cancer. DNA methylation, the best-known type of epigenetic marker, represses the expression of tumor-suppressor genes and is involved in the pathogenesis of various types of human cancer, including GC. Micro (mi)RNAs are critical in the initiation, progression, metastasis and invasion of GC through gene regulation. The dysregulation of miRNAs is widely recognized as a hallmark of cancer. Recently, studies concerning DNA methylation of miRNAs in GC have been frequently reported, and these studies deepen the knowledge of how epigenetic regulation of miRNAs results in GC pathogenesis and indicate novel therapeutic strategies for GC. The present review provides an overview of the reported DNA methylation of miRNAs in GC.
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Affiliation(s)
- Xiaoqiang Guo
- Department of General Surgery and Center of Translational Medicine, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Jiazeng Xia
- Department of General Surgery and Center of Translational Medicine, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Jiang Yan
- Department of General Surgery and Center of Translational Medicine, Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
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26
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Lv L, Deng H, Li Y, Zhang C, Liu X, Liu Q, Zhang D, Wang L, Pu Y, Zhang H, He Y, Wang Y, Yu Y, Yu T, Zhu J. The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. Cell Death Dis 2014; 5:e1402. [PMID: 25188512 PMCID: PMC4540198 DOI: 10.1038/cddis.2014.367] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 06/30/2014] [Accepted: 07/24/2014] [Indexed: 01/18/2023]
Abstract
Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer.
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MESH Headings
- 3' Untranslated Regions
- Animals
- Antineoplastic Agents, Phytogenic/therapeutic use
- Antineoplastic Agents, Phytogenic/toxicity
- Base Sequence
- Cell Line, Tumor
- Cell Survival/drug effects
- DNA Damage
- DNA Methylation
- Drug Resistance, Neoplasm
- Gene Expression Regulation, Neoplastic
- Humans
- Kruppel-Like Transcription Factors/antagonists & inhibitors
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Molecular Sequence Data
- NF-kappa B/metabolism
- Nuclear Proteins/antagonists & inhibitors
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Oligonucleotides, Antisense/genetics
- Oligonucleotides, Antisense/metabolism
- Oxidative Stress
- Plasminogen Activators/antagonists & inhibitors
- Plasminogen Activators/genetics
- Plasminogen Activators/metabolism
- Proto-Oncogene Proteins c-myc/metabolism
- RNA Interference
- RNA, Small Interfering/metabolism
- Receptors, Notch/metabolism
- Ribonucleoproteins/antagonists & inhibitors
- Ribonucleoproteins/genetics
- Ribonucleoproteins/metabolism
- Serine-Arginine Splicing Factors
- Signal Transduction
- Transplantation, Heterologous
- Tumor Suppressor Proteins/antagonists & inhibitors
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism
- Urinary Bladder Neoplasms/drug therapy
- Urinary Bladder Neoplasms/metabolism
- Urinary Bladder Neoplasms/pathology
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Affiliation(s)
- L Lv
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
| | - H Deng
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
| | - Y Li
- Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China
| | - C Zhang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - X Liu
- Department of Bioinformatics, MHBI (Shanghai) Biotech Inc., GuiPing Road 333, Building 4/104, Shanghai Juke Biotech Park, Shanghai, China
| | - Q Liu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China
| | - D Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - L Wang
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
| | - Y Pu
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
| | - H Zhang
- Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China
| | - Y He
- Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China
| | - Y Wang
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Y Yu
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - T Yu
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
| | - J Zhu
- Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China
- Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China
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27
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MicroRNA and signaling pathways in gastric cancer. Cancer Gene Ther 2014; 21:305-16. [PMID: 25060632 DOI: 10.1038/cgt.2014.37] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Revised: 06/19/2014] [Accepted: 06/20/2014] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. The relationship between miRNAs and signaling pathways in gastric cancer is extremely complicated. In this paper, we determined the pathogenic mechanism of gastric cancer related to miRNA expression based on recent high-quality studies and then clarified the regulation network of miRNA expression and the correlated functions of these miRNAs during the progression of gastric cancer. We try to illustrate the correlation between the expression of miRNAs and outcomes of patients with gastric cancer. Understanding this will allow us to take a big step forward in the treatment of gastric cancer.
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28
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A functional variant at miR-132-3p, miR-212-3p, and miR-361-5p binding site in CD80 gene alters susceptibility to gastric cancer in a Chinese Han population. Med Oncol 2014; 31:60. [PMID: 24981235 DOI: 10.1007/s12032-014-0060-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 05/29/2014] [Indexed: 12/22/2022]
Abstract
A number of single-nucleotide polymorphisms within the 3'-UTR of genes have been shown to relate to the occurrence of cancers. In this study, by using polymerase chain reaction-restriction fragment length analysis method, we determined an SNP rs1599795 in the 3'-UTR of CD80 gene in 183 gastric cancer patients and 348 healthy controls. Statistical analysis results showed that SNP rs1599795 genotypes were significantly correlated with the risk of gastric cancer. Compared with the AA homozygotes, the TA heterozygotes were significantly more prevalent in the patients (OR 1.44, 95 % CI 0.98-2.11) with a larger tumor size (P = 0.001), deeper infiltration (P = 1.5 × 10(-5)), higher possibility of lymph node metastasis (P = 0.003), and more in the late stage (TNM stage III and IV; P = 0.003); the TT homozygotes had larger tumor size (P = 0.001) and lower degree of differentiation (P = 2.2 × 10(-4)). Dual-luciferase reporter assays showed that miR-132-3p, miR-212-3p, and miR-361-5p inhibited the expression of CD80 through binding with the CD80 3'-UTR, and this inhibitory role of miR-132-3p, miR-212-3p, and miR-361-5p was impacted by rs1599795. Our findings have shown that the SNP rs1599795 in CD80 3'-UTR, through disrupting the regulatory role of miR-132-3p, miR-212-3p, and miR-361-5p in CD80 expression, contributed to the occurrence of gastric cancer.
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Ma C, Nong K, Wu B, Dong B, Bai Y, Zhu H, Wang W, Huang X, Yuan Z, Ai K. miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1. J Exp Clin Cancer Res 2014; 33:54. [PMID: 24961235 PMCID: PMC4085644 DOI: 10.1186/1756-9966-33-54] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Accepted: 06/20/2014] [Indexed: 01/17/2023] Open
Abstract
Background microRNAs (miRNAs) are a class of small non-coding RNAs that play important roles in carcinogenesis. In the present study, we investigated the effect of miR-212 on pancreatic ductal adenocarcinoma (PDAC) and its target protein. Methods Quantitative real-time PCR(qRT-PCR) was performed to detect the expression of miR-212 in PDAC tissues and pancreatic cancer cell lines. miR-212 mimic, miR-212 inhibitor and negative control were transfected into pancreatic cancer cells and the effect of miR-212 up-regulation and down-regulation on the proliferation, migration and invasion of cells were investigated. Furthermore, the mRNA and protein levels of Patched-1(PTCH1) were measured. Meanwhile, luciferase assays were performed to validate PTCH1 as miR-212 target in PDAC. Results miR-212 was up-regulated in PDAC tissues and cells.Using both gain-of function and loss-of function experiments, a pro-oncogenic function of miR-212 was demonstrated in PDAC. Moreover, up-regulated of PTCH1 could attenuate the effect induced by miR-212. Conclusion These data suggest that miR-212 could facilitate PDAC progression and metastasis through targeting PTCH1, implicating a novel mechanism for the progression of PDAC.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Kaixing Ai
- Department of General Surgery, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, China.
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30
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Kang C, Song JJ, Lee J, Kim MY. Epigenetics: An emerging player in gastric cancer. World J Gastroenterol 2014; 20:6433-6447. [PMID: 24914365 PMCID: PMC4047329 DOI: 10.3748/wjg.v20.i21.6433] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 01/21/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Cancers, like other diseases, arise from gene mutations and/or altered gene expression, which eventually cause dysregulation of numerous proteins and noncoding RNAs. Changes in gene expression, i.e., upregulation of oncogenes and/or downregulation of tumor suppressor genes, can be generated not only by genetic and environmental factors but also by epigenetic factors, which are inheritable but nongenetic modifications of cellular chromosome components. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. The search for genetic and environmental factors has a long history in cancer research, but epigenetic factors only recently began to be associated with cancer formation, progression, and metastasis. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Recent studies have revealed diverse mechanisms by which chromatin modifiers, including writers, erasers and readers of the aforementioned modifications, contribute to the formation and progression of cancer. Furthermore, functional RNAs, such as microRNAs and long noncoding RNAs, have also been identified as key players in these processes. This review highlights recent findings concerning the epigenetic alterations associated with cancers, especially gastric cancer.
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31
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Jiping Z, Ming F, Lixiang W, Xiuming L, Yuqun S, Han Y, Zhifang L, Yundong S, Shili L, Chunyan C, Jihui J. MicroRNA-212 inhibits proliferation of gastric cancer by directly repressing retinoblastoma binding protein 2. J Cell Biochem 2014; 114:2666-72. [PMID: 23794145 DOI: 10.1002/jcb.24613] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 06/11/2013] [Indexed: 01/02/2023]
Abstract
Retinoblastoma binding protein 2 (RBP2), a newly found histone demethylase, is overexpressed in gastric cancer. We examined the upstream regulatory mechanism of RBP2 at the microRNA (miRNA) level and the role in gastric carcinogenesis. We used bioinformatics to predict that microRNA-212 (miR-212) might be a direct upstream regulator of RBP2 and verified the regulation in gastric epithelial-derived cell lines. Overexpression of miR-212 significantly inhibited the expression levels of RBP2, whereas knockdown of miR-212 promoted RBP2 expression. Furthermore, we identified the putative miR-212 targeting sequence in the RBP2 3' UTR by luciferase assay. MiR-212 inhibited the colony formation ability of cells by repressing RBP2 expression and increasing that of P21(CIP1) and P27(kip1), both critical in cell cycle arrest. In addition, the expression of RBP2 and miR-212 in tumor tissue and matched normal tissue from 18 patients further supported the results in vivo. MiR-212 directly regulates the expression of RBP2 and inhibits cell growth in gastric cancer, which may provide new clues to treatment.
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Affiliation(s)
- Zeng Jiping
- Department of Microbiology/Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, Shandong University School of Medicine, Jinan, China; Department of Biochemistry, Shandong University School of Medicine, Jinan, China
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32
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Epigenetically regulated microRNAs in Alzheimer's disease. Neurobiol Aging 2014; 35:731-45. [DOI: 10.1016/j.neurobiolaging.2013.10.082] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Revised: 10/09/2013] [Accepted: 10/16/2013] [Indexed: 12/12/2022]
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33
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Ma J, Hong L, Chen Z, Nie Y, Fan D. Epigenetic regulation of microRNAs in gastric cancer. Dig Dis Sci 2014; 59:716-23. [PMID: 24248419 DOI: 10.1007/s10620-013-2939-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 10/28/2013] [Indexed: 01/02/2023]
Abstract
Gastric cancer is one of the most common cancers and accounts for a large proportion of cancer-related deaths in the world, while the pathogenesis of it is still not clear. Epigenetic changes have been found to participate in the development and progression of gastric cancer. Epigenetic changes involve methylation of cytosines in DNA, modifications of histone, chromatin remodeling, and alterations in the expression of microRNAs. MicroRNAs, a family of small non-coding RNAs, have been demonstrated to participate in many fundamental biological processes including the carcinogenesis of gastric cancer. Previous studies have shown that the downregulation of microRNAs are often caused by the methylation in the CpG islands of microRNA promoters. Here, we have summarized the functions and molecular mechanisms of gastric cancer related methylated microRNAs in gastric carcinogenesis. We further envisage the clinical application of microRNA methylation in the early diagnosis, treatment and prognosis assessment of gastric cancer.
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Affiliation(s)
- Jiaojiao Ma
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, No. 127 West Changle Road, Xi'an, 710032, Shaanxi, China
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34
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Liang X, Zeng J, Wang L, Fang M, Wang Q, Zhao M, Xu X, Liu Z, Li W, Liu S, Yu H, Jia J, Chen C. Histone demethylase retinoblastoma binding protein 2 is overexpressed in hepatocellular carcinoma and negatively regulated by hsa-miR-212. PLoS One 2013; 8:e69784. [PMID: 23922798 PMCID: PMC3726779 DOI: 10.1371/journal.pone.0069784] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 06/12/2013] [Indexed: 12/18/2022] Open
Abstract
Background The H3K4 demethylase retinoblastoma binding protein 2 (RBP2) is involved in the pathogenesis of gastric cancer, but its role and regulation in hepatocellular carcinoma (HCC) is unknown. We determined the function of RBP2 and its regulation in HCC in vitro and in human tissues. Methods We analyzed gene expression in 20 specimens each of human HCC and normal liver tissue by quantitative real-time PCR and immunohistochemistry. Proliferation was analyzed by foci formation and senescence by β-galactosidase staining. Promoter activity was detected by luciferase reporter assay. Results The expression of RBP2 was stronger in cancerous than non-cancerous tissues, but that of its binding microRNA, Homo sapiens miR-212 (hsa-miR-212), showed an opposite pattern. SiRNA knockdown of RBP2 significantly upregulated cyclin-dependent kinase inhibitors (CDKIs), with suppression of HCC cell proliferation and induction of senescence. Overexpression of hsa-miR-212 suppressed RBP2 expression, with inhibited cell proliferation and induced cellular senescence, which coincided with upregulated CDKIs; with low hsa-miR-212 expression, CDKIs were downregulated in HCC tissue. Inhibition of hsa-miR-212 expression upregulated RBP2 expression. Luciferase reporter assay detected the direct binding of hsa-miR-212 to the RBP2 3′ UTR. Conclusions RBP2 is overexpressed in HCC and negatively regulated by hsa-miR-212. The hsa-miR-212–RBP2–CDKI pathway may be important in the pathogenesis of HCC.
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Affiliation(s)
- Xiuming Liang
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Jiping Zeng
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
- Department of Biochemistry, Shandong University School of Medicine, Jinan, P. R. China
| | - Lixiang Wang
- Department of Pharmacology, Shandong University School of Medicine, Jinan, P. R. China
| | - Ming Fang
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Qing Wang
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Min Zhao
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Xia Xu
- Department of Biochemistry, Shandong University School of Medicine, Jinan, P. R. China
| | - Zhifang Liu
- Department of Biochemistry, Shandong University School of Medicine, Jinan, P. R. China
| | - Wenjuan Li
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Shili Liu
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Han Yu
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Jihui Jia
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
| | - Chunyan Chen
- Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, Shandong University School of Medicine, Jinan, P. R. China
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, P. R. China
- * E-mail:
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35
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Gigek CO, Chen ES, Calcagno DQ, Wisnieski F, Burbano RR, Smith MAC. Epigenetic mechanisms in gastric cancer. Epigenomics 2012; 4:279-94. [PMID: 22690664 DOI: 10.2217/epi.12.22] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer is considered one of the major health issues worldwide, and gastric cancer accounted for 8% of total cases and 10% of total deaths in 2008. Gastric cancer is considered an age-related disease, and the total number of newly diagnosed cases has been increasing as a result of the higher life expectancy. Therefore, the basic mechanisms underlying gastric tumorigenesis is worth investigation. This review provides an overview of the epigenetic mechanisms, such as DNA methylation, histone modifications, chromatin remodeling complex and miRNA, involved in gastric cancer. As the studies in gastric cancer continue, the mapping of an epigenome code is not far for this disease. In conclusion, an epigenetic therapy might appear in the not too distant future.
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Affiliation(s)
- Carolina Oliveira Gigek
- Disciplina de Genética, Departamento de Morfologia e Genética, Escola Paulista de Medicina/Universidade Federal de São Paulo, Rua Botucatu 740, São Paulo, SP, Brazil.
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36
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Sun SM, Rockova V, Bullinger L, Dijkstra MK, Döhner H, Löwenberg B, Jongen-Lavrencic M. The prognostic relevance of miR-212 expression with survival in cytogenetically and molecularly heterogeneous AML. Leukemia 2012; 27:100-6. [PMID: 22692398 DOI: 10.1038/leu.2012.158] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous disease, characterized by various cytogenetic and molecular abnormalities, many of which may express prognostic value. MicroRNAs (miRNAs) are a class of small regulatory RNAs. The prognostic value of miRNAs in AML is yet to be determined. Here, we set out to identify miRNAs that are consistent significant prognostic determinants, independent from other known prognostic factors. A discovery cohort (n=167) and validation cohort (n=409) of a heterogeneous AML population were used to reliably identify miRNAs with prognostic value. We report miR-212 as an independent prognostic factor, significantly associated with a prolonged overall survival (OS) and also event-free and relapse-free survival in a discovery cohort (hazard ratio (HR)s=0.77, P=0.015 for OS) that was subsequently confirmed in an independent validation cohort of 409 cases (HR=0.83, P=0.016). The prognostic significance and the prevalence of high miR-212 did not correlate with specific (cyto)genetic subtypes of AML. High miR-212 expression levels are associated with a gene expression profile that is significantly enriched for genes involved in the immune response. MiR-212 may improve the current prognostic risk stratification of mixed AML including normal karyotype AML and AML with cytogenetic and molecular abnormalities.
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Affiliation(s)
- S M Sun
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
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37
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Noto JM, Peek RM. The role of microRNAs in Helicobacter pylori pathogenesis and gastric carcinogenesis. Front Cell Infect Microbiol 2012; 1:21. [PMID: 22919587 PMCID: PMC3417373 DOI: 10.3389/fcimb.2011.00021] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/12/2011] [Indexed: 12/13/2022] Open
Abstract
Gastric carcinogenesis is a multistep process orchestrated by aberrancies in the genetic and epigenetic regulation of oncogenes and tumor suppressor genes. Chronic infection with Helicobacter pylori is the strongest known risk factor for the development of gastric cancer. H. pylori expresses a spectrum of virulence factors that dysregulate host intracellular signaling pathways that lower the threshold for neoplastic transformation. In addition to bacterial determinants, numerous host and environmental factors increase the risk of gastric carcinogenesis. Recent discoveries have shed new light on the involvement of microRNAs (miRNAs) in gastric carcinogenesis. miRNAs represent an abundant class of small, non-coding RNAs involved in global post-transcriptional regulation and, consequently, play an integral role at multiple steps in carcinogenesis, including cell cycle progression, proliferation, apoptosis, invasion, and metastasis. Expression levels of miRNAs are frequently altered in malignancies, where they function as either oncogenic miRNAs or tumor suppressor miRNAs. This review focuses on miRNAs dysregulated by H. pylori and potential etiologic roles they play in H. pylori-mediated gastric carcinogenesis.
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Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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38
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Hanin G, Soreq H. Cholinesterase-Targeting microRNAs Identified in silico Affect Specific Biological Processes. Front Mol Neurosci 2011; 4:28. [PMID: 22007158 PMCID: PMC3186941 DOI: 10.3389/fnmol.2011.00028] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2011] [Accepted: 09/14/2011] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRs) have emerged as important gene silencers affecting many target mRNAs. Here, we report the identification of 244 miRs that target the 3′-untranslated regions of different cholinesterase transcripts: 116 for butyrylcholinesterase (BChE), 47 for the synaptic acetylcholinesterase (AChE-S) splice variant, and 81 for the normally rare splice variant AChE-R. Of these, 11 and 6 miRs target both AChE-S and AChE-R, and AChE-R and BChE transcripts, respectively. BChE and AChE-S showed no overlapping miRs, attesting to their distinct modes of miR regulation. Generally, miRs can suppress a number of targets; thereby controlling an entire battery of functions. To evaluate the importance of the cholinesterase-targeted miRs in other specific biological processes we searched for their other experimentally validated target transcripts and analyzed the gene ontology enriched biological processes these transcripts are involved in. Interestingly, a number of the resulting categories are also related to cholinesterases. They include, for BChE, response to glucocorticoid stimulus, and for AChE, response to wounding and two child terms of neuron development: regulation of axonogenesis and regulation of dendrite morphogenesis. Importantly, all of the AChE-targeting miRs found to be related to these selected processes were directed against the normally rare AChE-R splice variant, with three of them, including the neurogenesis regulator miR-132, also directed against AChE-S. Our findings point at the AChE-R splice variant as particularly susceptible to miR regulation, highlight those biological functions of cholinesterases that are likely to be subject to miR post-transcriptional control, demonstrate the selectivity of miRs in regulating specific biological processes, and open new venues for targeted interference with these specific processes.
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Affiliation(s)
- Geula Hanin
- The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Jerusalem, Israel
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Tsai KW, Liao YL, Wu CW, Hu LY, Li SC, Chan WC, Ho MR, Lai CH, Kao HW, Fang WL, Huang KH, Lin WC. Aberrant hypermethylation of miR-9 genes in gastric cancer. Epigenetics 2011; 6:1189-97. [PMID: 21931274 DOI: 10.4161/epi.6.10.16535] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Carcinogenesis of the stomach involves multiple steps including genetic mutation or epigenetic alteration of tumor suppressor genes or oncogenes. Recently, tumor suppressive miRNAs have been shown to be deregulated by aberrant hypermethylation during gastric cancer progression. In this study, we demonstrate that three independent genetic loci encoding for miR-9 (miR-9-1, miR-9-2 and miR-9-3) are simultaneously modified by DNA methylation in gastric cancer cells. Methylation-mediated silencing of these three miR-9 genes can be reactivated in gastric cancer cells through 5-Aza-dC treatment. Subsequent analysis of the expression levels of miR-9 showed that it was significantly down-regulated in gastric cancers compared with adjacent normal tissues (P value < 0.005). A similar tendency toward a tumor-specific DNA methylation pattern was shown for miR-9-1, miR-9-2 and miR-9-3 in 72 primary human gastric cancer specimens. Ectopic expression of miR-9 inhibited cell proliferation, migration and invasion, suggesting its tumor suppressive potential in gastric cancer progression.
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Affiliation(s)
- Kuo-Wang Tsai
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, China
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Park JK, Henry JC, Jiang J, Esau C, Gusev Y, Lerner MR, Postier RG, Brackett DJ, Schmittgen TD. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. Biochem Biophys Res Commun 2011; 406:518-23. [PMID: 21329664 DOI: 10.1016/j.bbrc.2011.02.065] [Citation(s) in RCA: 143] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Accepted: 02/10/2011] [Indexed: 02/07/2023]
Abstract
Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G(2)/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the β2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The β2 adrenergic pathway may play an important role in this novel mechanism.
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Affiliation(s)
- Jong-Kook Park
- College of Pharmacy, Ohio State University, Columbus, OH 43210, United States
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