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1
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Villagrán-Silva F, Loren P, Sandoval C, Lanas F, Salazar LA. Circulating microRNAs as Potential Biomarkers of Overweight and Obesity in Adults: A Narrative Review. Genes (Basel) 2025; 16:349. [PMID: 40149500 PMCID: PMC11942292 DOI: 10.3390/genes16030349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Revised: 03/12/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
In an obesogenic environment, such as the one we have been experiencing in recent decades, epigenetics provides answers to the relationship between hereditary and environmentally acquired patterns that have significantly contributed to the global rise in obesity prevalence. MicroRNA (miRNA) constitutes a diminutive non-coding small RNA molecule, 20 to 24 nucleotides in length, that functions as a regulator of gene regulation at the post-translational level. Circulating miRNAs (c-miRNAs) have been detected in multiple body fluids, including blood, plasma, serum, saliva, milk from breastfeeding mothers, and urine. These molecules hold significant therapeutic value and serve as extracellular biomarkers in metabolic diseases. They aid in the diagnosis and tracking of therapy responses, as well as dietary and physical habit modifications. Researchers have studied c-miRNAs as potential biomarkers for diagnosing and characterizing systemic diseases in people of all ages and backgrounds since then. These conditions encompass dyslipidemia, type 2 diabetes mellitus (T2DM), cardiovascular risk, metabolic syndrome, cardiovascular diseases, and obesity. This review therefore analyzes the usefulness of c-miRNAs as therapeutic markers over the past decades. It also provides an update on c-miRNAs associated with general obesity and overweight, as well as with the most prevalent pathologies in the adult population. It also examines the effect of different nutritional approaches and physical activity regarding the activity of miRNAs in circulation in adults with overweight or general obesity. All of this is done with the aim of evaluating their potential use as biomarkers in various research contexts related to overweight and obesity in adults.
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Affiliation(s)
- Francisca Villagrán-Silva
- Doctoral Program in Morphological Sciences, Faculty of Medicine, Universidad de la Frontera, Temuco 4811230, Chile;
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
| | - Pía Loren
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
| | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile;
- Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile
| | - Fernando Lanas
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
- Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (F.L.)
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2
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Herbst E, Mandel-Gutfreund Y, Yakhini Z, Biran H. Inferring single-cell and spatial microRNA activity from transcriptomics data. Commun Biol 2025; 8:87. [PMID: 39827321 PMCID: PMC11743151 DOI: 10.1038/s42003-025-07454-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025] Open
Abstract
The activity of miRNA varies across different cell populations and systems, as part of the mechanisms that distinguish cell types and roles in living organisms and in human health and disease. Typically, miRNA regulation drives changes in the composition and levels of protein-coding RNA and of lncRNA, with targets being down-regulated when miRNAs are active. The term "miRNA activity" is used to refer to this transcriptional effect of miRNAs. This study introduces miTEA-HiRes, a method designed to facilitate the evaluation of miRNA activity at high resolution. The method applies to single-cell transcriptomics, type-specific single-cell populations, and spatial transcriptomics data. By comparing different conditions, differential miRNA activity is inferred. For instance, miTEA-HiRes analysis of peripheral blood mononuclear cells comparing Multiple Sclerosis patients to control groups revealed differential activity of miR-20a-5p and others, consistent with the literature on miRNA underexpression in Multiple Sclerosis. We also show miR-519a-3p differential activity in specific cell populations.
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Affiliation(s)
- Efrat Herbst
- Arazi School of Computer Science, Reichman University, Herzliya, Israel.
| | - Yael Mandel-Gutfreund
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
- Faculty of Biology, Technion - Israel Institute of Technology, Haifa, Israel
| | - Zohar Yakhini
- Arazi School of Computer Science, Reichman University, Herzliya, Israel
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
| | - Hadas Biran
- Computer Science Department, Technion - Israel Institute of Technology, Haifa, Israel
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3
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Jeong HR, Hwang IT. MicroRNAs as novel biomarkers for the diagnosis and treatment of pediatric diseases. Clin Exp Pediatr 2024; 67:119-125. [PMID: 37232075 PMCID: PMC10915459 DOI: 10.3345/cep.2023.00171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 05/27/2023] Open
Abstract
MicroRNAs (miRNAs) are highly conserved noncoding RNAs that regulate gene expression by silencing or degrading messenger RNAs. Many of the approximately 2,500 miRNAs discovered in humans are known to regulate vital biological processes, including cell differentiation, proliferation, apoptosis, and embryonic tissue development. Aberrant miRNA expression may have pathological and malignant consequences. Therefore, miRNAs have emerged as novel diagnostic markers and potential therapeutic targets for various diseases. Children undergo various stages of growth, development, and maturation between birth and adulthood. It is important to study the role of miRNA expression in normal growth and disease development during these developmental stages. In this mini-review, we discuss the role of miRNAs as diagnostic and prognostic biomarkers in various pediatric diseases.
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Affiliation(s)
- Hwal Rim Jeong
- Department of Pediatrics, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Il Tae Hwang
- Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
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4
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Alemi F, Sadeghsoltani F, Fattah K, Hassanpour P, Malakoti F, Kardeh S, Izadpanah M, de Campos Zuccari DAP, Yousefi B, Majidinia M. Applications of engineered exosomes in drugging noncoding RNAs for cancer therapy. Chem Biol Drug Des 2023; 102:1257-1275. [PMID: 37496299 DOI: 10.1111/cbdd.14300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 05/31/2023] [Accepted: 07/17/2023] [Indexed: 07/28/2023]
Abstract
Noncoding RNAs (ncRNAs) are engaged in key cell biological and pathological events, and their expression alteration is connected to cancer progression both directly and indirectly. A huge number of studies have mentioned the significant role of ncRNAs in cancer prevention and therapy that make them an interesting subject for cancer therapy. However, there are several limitations, including delivery, uptake, and short half-life, in the application of ncRNAs in cancer treatment. Exosomes are introduced as promising options for the delivery of ncRNAs to the target cells. In this review, we will briefly discuss the application and barriers of ncRNAs. After that we will focus on exosome-based ncRNAs delivery and their advantages as well as the latest achievements in drugging ncRNAs with exosomes.
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Affiliation(s)
- Forough Alemi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Khashayar Fattah
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Kardeh
- Central Clinical School, Monash University, Melbourne, Australia
| | - Melika Izadpanah
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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5
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Yoshikawa R, Inoue J, Iwasaki R, Terauchi M, Fujii Y, Ohta M, Hasegawa T, Mizuno R, Mori T, Inazawa J. Therapeutic applications of local injection of hsa-miR-634 into canine spontaneous malignant melanoma tumors. Cancer Gene Ther 2023; 30:1524-1529. [PMID: 37553484 DOI: 10.1038/s41417-023-00656-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 07/10/2023] [Accepted: 08/01/2023] [Indexed: 08/10/2023]
Abstract
Malignant melanoma (MM) is one of the most common tumors in both dogs and humans. As canine MM (CMM) and human MM (HMM) have similar clinical characteristics, CMM appears to be a good clinical model for HMM. We previously demonstrated that the introduction of a synthetic double-strand-microRNA-634 (miR-634) mimic triggered apoptotic cell death by directly targeting the genes associated with cytoprotective processes in various human cancer cell lines, including those of HMM. This study aimed to investigate the antitumor effects of the local administration of miR-634 on spontaneous CMMs to provide a basis for future applications of miR-634 formulations in HMM treatment. We found that miR-634 administration induced apoptosis in CMM cell lines in vitro via downregulation of Asct2, Nrf2, and survivin expression, similar to the mechanisms in HMM cell lines. Furthermore, intratumoral miR-634 administration induced antitumor effects in four of seven spontaneous CMM cases, with no adverse effects. Local administration of miR-634 to lung metastasis under ultrasound guidance induced tumor shrinkage. These results confirm the antitumor effect of the local administration of miR-634 in spontaneous CMM, a model for spontaneous HMM, thereby providing a novel treatment strategy for HMM.
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Affiliation(s)
| | - Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryota Iwasaki
- Animal Medical Center, Gifu University, Gifu, Japan
- Joint Department of Veterinary Medicine Gifu University, Gifu, Japan
| | | | - Yuji Fujii
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
| | - Maya Ohta
- Animal Medical Center, Gifu University, Gifu, Japan
| | | | - Rui Mizuno
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
| | - Takashi Mori
- Animal Medical Center, Gifu University, Gifu, Japan
- Joint Department of Veterinary Medicine Gifu University, Gifu, Japan
- Joint Graduate School of Veterinary Sciences, Gifu University, Gifu, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
- Research Core Center, Tokyo Medical and Dental University, Tokyo, Japan
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6
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Zhang T, Chen L, Xu X, Shen C. Knockdown of Long Noncoding RNA Urothelial Carcinoma-Associated 1 Represses Gallbladder Cancer Advancement by Regulating SPOCK1 Expression Through Sponging miR-613. Cancer Biother Radiopharm 2023; 38:354-363. [PMID: 33090888 DOI: 10.1089/cbr.2020.4290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Gallbladder cancer (GBC) is the most common biliary tract malignancy. Long noncoding RNA urothelial carcinoma-associated 1 (UCA1) and MicroRNA-613 (miR-613) have been reported to be involved in the progression of various cancers. However, the regulatory mechanism between UCA1 and miR-613 in GBC is unclear. Materials and Methods: The expression levels of UCA1, miR-613, and secreted protein/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) mRNA were detected using quantitative real-time polymerase chain reaction. Cell proliferation, migration, invasion, and apoptosis were determined with MTT, transwell, or flow cytometry assays. The levels of SPOCK1 protein, Bax, cleaved-casp-3, and Bcl-2 were determined by Western blot analysis. The relationship between miR-613 and UCA1 or SPOCK1 was verified through dual-luciferase reporter and/or RNA immunoprecipitation assays. Xenograft assay was performed to verify the role of UCA1 in vivo. Results: UCA1 and SPOCK1 were upregulated, whereas miR-613 was downregulated in GBC tissues and cells. UCA1 silencing decreased tumor growth in vivo and impeded proliferation, migration, invasion, and induced apoptosis of GBC cells in vitro. Notably, UCA1 acted as a sponge for miR-613, which targeted SPOCK1 in GBC cells. Moreover, UCA1 enhancement reversed the repressive impact of miR-613 mimic on the malignancy of GBC cells. UCA1 regulated SPOCK1 expression through adsorbing miR-613. Furthermore, SPOCK1 elevation overturned UCA1 silencing mediated the malignant behaviors of GBC cells. Conclusion: UCA1 knockdown suppressed GBC progression through downregulating SPOCK1 via sponging miR-613, providing an evidence for UCA1 as a target for GBC treatment.
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Affiliation(s)
- Tao Zhang
- Department of Hepatobiliary Surgery, Loudi Central Hospital of Hunan, Loudi, China
| | - Lijian Chen
- Department of General Surgery, Hunan Children's Hospital, Changsha, China
| | - Xundi Xu
- Department of Hepatobiliary Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chao Shen
- Department of Urology, Loudi Central Hospital of Hunan, Loudi, China
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7
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Expression profiling of miRNA-196a biomarker in naïve hepatitis C virus-infected and Sofosbuvir plus Daclatasvir-treated patients. Arch Microbiol 2021; 203:2365-2371. [PMID: 33660021 DOI: 10.1007/s00203-021-02233-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 12/31/2020] [Accepted: 02/11/2021] [Indexed: 10/22/2022]
Abstract
Micro-RNA (miRNA) is a short stretch of nucleotides that can regulate many genes associated with the various stages of the hepatitis C virus (HCV) life cycle and disease progression. This study evaluates the expression profiling of miRNA-196a in naïve HCV-infected, and Sofosbuvir plus Daclatasvir-treated patients. MiRNA-196a can inhibit HCV replication by silencing the HCV NS5A protein or downregulating the human BACH-I mRNA. The expression level of miRNA-196a was determined by quantitative reverse transcription PCR (RT-qPCR) using the whole RNA extracted from the recruited participant's serum. Results showed a 0.83-fold decrease in the miRNA-196a level in naïve HCV-infected than controls. On the contrary, an increase in the expression level by 0.06-fold was observed in Sofosbuvir plus Daclatasvir-treated patients. A negative but significant correlation was recorded between the HCV-RNA load and miRNA-196a expression level in the naïve-infected patients. Serum miRNA-196a ROC curve analysis revealed an area under the curve of 0.8278 (95% CI 0.7033-0.9524, p < 0.0001) with 82.05% sensitivity and 76.19% specificity in discriminating the healthy controls from the HCV-infected samples. In conclusion, our study explored the comparative expression levels of miRNA-196a in HCV-infected and Sofosbuvir plus Daclatasvir patients. Further studies are needed to examine the possible role of miR-196a as a therapeutic agent for treating HCV-infected patients.
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8
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Soltani S, Zakeri A, Tabibzadeh A, Zakeri AM, Zandi M, Siavoshi S, Seifpour S, Farahani A. A review on EBV encoded and EBV-induced host microRNAs expression profile in different lymphoma types. Mol Biol Rep 2021; 48:1801-1817. [PMID: 33523370 DOI: 10.1007/s11033-021-06152-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/12/2021] [Indexed: 01/10/2023]
Abstract
Previous literature supports the variations in microRNAs expression levels among lymphoma patients due to EBV infection. These alterations can be observed in both EBV-encoded-microRNAs and EBV-induced cellular microRNAs. Moreover, changes in the microRNA profile could be significant in disease progression. This study aimed to assess published literature to obtain a microRNA profile for both EBV-encoded microRNAs and EBV-induced cellular microRNAs among lymphoma patients. We searched common available electronic databases by using relevant keywords. The result demonstrated that EBV infection could alter the microRNA expression levels among lymphoma patients. In Burkitt lymphoma, hsa-miR197 and miR510 were most frequently assessed human micro RNAs. Also, miR-BART6-3P and miR-BART17-5P were the most frequent viral micro RNAs in Burkitt lymphoma. Other human important micro RNAs were hsa-miR155 (in Diffuse large B cell lymphoma (DLBCL)), hsa-miR145 (in Nasal natural killer T cell lymphoma (NNKTCL)), miR-96, miR-128a, miR-128b, miR-129, and miR-205 (in Classic Hodgkin lymphoma (CHL)), miR-21, miR-142-3P, miR-126, miR-451 and miR-494-3P (in Nasal natural killer cell lymphoma (NNKCL)). Also, viral assessed micro RNAs were miR-BART1-5P (in DLBCL and NNKTCL), miR-BART-5 (in CHL), and EBV-miR-BART20-5P (in NNKCL). In conclusion, it could be suggested that EBV-encoded-microRNAs and EBV-induced cellular-microRNAs can be utilized as helpful factors for different types of lymphoma diagnoses or prognostic factors. Moreover, the mentioned microRNAs can also be promising therapeutic targets and can be used to modulate the oncogenes.
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Affiliation(s)
- Saber Soltani
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Armin Zakeri
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Alireza Tabibzadeh
- Department of Virology, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Mohammad Zakeri
- Pediatric Surgery Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Milad Zandi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Saba Siavoshi
- Razi Vaccine and Serum Research Institute, Karaj, Iran
| | - Saba Seifpour
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abbas Farahani
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
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9
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Yoshikawa R, Heishima K, Ueno Y, Kawade M, Maeda Y, Yoshida K, Murakami M, Sakai H, Akao Y, Mori T. Development of synthetic microRNA-214 showing enhanced cytotoxicity and RNase resistance for treatment of canine hemangiosarcoma. Vet Comp Oncol 2020; 18:570-579. [PMID: 32072720 DOI: 10.1111/vco.12580] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 02/06/2023]
Abstract
MicroRNA-214 (miR-214), a pivotal tumour-suppressive miRNA, is downregulated in canine hemangiosarcoma (HSA) cells. Although these tumour-suppressive miRNAs are potential therapeutic agents, their clinical efficacy may be limited because of their vulnerability to RNase-rich microenvironments and low in vivo transfection rates. We developed synthetic miR-214s with enhanced cytotoxicity, RNase resistance and quantity of miR-214 in/on cells. These synthetic miR-214s were synthesized by various chemical modifications (such as 4'-aminoethyl-2'-fluoro, 2'-fluoro, 2'-O-methyl, phosphorothioate and oligospermine modifications) of the wild-type mature miR-214 sequences. Transfection of HSA cells with synthetic miR-214 (miR-214 5AE) demonstrated significant growth suppressive effect and induced the strongest apoptotic response. Synthetic miR-214s (miR-214 5AE, miR-214 10AE and miR-214 OS) were much more stable than mature miR-214s in foetal bovine serum. Similar to mature miR-214, 5AE and OS suppressed the expression level of COP1 in HSA cells. The quantity of synthetic miR-214s in/on cells was higher than that of mature miR-214. In conclusion, we developed a clinically applicable, synthetic miR-214 5AE that regulates the COP1 protein expression similar to that mediated by mature miR-214. Additionally, miR-214 5AE confers better cytotoxicity, nuclease resistance and transfection rate than mature miR-214. Thus, miR-214 5AE could potentially be a novel miRNA-based chemotherapeutic agent that could improve the prognosis of HSA. Its in vivo effects on canine HSA need to be examined in future.
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Affiliation(s)
- Ryutaro Yoshikawa
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Kazuki Heishima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Yoshihito Ueno
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan.,United Graduate School of Agricultural Science, Gifu University, Gifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan
| | - Miwa Kawade
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Yusuke Maeda
- Course of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kyoko Yoshida
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Mami Murakami
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan
| | - Hiroki Sakai
- Department of Veterinary Pathology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Takashi Mori
- Laboratory of Veterinary Clinical Oncology, Joint Department of Veterinary Medicine, Gifu University, Gifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan
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10
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Bhat SA, Majid S, Rehman MU. Scenario and future prospects of microRNAs in gastric cancer: A review. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2019; 22:345-352. [PMID: 31168337 PMCID: PMC6535194 DOI: 10.22038/ijbms.2019.32399.7765] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 12/11/2018] [Indexed: 12/19/2022]
Abstract
Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC.
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Affiliation(s)
- Showkat Ahmad Bhat
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
| | - Sabhiya Majid
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
| | - Muneeb U Rehman
- Department of Biochemistry, Govt. Medical College, Srinagar Jammu & Kashmir, India
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11
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Liu X, Liu S, Lyu H, Riker AI, Zhang Y, Liu B. Development of Effective Therapeutics Targeting HER3 for Cancer Treatment. Biol Proced Online 2019; 21:5. [PMID: 30930695 PMCID: PMC6425631 DOI: 10.1186/s12575-019-0093-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 03/05/2019] [Indexed: 02/08/2023] Open
Abstract
HER3 is the third member of the human epidermal growth factor receptor (HER/EGFR) family, and unlike its other family members, is unique due to its minimal intrinsic kinase activity. As a result, HER3 has to interact with another receptor tyrosine kinase (RTK), such as EGFR or HER2, in order to activate the PI-3 K/Akt, MEK/MAPK, Jak/Stat pathways, as well as Src kinase. Over-expression of HER3 in various human cancers promotes tumor progression by increasing metastatic potential and acting as a major cause of treatment failure. Effective inhibition of HER3, and/or the key downstream mediators of HER3 signaling, is thought to be required to overcome resistance and enhance therapeutic efficacy. To date, there is no known HER3-targeted therapy that is approved for breast cancer, with a number of anti-HER3 antibodies current in various stages of development and clinical testing. Recent data suggests that the epigenetic strategy of using a histone deacetylase (HDAC) inhibitor, or functional cooperative miRNAs, may be an effective way to abrogate HER3 signaling. Here, we summarize the latest advances in our understanding of the mechanism of HER3 signaling in tumor progression, with continuing research towards the identification of therapeutic anti-HER3 antibodies. We will also examine the potential to develop novel epigenetic approaches that specifically target the HER3 receptor, along with important key downstream mediators that are involved in cancer treatment.
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Affiliation(s)
- Xiaolong Liu
- 1Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Shuang Liu
- 2Department of Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA USA
| | - Hui Lyu
- 2Department of Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA USA
| | - Adam I Riker
- 3Department of Surgery, Section of Surgical Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA USA
| | - Yamin Zhang
- 1Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Bolin Liu
- 2Department of Genetics, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA USA
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12
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Lyu H, Huang J, He Z, Liu B. Targeting of HER3 with Functional Cooperative miRNAs Enhances Therapeutic Activity in HER2-Overexpressing Breast Cancer Cells. Biol Proced Online 2018; 20:16. [PMID: 30093840 PMCID: PMC6081814 DOI: 10.1186/s12575-018-0081-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 07/23/2018] [Indexed: 02/05/2023] Open
Abstract
Background The HER3 receptor functions as a major cause of drug resistance in cancer treatment. It is believed that therapeutic targeting of HER3 is required to improve patient outcomes. It is not clear whether a novel strategy with two functional cooperative miRNAs would effectively inhibit erbB3 expression and potentiate the anti-proliferative/anti-survival effects of a HER2-targeted therapy (trastuzumab) and chemotherapy (paclitaxel) on HER2-overexpressing breast cancer cells. Results Combination of miR-125a and miR-205, as compared to either miRNA alone, potently inhibited expression of HER3 in HER2-overexpressing breast cancer BT474 cells. Co-expression of the two miRNAs not only reduced the levels of phosphorylated erbB3 (P-erbB3), Akt (P-Akt), and Src (P-Src), it also inhibited cell proliferation and increased cells at G1 phase. A multi-miRNA lentiviral vector - the cluster of miR-125a and miR-205 - was constructed to simultaneously express the two miRNAs in HER2-overexpressing breast cancer cells. Concurrent expression of miR-125a and miR-205 via the miRNA cluster transfection significantly enhanced trastuzumab-mediated growth inhibition and cell cycle G1 arrest in BT474 cells and markedly increased paclitaxel-induced apoptosis in another HER2-overexpressing breast cancer cell line HCC1954. Conclusions Here, we showed that functional cooperative miRNAs effectively suppressed erbB3 expression. This novel approach targeting of HER3 was able to enhance the therapeutic efficacy of trastuzumab and paclitaxel against HER2-overexpressing breast cancer.
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Affiliation(s)
- Hui Lyu
- 1Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, MS-8104, 12801 E. 17th Ave, Aurora, CO 80045 USA
| | - Jingcao Huang
- 2Department of Hematology, Hematologic Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Zhimin He
- 3Cancer Research Institute and Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong China
| | - Bolin Liu
- 1Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, MS-8104, 12801 E. 17th Ave, Aurora, CO 80045 USA
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13
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Abtin M, Alivand MR, Khaniani MS, Bastami M, Zaeifizadeh M, Derakhshan SM. Simultaneous downregulation of miR-21 and miR-155 through oleuropein for breast cancer prevention and therapy. J Cell Biochem 2018; 119:7151-7165. [PMID: 29905007 DOI: 10.1002/jcb.26754] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 01/29/2018] [Indexed: 02/06/2023]
Abstract
Breast cancer (BC) is the leading cause of cancer mortality in women worldwide. It recently was proven that miRNAs play a critical role in BC development. The use of natural agents for control of cancer by modulating miRNAs is promising. Oleuropein is a natural polyphenolic agent with anti-neoplastic properties and is well tolerated by humans. This study was undertaken to determine the therapeutic effects of oleuropein through modulation of master oncomiRs (miR-21 and miR-155) in BC cells. The present study provides the first link between miRNA and oleuropein as a mechanism in BC. MCF-7 cells were tested with and without oleuropein and the cell viability, apoptosis, and migration were examined. The effect of oleuropein on miR-21 and miR-155 expression was assessed through qRT-PCR. It was found that oleuropein induced apoptosis and retarded cell migration and invasion in a dose-dependent manner in the human MCF7 BC cell line. It was observed that oleuropein significantly decreased expression of both miR-21 and miR-155 over time in a dose-dependent manner. These results demonstrate that oleuropein is a potential therapeutic and preventive agent for BC. Oleuropein exhibits an anti-cancer effect by modulation of tumor suppressor gene expression, which is targeted by oncomiRs.
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Affiliation(s)
- Maryam Abtin
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad R Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud S Khaniani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Milad Bastami
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sima M Derakhshan
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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14
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MicroRNA-193b-3p represses neuroblastoma cell growth via downregulation of Cyclin D1, MCL-1 and MYCN. Oncotarget 2018; 9:18160-18179. [PMID: 29719597 PMCID: PMC5915064 DOI: 10.18632/oncotarget.24793] [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: 10/26/2016] [Accepted: 02/28/2018] [Indexed: 12/29/2022] Open
Abstract
Neuroblastoma is the most common diagnosed tumor in infants and the second most common extracranial tumor of childhood. The survival rate of patients with high-risk neuroblastoma is still very low despite intensive multimodal treatments. Therefore, new treatment strategies are needed. In recent years, miRNA-based anticancer therapy has received growing attention. Advances in this novel treatment strategy strongly depends on the identification of candidate miRNAs with broad-spectrum antitumor activity. Here, we identify miR-193b as a miRNA with tumor suppressive properties. We show that miR-193b is expressed at low levels in neuroblastoma cell lines and primary tumor samples. Introduction of miR-193b mimics into nine neuroblastoma cell lines with distinct genetic characteristics significantly reduces cell growth in vitro independent of risk factors such as p53 functionality or MYCN amplification. Functionally, miR-193b induces a G1 cell cycle arrest and cell death in neuroblastoma cell lines by reducing the expression of MYCN, Cyclin D1 and MCL-1, three important oncogenes in neuroblastoma of which inhibition has shown promising results in preclinical testing. Therefore, we suggest that miR-193b may represent a new candidate for miRNA-based anticancer therapy in neuroblastoma.
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15
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Teng Y, Mu J, Hu X, Samykutty A, Zhuang X, Deng Z, Zhang L, Cao P, Yan J, Miller D, Zhang HG. Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages. Oncotarget 2018; 7:25683-97. [PMID: 27028860 PMCID: PMC5041936 DOI: 10.18632/oncotarget.8361] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/10/2016] [Indexed: 02/06/2023] Open
Abstract
Liver metastasis accounts for many of the cancer deaths in patients. Effective treatment for metastatic liver tumors is not available. Here, we provide evidence for the role of miR-18a in the induction of liver M1 (F4/80+interferon gamma (IFNγ)+IL-12+) macrophages. We found that miR-18a encapsulated in grapefruit-derived nanovector (GNV) mediated inhibition of liver metastasis that is dependent upon the induction of M1 (F4/80+IFNγ+IL-12+) macrophages; depletion of macrophages eliminated its anti-metastasis effect. Furthermore, the miR-18a mediated induction of macrophage IFNγ by targeting IRF2 is required for subsequent induction of IL-12. IL-12 then activates natural killer (NK) and natural killer T (NKT) cells for inhibition of liver metastasis of colon cancer. This conclusion is supported by the fact that knockout of IFNγ eliminates miR-18a mediated induction of IL-12, miR-18a treatment has an anti-metastatic effects in T cell deficient mice but there is no anti-metastatic effect on NK and NKT deficient mice. Co-delivery of miR-18a and siRNA IL-12 to macrophages did not result in activation of co-cultured NK and NKT cells. Taken together our results indicate that miR-18a can act as an inhibitor for liver metastasis through induction of M1 macrophages.
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Affiliation(s)
- Yun Teng
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Jingyao Mu
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Xin Hu
- Program in Biostatistics, Bioinformatics and Systems Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.,Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Abhilash Samykutty
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Xiaoying Zhuang
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Zhongbin Deng
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Lifeng Zhang
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Pengxiao Cao
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Jun Yan
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Donald Miller
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
| | - Huang-Ge Zhang
- Robley Rex VA Medical Center, Louisville, KY 40206, USA.,James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.,Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA
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16
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Liao Z, Wang X, Liang H, Yu A, ur Rehman U, Fan Q, Hu Y, Wang C, Zhou Z, Wang T. miR-1 suppresses the proliferation and promotes the apoptosis of esophageal carcinoma cells by targeting Src. Cancer Med 2017; 6:2957-2965. [PMID: 29034995 PMCID: PMC5727306 DOI: 10.1002/cam4.1214] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/29/2017] [Accepted: 08/31/2017] [Indexed: 11/23/2022] Open
Abstract
Nonreceptor tyrosine kinase c-Src, also known as Src, is a potent oncogene involved in a series of biological processes including cell growth, differentiation, and apoptosis; however, its expression pattern and function in esophageal cancer is poorly addressed. In this study, abnormal overexpression of Src protein was observed in esophageal cancer tissues, which fuelled the speculation that microRNA-mediated posttranscriptional regulatory mechanism might be involved. Bioinformatic analyses were applied to identify miRNAs that could potentially target Src. miR-1 was predicted and further validated as a direct repressor of Src. Moreover, we manipulated knockdown and overexpression experiment on TE-1 and TE-10 cells to demonstrate miR-1 suppressed proliferation and promoted apoptosis in esophageal cancer cells by inhibiting Src. Taken together, this study underlines a negative regulatory mechanism in which miR-1 serves as a suppressor of Src in esophageal cancer cells and may provide insights into novel therapeutic approaches for esophageal cancer.
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Affiliation(s)
- Zhicong Liao
- Department of Thoracic and Cardiovascular SurgeryNanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu210008China
| | - Xiaojun Wang
- Nanjing Medical University Affiliated Cancer HospitalNanjingJiangsu210009China
| | - Hongwei Liang
- State Key Laboratory of Pharmaceutical BiotechnologyNanjing Advanced Institute of Life SciencesJiangsu Engineering Research Center for MicroRNA Biology and BiotechnologyNanjingJiangsu210093China
| | - Ao Yu
- Department of Thoracic and Cardiovascular SurgeryNanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu210008China
| | - Uzair ur Rehman
- State Key Laboratory of Pharmaceutical BiotechnologyNanjing Advanced Institute of Life SciencesJiangsu Engineering Research Center for MicroRNA Biology and BiotechnologyNanjingJiangsu210093China
| | - Qian Fan
- Department of LymphomaTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center of CancerKey Laboratory of Cancer Prevention and TherapyTianjin300060China
| | - Yue Hu
- Nanjing Multicenter BiobankBiobank of Nanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu210008China
| | - Chen Wang
- State Key Laboratory of Pharmaceutical BiotechnologyNanjing Advanced Institute of Life SciencesJiangsu Engineering Research Center for MicroRNA Biology and BiotechnologyNanjingJiangsu210093China
| | - Zhen Zhou
- State Key Laboratory of Pharmaceutical BiotechnologyNanjing Advanced Institute of Life SciencesJiangsu Engineering Research Center for MicroRNA Biology and BiotechnologyNanjingJiangsu210093China
| | - Tao Wang
- Department of Thoracic and Cardiovascular SurgeryNanjing Drum Tower Hospitalthe Affiliated Hospital of Nanjing University Medical SchoolNanjingJiangsu210008China
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17
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Zhuang C, Huang X, Zhuang C, Luo X, Zhang X, Cai Z, Gui Y. Synthetic regulatory RNAs selectively suppress the progression of bladder cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:151. [PMID: 29084575 PMCID: PMC5663129 DOI: 10.1186/s13046-017-0626-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/23/2017] [Indexed: 11/10/2022]
Abstract
The traditional treatment for cancer is lack of specificity and efficacy. Modular synthetic regulatory RNAs, such as inhibitive RNA (iRNA) and active RNA (aRNA), may overcome these limitations. Here, we synthesize a new iRNA to bind the upstream activating sequence (UAS) of a minimal promoter that drives expression of artificial miRNAs (amiRNAs) targeting MYC, which represses the binding interaction between UAS and GAL4 fusion protein (GAL4-VP64) in GAL4/UAS system. The aRNA driven by a tumor-specific mutant human telomerase reverse transcriptase (hTERT) promoter is created to interact with iRNA to expose UAS again in bladder cancer. Without the aRNA, mRNA and protein levels of MYC, cell growth, cell apoptosis and cell migration were no significance in two bladder cancer cell lines, T24 and 5637, and human foreskin fibroblast (HFF) cells. The aRNA significantly inhibited the expression of MYC in mRNA and protein levels, as well as the proliferation and migration of the cancer cells, but not in HFF cells. These results indicated that regulatory RNAs selectively controlled the expression of amiRNAs and ultimately suppress the progression of bladder cancer cells without affecting normal cells. Synthetic regulatory RNAs might be a selective therapeutic approach for bladder cancer.
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Affiliation(s)
- Chengle Zhuang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China
| | - Xinbo Huang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China
| | - Changshui Zhuang
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China
| | - Xiaomin Luo
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China
| | - Xiaowei Zhang
- The Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People's Republic of China
| | - Zhiming Cai
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China
| | - Yaoting Gui
- Guangdong and Shenzhen Key Laboratory of Male Reproductive Medicine and Genetics, Institute of Urology, Peking University Shenzhen Hospital, Shenzhen-Peking University-the Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People's Republic of China.
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18
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Wang H, Moyano AL, Ma Z, Deng Y, Lin Y, Zhao C, Zhang L, Jiang M, He X, Ma Z, Lu F, Xin M, Zhou W, Yoon SO, Bongarzone ER, Lu QR. miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS. Dev Cell 2017; 40:566-582.e5. [PMID: 28350989 DOI: 10.1016/j.devcel.2017.03.001] [Citation(s) in RCA: 126] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/25/2017] [Accepted: 02/28/2017] [Indexed: 10/19/2022]
Abstract
A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
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Affiliation(s)
- Haibo Wang
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Ana Lis Moyano
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Zhangyan Ma
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yaqi Deng
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yifeng Lin
- Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Chuntao Zhao
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Liguo Zhang
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Minqing Jiang
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Xuelian He
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Zhixing Ma
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Fanghui Lu
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Mei Xin
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Sung Ok Yoon
- Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA
| | - Ernesto R Bongarzone
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Q Richard Lu
- Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China.
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19
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20
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Leichter AL, Sullivan MJ, Eccles MR, Chatterjee A. MicroRNA expression patterns and signalling pathways in the development and progression of childhood solid tumours. Mol Cancer 2017; 16:15. [PMID: 28103887 PMCID: PMC5248531 DOI: 10.1186/s12943-017-0584-0] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 01/04/2017] [Indexed: 12/18/2022] Open
Abstract
The development of childhood solid tumours is tied to early developmental processes. These tumours may be complex and heterogeneous, and elucidating the aberrant mechanisms that alter the early embryonic environment and lead to disease is essential to our understanding of how these tumours function. MicroRNAs (miRNAs) are vital regulators of gene expression at all stages of development, and their crosstalk via developmental signalling pathways is essential for orchestrating regulatory control in processes such as proliferation, differentiation and apoptosis of cells. Oncogenesis, from aberrant miRNA expression, can occur through amplification and overexpression of oncogenic miRNAs (oncomiRs), genetic loss of tumour suppressor miRNAs, and global miRNA reduction from genetic and epigenetic alterations in the components regulating miRNA biogenesis. While few driver mutations have been identified in many of these types of tumours, abnormal miRNA expression has been found in a number of childhood solid tumours compared to normal tissue. An exploration of the network of key developmental pathways and interacting miRNAs may provide insight into the development of childhood solid malignancies and how key regulators are affected. Here we present a comprehensive introduction to the roles and implications of miRNAs in normal early development and childhood solid tumours, highlighting several tumours in depth, including embryonal brain tumours, neuroblastoma, osteosarcoma, Wilms tumour, and hepatoblastoma. In light of recent literature describing newer classifications and subtyping of tumours based on miRNA profiling, we discuss commonly identified miRNAs, clusters or families associated with several solid tumours and future directions for improving therapeutic approaches.
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Affiliation(s)
- Anna L Leichter
- Department of Pathology, Dunedin School of Medicine, University of Otago, 56 Hanover Street, P.O. Box 913, Dunedin, 9016, New Zealand
| | | | - Michael R Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, 56 Hanover Street, P.O. Box 913, Dunedin, 9016, New Zealand. .,Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand.
| | - Aniruddha Chatterjee
- Department of Pathology, Dunedin School of Medicine, University of Otago, 56 Hanover Street, P.O. Box 913, Dunedin, 9016, New Zealand. .,Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand.
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21
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Lam SSN, Ip CKM, Mak ASC, Wong AST. A novel p70 S6 kinase-microRNA biogenesis axis mediates multicellular spheroid formation in ovarian cancer progression. Oncotarget 2016; 7:38064-38077. [PMID: 27191261 PMCID: PMC5122372 DOI: 10.18632/oncotarget.9345] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/26/2016] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is the leading cause of death of all gynecologic tumors, associated with widespread peritoneal dissemination and malignant ascites. Key to this is the ability to form multicellular spheroids (MCS); however, the tumor-specific factors that regulate MCS formation are unclear. p70 S6 kinase (p70S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt, is frequently constitutively active in ovarian carcinoma. Here we identify p70S6K as a vital regulator of MCS formation. We also uncover a new mechanism of p70S6K function as a component of the microRNA biogenesis machinery in this process. We show that p70S6K phosphorylates, and inhibits the interaction of tristetraprolin (TTP) and Dicer that promotes the expression of a subset of miRNAs, including the maturation of miR-145. Twist and Sox9 are two divergent targets of miR-145, thereby enhancing N-cadherin, but not other cadherin, expression and MCS formation. Activating miR-145 suppresses ovarian tumor growth and metastasis in an orthotopic xenograft mouse model. Meta-analysis in the Oncomine database reveals that high p70S6K and low TTP levels are associated with ovarian tumor progression. These results define a critical link between p70S6K, miRNA maturation, and MCS formation that may underlie poor clinical outcome of ovarian cancer patients for developing novel therapeutic strategies.
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Affiliation(s)
| | - Carman Ka Man Ip
- School of Biological Sciences, University of Hong Kong, Hong Kong
| | - Abby Sin Chi Mak
- School of Biological Sciences, University of Hong Kong, Hong Kong
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22
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DNA methylation contributes toward silencing of antioncogenic microRNA-203 in human and canine melanoma cells. Melanoma Res 2016. [PMID: 26225581 DOI: 10.1097/cmr.0000000000000183] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Melanoma is a poor-prognosis cancer in both humans and dogs. We have elucidated the antitumor mechanisms of antioncogenic microRNA (miR)-203 which is downregulated in human melanoma, as well as in canine melanoma. The aim of this study was to clarify the mechanism of this downregulation. We focused on epigenetic aberration of miR-203 transcription. Treatment with 5-aza-2'-deoxycitidine (5-aza) markedly upregulated the expression level of miR-203 in almost all of the cell lines tested. Furthermore, bisulfite sequencing or methylation-specific PCR showed DNA methylation of CpG islands upstream of the miR-203 coding region (MIR203) in both human and canine melanoma cells, as well as in canine clinical specimens, but not in human normal melanocytes. The results of a luciferase activity assay showed obvious suppression of the transcription of miR-203 by DNA methylation. The use of the luciferase activity assay for CREB1 and an inhibition assay of miR-203 function performed with an miR-203 inhibitor confirmed the contribution of miR-203 upregulation toward the negative regulation of the target gene of miR-203. These results indicate that canine melanoma might be a preclinical model of human melanoma for epigenetic studies. In addition, this study suggests that agents that can demethylate MIR203 could be a common promising therapeutic agent for the treatment of human and canine melanomas.
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Hemmatzadeh M, Mohammadi H, Karimi M, Musavishenas MH, Baradaran B. Differential role of microRNAs in the pathogenesis and treatment of Esophageal cancer. Biomed Pharmacother 2016; 82:509-19. [PMID: 27470391 DOI: 10.1016/j.biopha.2016.05.009] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 05/06/2016] [Accepted: 05/09/2016] [Indexed: 12/22/2022] Open
Abstract
Esophageal cancer (EC) is the most invasive disease associated with inclusive poor prognosis. EC usually is found as either adenocarcinoma (EAC) or squamous cell carcinomas (ESCC). ESCC forms in squamous cells and highly occurs in the upper third of the esophagus. EAC appears in glandular cells and ordinarily develops in the lower one third of the esophagus near the stomach. Barrett's esophagus (BE) is a metaplastic precursor of EAC. There is a persistent need for improving our understanding of the molecular basis of this disease. MicroRNAs (miRNAs) demonstrate an uncovered class of small, non-coding RNAs that can negatively regulate the protein coding gene, and are associated with approximately all known physiological and pathological processes, especially cancer. MiRNAs can affect cancer pathogenesis, playing a crucial role as either oncogenes or tumor suppressors. The recent emergence of observations on the role of miRNAs in cancer and their functions has induced many investigations to examine their relevance to esophageal cancer. In esophageal cancer, miRNA dysregulation plays a crucial role in cancer prognosis and in patients' responsiveness to neo-adjuvant and adjuvant therapies. In this review, the oncogenic, tumor suppressive, and drug resistance related roles of miRNAs, and their involvement in the pathogenesis and treatment of esophageal cancer were summarized.
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Affiliation(s)
- Maryam Hemmatzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Tabriz University of Medical Sciences, International Branch (Aras), Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Karimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Tabriz University of Medical Sciences, International Branch (Aras), Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Musavishenas
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Tabriz University of Medical Sciences, International Branch (Aras), Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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24
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Zhang S, Gao L, Thakur A, Shi P, Liu F, Feng J, Wang T, Liang Y, Liu JJ, Chen M, Ren H. miRNA-204 suppresses human non-small cell lung cancer by targeting ATF2. Tumour Biol 2016; 37:11177-86. [PMID: 26935060 DOI: 10.1007/s13277-016-4906-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 01/22/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) play a critical role in cancer development and progression. Deregulated expression of miR-204 has been reported in several cancers, but the mechanism through which miR-204 modulates human non-small cell lung cancer (NSCLC) is largely unknown. In this study, we investigate the expression and functional role of miR-204 in human NSCLC tissues and cell lines. RNA isolation, qRT-PCR, MTT, colony formation assay, cell cycle assay, cell apoptosis assay, cell migration assay, and Western blot were performed. Statistical analysis was performed using SPSS 18.0 software and statistical significance was accepted at p value <0.05. miR-204 level was significantly reduced in NSCLC tissues as compared to that of non-neoplastic tissues. Transient over-expression of miR-204 by transfecting with miR-204 mimics suppressed NSCLC cell proliferation, migration, and induced apoptosis and G1 arrest, whereas inhibition of miR-204 showed the converse effects. Additionally, activating transcription factor 2 (ATF2), an important transcription factor, was demonstrated as a potential target gene of miR-204. Subsequent investigations found a negative correlation between miR-204 level and ATF2 expression in NSCLC tissue samples. Moreover, we observed that miR-204 expression inversely affected endogenous ATF2 expression at both mRNA and protein levels in vitro. Taken together, miR-204 may act as a tumor suppressor by directly targeting ATF2 in NSCLC.
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Affiliation(s)
- Shuo Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Lei Gao
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Asmitananda Thakur
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China.,Department of Internal Medicine, Life Guard Hospital, Biratnagar, Nepal.,S. R. Laboratory and Diagnostic Center, Biratnagar, Nepal
| | - Puyu Shi
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Feng Liu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Jing Feng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Ting Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Yiqian Liang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China.,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China
| | - Johnson J Liu
- Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Mingwei Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China. .,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China.
| | - Hui Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, People's Republic of China. .,Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi'an, Shaanxi, People's Republic of China.
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25
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Luqmani YA, Alam-Eldin N. Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem. Med Princ Pract 2016; 25 Suppl 2:28-40. [PMID: 26849149 PMCID: PMC5588530 DOI: 10.1159/000444451] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 02/04/2016] [Indexed: 01/02/2023] Open
Abstract
In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed oestrogen receptors (ER). Therapeutic strategies include: (i) reduction of circulating ovarian oestrogens or of peripherally produced oestrogen (in postmenopausal women) with aromatase inhibitors and (ii) application of selective ER modulators for receptor blockade. The success of these interventions is limited by the variable but persistent onset of acquired resistance and by an intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to trans-differentiation of the epithelial cancer cells into a mesenchymal-like phenotype (epithelial-mesenchymal transition; EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: (i) loss or modification of ER expression including epigenetic mechanisms, (ii) agonistic actions of selective ER modulators that may be enhanced through an increased expression of co-activators, (iii) attenuation of the tamoxifen metabolism through expression of genetic variants of P450 cytochromes which leads to more or less active metabolites and (iv) increased growth factor signalling particularly through epidermal growth factor receptor activation of pathways involving keratinocyte growth factor, platelet-derived growth factor, and nuclear factor x03BA;B. In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen-sensitive versus resistant cell lines. Several studies suggest the potential of using these either as targets or as therapeutic agents to modulate EMT regulators as a means of reversing the aggressive metastatic phenotype by reversal of the EMT, with the added benefit of re-sensitization to anti-oestrogens.
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Affiliation(s)
- Yunus A. Luqmani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat, Kuwait
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26
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Roth SA, Knutsen E, Fiskaa T, Utnes P, Bhavsar S, Hald ØH, Løkke C, Mestdagh P, Johansen SD, Flægstad T, Einvik C. Next generation sequencing of microRNAs from isogenic neuroblastoma cell lines isolated before and after treatment. Cancer Lett 2015; 372:128-36. [PMID: 26708804 DOI: 10.1016/j.canlet.2015.11.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 10/22/2022]
Abstract
Neuroblastoma is a pediatric cancer of the developing sympathetic nervous system. High risk neuroblastoma patients typically undergo an initial remission in response to treatment, followed by recurrence of aggressive tumors that have become refractory to further treatment. Recent works have underlined the involvement of microRNAs (miRNAs) in neuroblastoma development and evolution of drug resistance. In this study we have used deep sequencing technology to identify miRNAs differentially expressed in neuroblastoma cell lines isolated from 6 patients at diagnosis and at relapse after intensive treatments. This approach revealed a panel of 42 differentially expressed miRNAs, 8 of which were upregulated and 34 were downregulated. Most strikingly, the 14q32 miRNA clusters encode 22 of the downregulated miRNAs. Reduced expression of 14q32 miRNAs in tumors associated with poor prognosis factors was confirmed in a cohort consisting of 226 primary neuroblastomas. In order to gain insight into the nature of the genes that may be affected by the differentially expressed miRNAs we utilized Ingenuity Pathway Analysis (IPA). This analysis revealed several biological functions and canonical pathways associated with cancer progression and drug resistance. The results of this study contribute to the identification of miRNAs involved in the complex processes of surviving therapeutic treatment and developing drug resistance in neuroblastoma.
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Affiliation(s)
- Sarah Andrea Roth
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway
| | - Erik Knutsen
- RNA and Molecular Pathology (RAMP), Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway
| | - Tonje Fiskaa
- RNA and Molecular Pathology (RAMP), Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway
| | - Peter Utnes
- Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038 Tromsø, Norway
| | - Swapnil Bhavsar
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway
| | - Øyvind H Hald
- Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038 Tromsø, Norway
| | - Cecilie Løkke
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway
| | - Pieter Mestdagh
- Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium
| | - Steinar D Johansen
- RNA and Molecular Pathology (RAMP), Department of Medical Biology, Faculty of Health Sciences, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway; Marine Genomics Group, Faculty of Biosciences and Aquaculture, University of Nordland, Bodø, Norway
| | - Trond Flægstad
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway; Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038 Tromsø, Norway
| | - Christer Einvik
- Pediatric Research Group, Department of Clinical Medicine, Faculty of Health Science, The Arctic University of Norway - UiT, NO-9037 Tromsø, Norway; Department of Pediatrics, Division of Child and Adolescent Health, UNN - University Hospital of North-Norway, NO-9038 Tromsø, Norway.
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27
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Ragusa M, Barbagallo C, Statello L, Condorelli AG, Battaglia R, Tamburello L, Barbagallo D, Di Pietro C, Purrello M. Non-coding landscapes of colorectal cancer. World J Gastroenterol 2015; 21:11709-11739. [PMID: 26556998 PMCID: PMC4631972 DOI: 10.3748/wjg.v21.i41.11709] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 07/28/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
For two decades Vogelstein’s model has been the paradigm for describing the sequence of molecular changes within protein-coding genes that would lead to overt colorectal cancer (CRC). This model is now too simplistic in the light of recent studies, which have shown that our genome is pervasively transcribed in RNAs other than mRNAs, denominated non-coding RNAs (ncRNAs). The discovery that mutations in genes encoding these RNAs [i.e., microRNAs (miRNAs), long non-coding RNAs, and circular RNAs] are causally involved in cancer phenotypes has profoundly modified our vision of tumour molecular genetics and pathobiology. By exploiting a wide range of different mechanisms, ncRNAs control fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis: these data have also confirmed their role as oncogenes or tumor suppressors in cancer development and progression. The existence of a sophisticated RNA-based regulatory system, which dictates the correct functioning of protein-coding networks, has relevant biological and biomedical consequences. Different miRNAs involved in neoplastic and degenerative diseases exhibit potential predictive and prognostic properties. Furthermore, the key roles of ncRNAs make them very attractive targets for innovative therapeutic approaches. Several recent reports have shown that ncRNAs can be secreted by cells into the extracellular environment (i.e., blood and other body fluids): this suggests the existence of extracellular signalling mechanisms, which may be exploited by cells in physiology and pathology. In this review, we will summarize the most relevant issues on the involvement of cellular and extracellular ncRNAs in disease. We will then specifically describe their involvement in CRC pathobiology and their translational applications to CRC diagnosis, prognosis and therapy.
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28
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Schwarzenbach H. The clinical relevance of circulating, exosomal miRNAs as biomarkers for cancer. Expert Rev Mol Diagn 2015. [DOI: 10.1586/14737159.2015.1069183] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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29
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Brighenti M. MicroRNA and MET in lung cancer. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:68. [PMID: 25992367 DOI: 10.3978/j.issn.2305-5839.2015.01.26] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Accepted: 01/16/2015] [Indexed: 12/28/2022]
Abstract
MicroRNAs (miRNAs) are a class of small non-protein coding RNAs that modulate important cellular functions via their post-transcriptional regulation of messenger RNAs (mRNAs). Recent evidences from multiple tumor types and model systems implicate miRNA dysregulation as a common mechanism of tumorigenesis, cancer progression and resistance to therapy. Several miRNAs are dysregulated in cancers and a single miRNA can have multiple targets involved in different oncogenic pathways. MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), has a central role in lung cancer development and in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors; it has been predicted and shown to be the target gene of multiple miRNAs, which play a crucial role in controlling its activity in a stimulatory or inhibitory sense. In this review we will focus on the most important and recent studies about the role of miRNAs in the control of MET expression, reporting also the progress made using miRNAs for therapy of lung cancer.
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30
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Xu YF, Mao YP, Li YQ, Ren XY, He QM, Tang XR, Sun Y, Liu N, Ma J. MicroRNA-93 promotes cell growth and invasion in nasopharyngeal carcinoma by targeting disabled homolog-2. Cancer Lett 2015; 363:146-55. [PMID: 25892549 DOI: 10.1016/j.canlet.2015.04.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Revised: 04/06/2015] [Accepted: 04/08/2015] [Indexed: 12/13/2022]
Abstract
Dysregulation of microRNAs (miRNAs) has been demonstrated to contribute to malignant progression in nasopharyngeal carcinoma (NPC). We previously reported that miR-93 was significantly upregulated in NPC based on a microarray analysis. However, the potential role and mechanism of action of miR-93 in the initiation and progression of NPC remain largely unknown. Quantitative RT-PCR demonstrated that miR-93 was significantly upregulated in NPC cell lines and clinical specimens. The MTT assay, colony formation assay, anchorage-independent growth, and Transwell migration and invasion assays showed that depletion of miR-93 inhibited NPC cell growth, invasion and migration in vitro and suppressed tumor growth in vivo. Disabled homolog-2 (Dab2) was verified as a miR-93 target gene using Luciferase reporter assays, quantitative RT-PCR and Western blotting and was involved in miR-93-regulated NPC cell growth, invasion and migration. These results indicated that miR-93 plays an important role in the initiation and progression of NPC by targeting Dab2 and the miR-93/Dab2 pathway may contribute to the development of novel therapeutic strategies for NPC in the future.
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Affiliation(s)
- Ya Fei Xu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Yan Ping Mao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Ying Qin Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Xian Yue Ren
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Qing Mei He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Xin Ran Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Ying Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China
| | - Na Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China.
| | - Jun Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, China.
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31
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Wang T, Huang B, Guo R, Ma J, Peng C, Zu X, Tang H, Lei X. A let-7b binding site SNP in the 3'-UTR of the Bcl-xL gene enhances resistance to 5-fluorouracil and doxorubicin in breast cancer cells. Oncol Lett 2015; 9:1907-1911. [PMID: 25789066 PMCID: PMC4356428 DOI: 10.3892/ol.2015.2938] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 12/08/2014] [Indexed: 12/13/2022] Open
Abstract
The development of acquired resistance to chemotherapy is a major obstacle in the successful treatment of cancer. In breast cancer cells, B-cell lymphoma-extra large (Bcl-xL) is involved in the development of resistance to various chemotherapeutic agents; therefore, preliminary biological prediction was performed to identify a putative binding site for let-7b in the 3'-untranslated region (UTR) of the Bcl-xL gene and a single nucleotide polymorphism (SNP) within this binding region. The present study investigated the association between the SNP rs3208684 A>C and chemotherapeutic agent resistance in breast cancer cells. The data indicated that let-7b negatively regulates the expression of Bcl-xL and appears to sensitize MCF-7 cells to the chemotherapeutic agents 5-fluorouracil (5-FU) and doxorubicin. Furthermore, the SNP rs3208684 A>C was demonstrated to enhance Bcl-xL protein expression by disrupting the binding of let-7b to the 3'-UTR of Bcl-xL and, in MCF-7 cells, overexpression of let-7b in the presence of a mutant Bcl-xL 3'-UTR (C allele) significantly increased 5-FU and doxorubicin resistance. Thus, the results of the present study demonstrate that the SNP rs3208684 A>C may upregulate Bcl-xL protein expression and enhance the resistance of the MCF-7 cells to 5-FU and doxorubicin by decreasing the binding of let-7b to the 3'-UTR of Bcl-xL.
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Affiliation(s)
- Ting Wang
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China ; Department of Pharmacy, The Second Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Bin Huang
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Rui Guo
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jin Ma
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Cuiying Peng
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xuyu Zu
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Huifang Tang
- Department of Pharmacy, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoyong Lei
- Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan 421001, P.R. China
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32
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Gu DN, Huang Q, Tian L. The molecular mechanisms and therapeutic potential of microRNA-7 in cancer. Expert Opin Ther Targets 2014; 19:415-26. [PMID: 25434362 DOI: 10.1517/14728222.2014.988708] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Increasing evidence supports that microRNAs (miRNAs) play crucial roles in cancer through post-transcriptional gene silencing of their target genes, therefore, more and more effort has been devoted to develop miRNA-targeting therapeutics in cancer. MicroRNA-7 (miR-7) has been characterized as a potential tumor suppressor and regulates diverse fundamental biological processes of cancer cells including initiation, proliferation, migration, invasion, survival and death by targeting a number of oncogenic signaling pathways. AREAS COVERED This review examines evidence of the biological responses of miR-7 in cancer, with an emphasis on its regulation of the vital oncogenic signaling pathways. It also discusses the rationale, strategies and challenges of miR-7 as a potential therapeutic target for cancer. EXPERT OPINION With the increasing understanding of molecular mechanisms of miR-7-mediated regulatory networks and the advancement of miRNA-based therapeutics, targeting miR-7 may be a potential and promising strategy for cancer therapy.
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Affiliation(s)
- Dian-Na Gu
- Shanghai Jiao Tong University School of Medicine, Shanghai First People's Hospital, Experimental Research Center , Shanghai 201620 , PR China +86 21 37798755 ; +86 21 37798276 ;
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33
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Li J, Li P, Chen T, Gao G, Chen X, Du Y, Zhang R, Yang R, Zhao W, Dun S, Gao F, Zhang G. Expression of microRNA-96 and its potential functions by targeting FOXO3 in non-small cell lung cancer. Tumour Biol 2014; 36:685-92. [PMID: 25286764 DOI: 10.1007/s13277-014-2698-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Accepted: 09/30/2014] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs are implicated in the regulation of various cellular processes, including proliferation, differentiation, cell death, and cell mobility, and can function either as oncogenes or tumor suppressors in tumor progression. The effects of the expression of miR-96 in non-small cell lung cancer (NSCLC) remain unclear. In our study, qRT-PCR (quantitative reverse transcription PCR) was performed to identify the miR-96 expression level in 68 paired NSCLC and adjacent normal lung tissues. Trans-well, cell counting kit-8, and apoptosis assays were used to evaluate the effects of miR-96 expression on cell invasion, proliferation, and apoptosis. Dual-luciferase reporter assay and Western blotting were used to verify whether FOXO3 was a potential major target gene of miR-96. Finally, the effect of FOXO3 on miR-96-induced cell survival was determined by transfection of the genes expressing FOXO3 lacking 3'UTR and miR-96. The expression level of miR-96 in NSCLC tissues was higher than that in adjacent normal lung tissues, and this increased expression was significantly associated with lymph node metastasis. In contrast to the cells in the blank and negative control groups, the number of cells migrating through the matrigel was significantly lower and the incidence of apoptosis was significantly higher in cells transfected with a miR-96 inhibitor. Western blotting and dual-luciferase reporter assays demonstrated that miR-96 can bind to the putative seed region in FOXO3 mRNA 3'UTR, and can significantly lower the expression of FOXO3. The introduction of FOXO3 cDNA without 3'UTR restored miR-96 induced cell apoptosis and invasion. MiR-96 is up-regulated in NSCLC tissues. Downregulation of miR-96 inhibits invasion and promotes apoptosis in NSCLC cells A549 and SPC-A-1 by targeting FOXO3. Therefore, our study improves our understanding of the mechanisms underlying NSCLC pathogenesis and may promote the development of novel targeted therapies.
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Affiliation(s)
- Juan Li
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
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Noguchi S, Kumazaki M, Mori T, Baba K, Okuda M, Mizuno T, Akao Y. Analysis of microRNA-203 function in CREB/MITF/RAB27a pathway: comparison between canine and human melanoma cells. Vet Comp Oncol 2014; 14:384-394. [PMID: 25280339 DOI: 10.1111/vco.12118] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 09/04/2014] [Accepted: 09/05/2014] [Indexed: 12/21/2022]
Abstract
MicroRNA (miR)-203 is downregulated and acts as an anti-oncomir in melanoma cells. Here, using human and canine melanoma cells, we elucidated the effects of miR-203 on cyclic adenosine monophosphate response element binding protein (CREB)/microphthalmia-associated transcription factor (MITF)/RAB27a pathway, which is known to be important for the development and progression of human melanoma. In this study, we showed that miR-203 directly targeted CREB1 and regulated its downstream targets, MITF and RAB27a. miR-203 significantly suppressed the growth of human and canine melanoma cells and inhibited melanosome transport through the suppression of the signalling pathway. In conclusion, miR-203 was shown to be a common tumour-suppressive miRNA in human and canine melanoma and thus to play a crucial role in the biological mechanisms of melanoma development.
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Affiliation(s)
- S Noguchi
- Laboratory of Molecular Diagnostic and Therapeutics, Joint faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - M Kumazaki
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - T Mori
- Laboratory of Veterinary Clinical Oncology, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - K Baba
- Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamagushi University, Yamaguchi, Japan
| | - M Okuda
- Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamagushi University, Yamaguchi, Japan
| | - T Mizuno
- Laboratory of Molecular Diagnostic and Therapeutics, Joint faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Y Akao
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
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35
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Tanase CP, Neagu AI, Necula LG, Mambet C, Enciu AM, Calenic B, Cruceru ML, Albulescu R. Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics. World J Gastroenterol 2014; 20:10790-10801. [PMID: 25152582 PMCID: PMC4138459 DOI: 10.3748/wjg.v20.i31.10790] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 02/07/2014] [Accepted: 04/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.
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Huang J, Zhang SY, Gao YM, Liu YF, Liu YB, Zhao ZG, Yang K. MicroRNAs as oncogenes or tumour suppressors in oesophageal cancer: potential biomarkers and therapeutic targets. Cell Prolif 2014; 47:277-86. [PMID: 24909356 DOI: 10.1111/cpr.12109] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 02/24/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are a class of small, non-coding RNAs that can negatively regulate protein-coding genes, and are associated with almost all known physiological and pathological processes, especially cancer. The number of studies documenting miRNA expression patterns in malignancy continues to expand rapidly, with continuously gained critical information regarding how aberrantly expressed miRNAs may contribute to carcinogenesis. miRNAs can influence cancer pathogenesis, playing a potential role as either oncogenes or tumour suppressors. Recently, several miRNAs have been reported to exert different regulatory functions in oesophageal cancer - the carcinoma typically arising from the epithelial lining of the oesophagus. These miRNAs also have potential clinical applications towards developing biomarkers or targets for possible use in diagnosis or therapy in oesophageal cancer. In this review, we have summarized the two (oncogenic or tumour suppressive) roles of miRNAs here, and their applications as potential biomarkers or therapeutic targets, which may illuminate future treatment for oesophageal cancer.
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Affiliation(s)
- J Huang
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China
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Rothschild SI. microRNA therapies in cancer. MOLECULAR AND CELLULAR THERAPIES 2014; 2:7. [PMID: 26056576 PMCID: PMC4452061 DOI: 10.1186/2052-8426-2-7] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 01/29/2014] [Indexed: 02/08/2023]
Abstract
MicroRNAs (miRNAs or miRs) are a family of small non-coding RNA species that have been implicated in the control of many fundamental cellular and physiological processes such as cellular differentiation, proliferation, apoptosis and stem cell maintenance. miRNAs regulate gene expression by the sequence-selective targeting of mRNAs, leading to translational repression or mRNA degradation. Some microRNAs have been categorized as “oncomiRs” as opposed to “tumor suppressor miRs” Modulating the miRNA activities may provide exciting opportunities for cancer therapy. This review highlights the latest discovery of miRNAs involved in carcinogenesis as well as the potential applications of miRNA regulations in cancer treatment. Several studies have demonstrated the feasibility of restoring tumor suppressive miRNAs and targeting oncogenic miRNAs for cancer therapy using in vivo model systems.
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Affiliation(s)
- Sacha I Rothschild
- Department Internal Medicine, Medical Oncology, University Hospital Basel, Basel, Switzerland
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Kałużna EM. MicroRNA-155 and microRNA-196b: promising biomarkers in hepatitis C virus infection? Rev Med Virol 2014; 24:169-85. [PMID: 24591085 DOI: 10.1002/rmv.1785] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/16/2014] [Accepted: 01/21/2014] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are a class of small, evolutionarily conserved, noncoding RNA that regulate several important cellular processes. The versatility of these molecules allowed the accurate predictions that they would also affect the replication and life cycle of HCV. In this review, emphasis has been given to two selected miRNAs: miR-155 and miR-196b. Recent data indicate that miR-155 is overexpressed in HCV-infected patients, inducing an inflammatory state, and promoting virus replication and persistence even after the completion of antiviral treatment. It is also associated with the increased proliferation and inhibited apoptosis of hepatocytes, which promotes the growth of liver tumors. In contrast, miR-196b is reported as a factor inhibiting HCV replication with cytoprotective, anti-inflammatory, and antioxidant properties. Growing evidence suggests that these molecules could be used as potential prognostic and predictive factors and their antagonists or mimics as a promising therapeutic approach in HCV-infected patients.
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Fan R, Zhong J, Zheng S, Wang Z, Xu Y, Li S, Zhou J, Yuan F. MicroRNA-218 inhibits gastrointestinal stromal tumor cell and invasion by targeting KIT. Tumour Biol 2013; 35:4209-17. [PMID: 24375253 DOI: 10.1007/s13277-013-1551-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 12/13/2013] [Indexed: 12/14/2022] Open
Abstract
The objectives of this study were to detect the expressions of microRNA-218 (miR-218) in human gastrointestinal stromal tumor (GIST) tissues and cells and explore its effects on the biological features of GIST-T1 cells and the expression of its target gene KIT, so as to provide new insights for GIST treatment. Using quantitative real-time polymerase chain reaction (qRT-PCR), we detected the expressions of miR-218 in the tissues and adjacent tissues of GIST and in the GIST cell lines including GIST882, GIST430, GIST48, and GIST-T1. Forty-eight hours after the miR-218 mimic was transfected into the GIST-T1 cells, the expression of miR-218 in the GIST-T1 cells was detected by qRT-PCR. The effect of miR-218 on the GIST-T1 cell viability was detected using MTT. The effect of miR-218 on the proliferation and apoptosis of GIST-T1 cell was analyzed using flow cytometry. Transwell invasion chamber was applied to detect the effect of miR-218 on the invasion of GIST-T1 cells. KIT was identified to be a target gene of miR-218 by the luciferase reporter enzyme system, and the effect of miR-218 on the expression of KIT protein in cells was determined using Western blotting. As shown by qRT-PCR, compared with that in the GIST adjacent tissue, the expressions of miR-218 in the tumor tissue and GIST cell lines were significantly decreased (P < 0.0001). Compared with the control group, the expression of miR-218 increased significantly in GIST-T1 cells transfected with miR-218 mimic for 48 h (P < 0.01). MTT showed that the cell viability decreased significantly after the overexpression of miR-218 in the GIST-T1 cells (P < 0.01). Flow cytometry showed that the cell proliferation index significantly declined after the overexpression of miR-218 (P < 0.01); meanwhile, the apoptosis of cells also significantly increased (P < 0.01). Detection using the Transwell invasion chamber showed that the number of cells passing through the Transwell chamber significantly dropped after the enhanced expression of miR-218 (P < 0.01). Luciferase reporter gene assay showed that, compared with the control group, the relative luciferase activity significantly declined in the miR-218 mimic transfection group (P < 0.01). Compared with the control group, the expression of KIT protein in the GIST-T1 cells transfected with miR-218 mimic for 48 h significantly decreased (P < 0.01). In conclusion, the expression of miR-218 decreases in human GIST tissue and cell lines. miR-218 can negatively regulate the expression of KIT protein and inhibit the proliferation and invasion of GIST cells. Treatment based on the enhanced expression of miR-218 may be a promising strategy for GIST.
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Affiliation(s)
- Rong Fan
- Department of Gastroenterology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Rd, Shanghai, 200025, China
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Li L, Luo J, Wang B, Wang D, Xie X, Yuan L, Guo J, Xi S, Gao J, Lin X, Kong Y, Xu X, Tang H, Xie X, Liu M. Microrna-124 targets flotillin-1 to regulate proliferation and migration in breast cancer. Mol Cancer 2013; 12:163. [PMID: 24330780 PMCID: PMC4029407 DOI: 10.1186/1476-4598-12-163] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 12/11/2013] [Indexed: 12/21/2022] Open
Abstract
Background MicroRNAs (miRNAs) have been documented as playing important roles in cancer development. In this study, we investigated the role of miR-124 in breast cancer and clarified the regulation of flotillin-1 (FLOT1) by miR-124. Methods The expression levels of miR-124 were examined in breast cancer cell lines and patient specimens using quantitative reverse transcription-PCR. The clinicopathological significance of the resultant data was later analyzed. Next, we explored the function of miR-124 to determine its potential roles on cancer cell growth and migration in vitro. A luciferase reporter assay was conducted to confirm the target gene of miR-124, and the results were validated in cell lines and patient specimens. Results We found that miR-124 expression was significantly downregulated in breast cancer cell lines and patient specimen compared with normal cell lines and paired adjacent normal tissues (P < 0.0001), respectively. MiR-124 was also associated with tumor node metastasis (TNM) stage (P = 0.0007) and lymph node metastasis (P = 0.0004). In breast cancer cell lines, the ectopic expression of miR-124 inhibited cell growth and migration in vitro. Moreover, we identified the FLOT1 gene as a novel direct target of miR-124, and miR-124 ectopic expression significantly inhibited FLOT1. Luciferase assays confirmed that miR-124 could directly bind to the 3′ untranslated region of FLOT1 and suppress translation. Moreover, FLOT1 was widely upregulated, and inversely correlated with miR-124 in breast cancer tissues. Consistent with the effect of miR-124, the knockdown of FLOT1 significantly inhibited breast cancer cell growth and migration. We also observed that the rescue expression of FLOT1 partially restored the effects of miR-124. Conclusions Our study demonstrated that miR-124 might be a tumor suppressor in breast cancer via the regulation of FLOT1. This microRNA could serve as a potential diagnostic marker and therapeutic target for breast cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Min Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, People's Republic of China.
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Chen YF, Dong Z, Xia Y, Tang J, Peng L, Wang S, Lai D. Nucleoside analog inhibits microRNA-214 through targeting heat-shock factor 1 in human epithelial ovarian cancer. Cancer Sci 2013; 104:1683-9. [PMID: 24033540 DOI: 10.1111/cas.12277] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/29/2013] [Accepted: 08/30/2013] [Indexed: 01/06/2023] Open
Abstract
The important functions of heat shock factor 1 (HSF1) in certain malignant cancers have granted it to be an appealing target for developing novel strategy for cancer therapy. Here, we report that higher HSF1 expression is associated with more aggressive malignization in epithelial ovarian tumors, indicating that targeting HSF1 is also a promising strategy against ovarian cancer. We found that a nucleoside analog (Ly101-4B) elicits efficient inhibition on HSF1 expression and potent anticancer activity on epithelial ovarian cancer both in vitro and in vivo. Moreover, by targeting HSF1, Ly101-4B inhibits the biogenesis of microRNA-214, which has been revealed to be overexpressed and to promote cell survival in human ovarian epithelial tumors. These findings demonstrate that Ly101-4B is a promising candidate for ovarian cancer therapy, and expand our understanding of HSF1, by revealing that it can regulate microRNA biogenesis in addition to its canonical function of regulating protein-coding RNAs.
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Affiliation(s)
- Yi-Fei Chen
- The International Peace Maternity and Child Health Hospital, Shanghai Jiaotong University, Shanghai, China
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MicroRNA-203 regulates melanosome transport and tyrosinase expression in melanoma cells by targeting kinesin superfamily protein 5b. J Invest Dermatol 2013; 134:461-469. [PMID: 23884313 DOI: 10.1038/jid.2013.310] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Revised: 06/16/2013] [Accepted: 06/24/2013] [Indexed: 02/07/2023]
Abstract
MicroRNA (miR)-203 is known to be downregulated and to act as an anti-oncomir in melanoma cells. At present, we found that exogenous miR-203 increased pigmentation and protein expression levels of the melanoma antigen recognized by T cells (Melan-As/MART1s) and/or tyrosinase (TYR) in the human melanoma cells tested. Inversely, treatment with an inhibitor of miR-203 downregulated the expression level of TYR. The target gene of miR-203 involved in the mechanism was kinesin superfamily protein 5b (kif5b), which was revealed by gene silencing using short interfering RNA and luciferase activity assay. Furthermore, immunocytochemistry showed obvious accumulation of melanosomes around nuclei of human melanoma Mewo cells transfected with miR-203 or siR-kif5b. Importantly, treatment with the miR-203 inhibitor, but not miR-203, exhibited effects on human epidermal melanocytes isolated from lightly pigmented adult skin similar to those on melanoma cells. In addition, the data indicated that exogenous miR-203 also negatively regulated the cAMP response element-binding protein 1 (CREB1)/microphthalmia-associated transcription factor (MITF)/Rab27a pathway, which is one of the main pathways active in melanoma cells. In conclusion, our data indicated that anti-oncogenic miR-203 had a pivotal role in melanoma through reducing melanosome transport and promoting melanogenesis by targeting kif5b and through negative regulation of the CREB1/MITF/Rab27a pathway.
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43
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Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. Toxicol Lett 2013; 222:1-9. [PMID: 23845851 DOI: 10.1016/j.toxlet.2013.06.242] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 06/25/2013] [Accepted: 06/28/2013] [Indexed: 02/01/2023]
Abstract
Epirubicin is widely used in osteosarcoma chemotherapy. Growing evidence indicates that the microRNA (miRNA) expression levels which are induced by chemotherapeutic agents play an important role in osteosarcoma development and progression. In this study we investigate the alterations of miRNA expression in the osteosarcoma cells after epirubicin treatment and whether miRNAs can enhance its anti-osteosarcoma effect. After epirubicin exposure, microarray shows 40 miRNAs are differentially expressed in osteosarcoma cells including 24 down-regulated miRNAs. Notably, miR-302b, which is stably low-expressed in osteosarcoma, could be induced by the epirubicin. Furthermore, we find that miR-302b can inhibit the osteosarcoma cell proliferation, promote cell apoptosis and cell cycle arrest MiR-302b can activate caspase-3 and regulate the Akt/pAkt, Bcl-2, Bim expression to increase the cell apoptosis. Meanwhile, miR-302b also attenuates cyclin D1 and CDKs expression to induce cell cycle arrest. Therefore, our results suggest miR-302b can play an essential role in osteosarcoma treatment as a potential tumor suppressor.
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Rani SB, Rathod SS, Karthik S, Kaur N, Muzumdar D, Shiras AS. MiR-145 functions as a tumor-suppressive RNA by targeting Sox9 and adducin 3 in human glioma cells. Neuro Oncol 2013; 15:1302-16. [PMID: 23814265 DOI: 10.1093/neuonc/not090] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are increasingly being recognized as being involved in cancer development and progression in gliomas. METHODS Using a model cell system developed in our lab to study glioma progression comprising human neuroglial culture (HNGC)-1 and HNGC-2 cells, we report here that miR-145 is one of the miRNAs significantly downregulated during malignant transformation in glioblastoma multiforme (GBM). In a study using tumor samples derived from various glioma grades, we show that expression of miR-145 is decreased in a graded manner, with GBM patients showing lowest expression relative to lower-grade gliomas (P < .05) and normal brain tissues (P < .0001). Functional studies involving ectopic expression of miR-145 in glioma cells had a negative impact on cell proliferation and tumor development, as well as invasion and induced apoptosis, providing further support to the concept that inactivation of miR-145 is important for glioma disease pathogenesis. More notably, these growth-suppressive effects of miR-145 are mediated through its target proteins Sox9 and the cell adhesion-associated molecule adducin 3 (ADD3). RESULTS Inhibiting Sox9 and ADD3 rescued effects of miR-145 loss. Interestingly, miR-145 loss in glioma cells led to overexpression of molecules involved in cell proliferation, like cyclin D1, c-myc, and N-myc, as well as enhanced expression of cell adhesion- and invasion-related molecules N-cadherin and E-cadherin, an effect which was again restored upon miR-145 overexpression in glioma cells. The miR-145 promoter was methylated at its cytosine-phosphate-guanine (CpG) islands in the glioma cell lines studied. CONCLUSION Our study demonstrates that miR-145 has a tumor-suppressive function in glioblastoma in that it reduces proliferation, adhesion, and invasion of glioblastoma cells, apparently by suppressing the activity of oncogenic proteins Sox9 and ADD3. Reduced levels of miR-145 may lead to neoplastic transformation and malignant progression in glioma due to unregulated activity of these proteins.
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Affiliation(s)
- Sandhya B Rani
- Corresponding Author: Anjali Shiras, MSc, PhD, Scientist-F, National Centre for Cell Science (NCCS), NCCS Complex, University of Pune Campus, Ganeshkhind, Pune 411007, Maharashtra, India. ;
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Noguchi S, Iwasaki J, Kumazaki M, Mori T, Maruo K, Sakai H, Yamada N, Shimada K, Naoe T, Kitade Y, Akao Y. Chemically modified synthetic microRNA-205 inhibits the growth of melanoma cells in vitro and in vivo. Mol Ther 2013; 21:1204-11. [PMID: 23629002 PMCID: PMC3677302 DOI: 10.1038/mt.2013.70] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Accepted: 03/20/2013] [Indexed: 12/17/2022] Open
Abstract
microRNA (miR)-205 is downregulated and acts as a tumor suppressor in human melanoma cells. Previously, for clinical application, we added aromatic benzene-pyridine (BP-type) analogs to the 3'-overhang region of the RNA-strand and changed the sequences of the passenger strand in the miR-143 duplex. Here, we demonstrated the antitumor effect in vitro and in vivo of miR-205 that was also chemically modified by BP and had altered passenger sequence. In in vitro experiments, transfection with the synthetic miR-205 (miR-205BP/S3) significantly inhibited the growth of human melanoma cells. Exogenous miR-205BP/S3 suppressed the protein expression levels of E2F1 and VEGF, which are validated targets of miR-205-5p, and BCL2, a transcribed molecule of E2F1, as did Pre-miR-205, used as a miR-205 mimic having the wild-type sequence. On the basis of the results of a luciferase activity assay, miR-205BP/S3 directly targeted E2F1, as did Pre-miR-205. However, miR-205BP/S3 was much more resistant to RNase than Pre-miR-205 in fetal bovine serum and to RNase in mice xenografted with human melanoma tissues. In addition, the intratumoral injection of miR-205BP/S3 exhibited a significant antitumor effect compared with the case of control miRNA or Pre-miR-205 in human melanoma cell-xenografted mice. These findings indicate that miR-205BP/S3 is a possible promising therapeutic modality for melanoma.
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Affiliation(s)
- Shunsuke Noguchi
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
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Chen B, Duan L, Yin G, Tan J, Jiang X. Simultaneously expressed miR-424 and miR-381 synergistically suppress the proliferation and survival of renal cancer cells---Cdc2 activity is up-regulated by targeting WEE1. Clinics (Sao Paulo) 2013; 68:825-33. [PMID: 23778472 PMCID: PMC3674285 DOI: 10.6061/clinics/2013(06)17] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Accepted: 02/26/2013] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVES MiRNAs are intrinsic RNAs that interfere with protein translation. Few studies on the synergistic effects of miRNAs have been reported. Both miR-424 and miR-381 have been individually reported to be involved in carcinogenesis. They share a common putative target, WEE1, which is described as an inhibitor of G2/M progression. Here, we studied the synergistic effects of miR-424 and miR-381 on renal cancer cells. METHODS The viability of 786-O cells was analyzed after transfection with either a combination of miR-424 and miR-381 or each miRNA alone. We investigated cell cycle progression and apoptosis with flow cytometry. To confirm apoptosis and the abrogation of G2/M arrest, we determined the level of pHH3, which is an indicator of mitosis, and caspase-3/7 activity. The expression levels of WEE1, Cdc25, γH2AX, and Cdc2 were manipulated to investigate the roles of these proteins in the miRNA-induced anti-tumor effects. To verify that WEE1 was a direct target of both miR-424 and miR-381, we performed a dual luciferase reporter assay. RESULTS We showed that the combination of these miRNAs synergistically inhibited proliferation, abrogated G2/M arrest, and induced apoptosis. This combination led to Cdc2 activation through WEE1 inhibition. This regulation was more effective when cells were treated with both miRNAs than with either miRNA alone, indicating synergy between these miRNAs. WEE1 was verified to be a direct target of each miRNA according to the luciferase reporter assay. CONCLUSIONS These data clearly demonstrate that these two miRNAs might synergistically act as novel modulators of tumorigenesis by down-regulating WEE1 expression in renal cell cancer cells.
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Affiliation(s)
- Binghai Chen
- Third Xiang-Ya Hospital of Central South University, Department of Urology, Changsha, Hunan/China
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McAlexander MA, Phillips MJ, Witwer KW. Comparison of Methods for miRNA Extraction from Plasma and Quantitative Recovery of RNA from Cerebrospinal Fluid. Front Genet 2013; 4:83. [PMID: 23720669 PMCID: PMC3655275 DOI: 10.3389/fgene.2013.00083] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 04/24/2013] [Indexed: 11/30/2022] Open
Abstract
Interest in extracellular RNA (exRNA) has intensified as evidence accumulates that these molecules may be useful as indicators of a wide variety of biological conditions. To establish specific exRNA molecules as clinically relevant biomarkers, reproducible recovery from biological samples and reliable measurements of the isolated RNA are paramount. Toward these ends, careful and rigorous comparisons of technical procedures are needed at all steps from sample handling to RNA isolation to RNA measurement protocols. In the investigations described in this methods paper, RT-qPCR was used to examine the apparent recovery of specific endogenous miRNAs and a spiked-in synthetic RNA from blood plasma samples. RNA was isolated using several widely used RNA isolation kits, with or without the addition of glycogen as a carrier. Kits examined included total RNA isolation systems that have been commercially available for several years and commonly adapted for extraction of biofluid RNA, as well as more recently introduced biofluids-specific RNA methods. Our conclusions include the following: some RNA isolation methods appear to be superior to others for the recovery of RNA from biological fluids; addition of a carrier molecule seems to be beneficial for some but not all isolation methods; and quantitative recovery of RNA is observed from increasing volumes of cerebrospinal fluid.
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Affiliation(s)
- Melissa A McAlexander
- Retrovirus Laboratory, Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine Baltimore, MD, USA
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A pH-responsive cyclodextrin-based hybrid nanosystem as a nonviral vector for gene delivery. Biomaterials 2013; 34:4159-4172. [PMID: 23480956 DOI: 10.1016/j.biomaterials.2013.02.035] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2013] [Accepted: 02/11/2013] [Indexed: 12/31/2022]
Abstract
The absence of safe, efficient, cost-effective, and easily scalable delivery platforms is one of the most significant hurdles and critical issues that limit the bench to bedside translation of oligonucleotides-based therapeutics. Acid-labile materials are of special interest in developing nonviral vectors due to their capability of intracellularly delivering therapeutic payload. In this study, a nanovector was designed by integrating a pH-responsive cyclodextrin material and low molecular weight polyethylenimine (PEI). Antisense oligonucleotide (ASON) Bcl-xl could be encapsulated into this hybrid nanosystem with extremely high loading efficiency by a nanoemulsion technique. The developed pH-responsive ASON nanotherapeutics could be efficiently transfected into human lung adenocarcinoma cells in a time- and dose-dependent manner, resulting in effective cell growth inhibition, significant suppression on the expression of Bcl-xl mRNA/protein, and efficient cell apoptosis. Importantly, the new nanovector showed drastically higher efficacy and lower cytotoxicity when compared with PLGA-based counterpart and commonly used cationic vectors like branched PEI (25,000 Da) and Lipofectamine 2000. This pH-responsive hybrid nanosystem may serve as a safe and efficient nonviral vector that may find wide applications in gene therapy.
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Blancafort P, Jin J, Frye S. Writing and rewriting the epigenetic code of cancer cells: from engineered proteins to small molecules. Mol Pharmacol 2013; 83:563-76. [PMID: 23150486 PMCID: PMC3920093 DOI: 10.1124/mol.112.080697] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Accepted: 11/13/2012] [Indexed: 01/04/2023] Open
Abstract
The epigenomic era has revealed a well-connected network of molecular processes that shape the chromatin landscape. These processes comprise abnormal methylomes, transcriptosomes, genome-wide histone post-transcriptional modifications patterns, histone variants, and noncoding RNAs. The mapping of these processes in large scale by chromatin immunoprecipitation sequencing and other methodologies in both cancer and normal cells reveals novel therapeutic opportunities for anticancer intervention. The goal of this minireview is to summarize pharmacological strategies to modify the epigenetic landscape of cancer cells. These approaches include the use of novel small molecule inhibitors of epigenetic processes specifically deregulated in cancer cells and the design of engineered proteins able to stably reprogram the epigenetic code in cancer cells in a way that is similar to normal cells.
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Affiliation(s)
- Pilar Blancafort
- School of Anatomy, Physiology, and Human Biology, M309, the University of Western Australia, 35 Stirling Highway, Crawley, 6009, WA, Australia.
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New advances of microRNAs in the pathogenesis of rheumatoid arthritis, with a focus on the crosstalk between DNA methylation and the microRNA machinery. Cell Signal 2013; 25:1118-25. [PMID: 23385088 DOI: 10.1016/j.cellsig.2013.01.024] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Accepted: 01/25/2013] [Indexed: 12/28/2022]
Abstract
Rheumatoid arthritis (RA) is a symmetrical polyarticular disease of unknown aetiology that affects primarily the articular cartilage and bone. Characteristic features of RA pathogenesis are persistent inflammation, synovium hyperplasia and cartilage erosion accompanied by joint swelling and joint destruction. Several lines of evidence have showed a crucial role of activated fibroblast-like synoviocytes (FLS) in the pathogenesis of RA. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs with about 21 nucleotides in length and have been detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. In light of key roles of miRNAs in the regulation of gene expression, miRNAs influence a wide range of physiological and pathological processes. For example, miRNAs are evident in various malignant and nonmalignant diseases, and accumulating evidence also shows that miRNAs have important roles in the pathogenesis of RA. It has been demonstrated that miRNAs can be aberrantly expressed even in the different stages of RA progression, allowing miRNAs to help understand the pathogenesis of the disease, to act as important biomarkers, and to monitor the disease severity and the effects of drug treatment. In addition, miRNAs are emerging as potential targets for new therapeutic strategies of this kind of autoimmune disorders. The ultimate goal is the identification of miRNA targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the RA development. In this review, the importance of miRNAs in the pathogenesis of RA is discussed systematically, with particular emphasis on the role of the crosstalk between DNA methylation and the microRNA machinery.
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