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Alotaibi AG, Li JV, Gooderham NJ. Tumour Necrosis Factor-Alpha (TNF-α)-Induced Metastatic Phenotype in Colorectal Cancer Epithelial Cells: Mechanistic Support for the Role of MicroRNA-21. Cancers (Basel) 2023; 15:627. [PMID: 36765584 PMCID: PMC9913347 DOI: 10.3390/cancers15030627] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Colorectal cancer is driven by genetic and epigenetic changes in cells to confer phenotypes that promote metastatic transformation and development. Tumour necrosis factor-alpha (TNF-α), a pro-inflammatory mediator, regulates cellular communication within the tumour microenvironment and is associated with the progression of the metastatic phenotype. Oncogenic miR-21 has been shown to be overexpressed in most solid tumours, including colorectal cancer, and is known to target proteins involved in metastatic transformation. In this study, we investigated the relationship between TNF-α and miR-21 regulation in colorectal cancer epithelial cells (SW480 and HCT116). We observed that TNF-α, at concentrations reported to be present in serum and tumour tissue from colorectal cancer patients, upregulated miR-21 expression in both cell lines. TNF-α treatment also promoted cell migration, downregulation of the expression of E-cadherin, a marker of epithelial to mesenchymal transition, and anti-apoptotic BCL-2 (a validated target for miR-21). Knockdown of miR-21 had the opposite effect on each of these TNF-a induced phenotypic changes. Additionally, in the SW480 cell line, although TNF-α treatment selectively induced expression of a marker of metastatic progression VEGF-A, it failed to affect MMP2 expression or invasion activity. Our data indicate that exposing colorectal cancer epithelial cells to TNF-α, at concentrations occurring in the serum and tumour microenvironment of colorectal cancer patients, upregulated miR-21 expression and promoted the metastatic phenotype.
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Affiliation(s)
- Aminah G. Alotaibi
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
- National Centre for Genomic Technology, King Abdulaziz City for Science and Technology, KACST, Riyadh 11442, Saudi Arabia
| | - Jia V. Li
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
| | - Nigel J. Gooderham
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK
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2
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Circular Sponge against miR-21 Enhances the Antitumor Activity of Doxorubicin against Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms232314803. [PMID: 36499129 PMCID: PMC9736351 DOI: 10.3390/ijms232314803] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 12/02/2022] Open
Abstract
Breast cancer is the most common type of cancer in women, with chemotherapy being the main strategy. However, its effectiveness is reduced by drug resistance mechanisms. miR-21 is upregulated in breast cancer that has been linked to drug resistance and carcinogenic processes. Our aim was to capture miR-21 with a circular sponge (Circ-21) and thus inhibit the carcinogenic processes and drug resistance mechanisms in which it participates. Proliferation, migration, colony formation, cell cycle, and poly [ADP-ribose] polymerase 1 (PARP-1) and vascular endothelial growth factor (VEGF) detection assays were performed with MCF7 breast cancer cells and MCF10A non-tumor cells. In addition, doxorubicin resistance tests and detection of drug resistance gene expression were performed in MCF7 cells. Reduction in proliferation, as well as migration and colony formation, increased PARP-1 expression, inhibition of VEGF expression and cell cycle arrest in G2/M phase were displayed in the Circ-21 MCF7, which were not observed in the MCF10A cells. Furthermore, in the MCF7 cells, the Circ-21 enhanced the antitumor activity of doxorubicin and decreased the expression of resistance genes: ABCA1, ABCC4, and ABCC5. Based on these results, the use of Circ-21 can be considered a first step for the establishment of an effective gene therapy in the treatment of breast cancer.
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Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
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Doukas SG, Vageli DP, Doukas PG, Nikitovic D, Tsatsakis A, Judson BL. The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence. Curr Oncol 2022; 29:5531-5549. [PMID: 36005175 PMCID: PMC9406897 DOI: 10.3390/curroncol29080437] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 07/22/2022] [Accepted: 07/31/2022] [Indexed: 11/16/2022] Open
Abstract
Deregulation of the DNA mismatch repair (MMR) mechanism has been linked to poor prognosis of upper aerodigestive tract cancers. Our recent in vitro data have provided evidence of crosstalk between deregulated miRNAs and MMR genes, caused by tobacco smoke (TS) N-Nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in hypopharyngeal cells. Here, we explored whether chronic exposure to TS components can affect MMR mechanism and miRNA profiles in hypopharyngeal mucosa. Using a mouse model (C57Bl/6J wild type) of in vivo 14-week exposure to NNK (0.2 mmol/L) and N-Nitrosodiethylamine (NDEA; 0.004 mmol/L), with or without nicotine (0.02 μmol/L), we provide direct evidence that TS components can promote dysplasia, significant downregulation of Msh2 and Mlh1 genes and deregulation of miR-21, miR-155, miR-34a, and miR-451a. By analyzing eight human specimens from tobacco smokers and eight controls, we provide clinical evidence of a significant reduction in hMSH2 and hMLH1 mRNAs in hypopharyngeal squamous cell carcinoma (HSCC). In summary, deregulation of the MMR mechanism and miRNAs is caused by chronic exposure to TS-related N-Nitrosamines, with or without nicotine, in the early stages of upper aerodigestive tract carcinogenesis, and can also be detected in human HSCC. Thus, we encourage future studies to further elucidate a possible in vivo dose-dependent effect of individual or combined N-Nitrosamines, NNK and/or NDEA, and nicotine, on the MMR mechanism and their clinical testing to elaborate prognosis and risk assessment.
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Affiliation(s)
- Sotirios G. Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
- Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
- Department of Medicine, Rutgers/Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
| | - Dimitra P. Vageli
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Panagiotis G. Doukas
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Dragana Nikitovic
- Department of Histology & Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Aristidis Tsatsakis
- Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
| | - Benjamin L. Judson
- The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
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Luan G, Wang M, Yuan J, Bu X, Song J, Wang C, Zhang L. Regulatory network identified by pulmonary transcriptome and proteome profiling reveals extensive change of tumor-related genes in microRNA-21 knockout mice. J Cancer Res Clin Oncol 2022; 148:1919-1929. [PMID: 35511299 DOI: 10.1007/s00432-022-03967-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 02/21/2022] [Indexed: 01/08/2023]
Abstract
PURPOSE MicroRNA-21 (miR-21) is a well-known oncomiR and plays key roles in regulating various biological processes related to pulmonary diseases, especially lung carcinoma. The regulatory roles and downstream targets of miR-21 remain far from well understood. We aimed to identify miR-21-gene regulatory network in lung tissue. METHODS Transcriptome and proteome analyses were performed on lung tissues from miR-21 knockout (KO) mice and their wildtype (WT) littermates. Differentially expressed genes (DEGs) and proteins (DEPs) between miR-21KO and WT were analyzed, and correlation analysis was performed between transcriptional and translational level. DEPs were used for prediction of miR-21 target genes and construction of co-expression network. RESULTS Comparing with WT mice, 820 DEGs and 623 DEPs were identified in lung tissues of miR-21KO mice. Upregulated DEGs and DEPs were both significantly enriched in pathways of metabolism of xenobiotics by cytochrome P450, drug metabolism, and chemical carcinogenesis. Of the 31 molecules commonly identified in DEGs and DEPs, 9 upregulated genes were tumor suppressor genes while 8 downregulated genes were oncogenes, and 12 genes showed closely positive correlation between mRNA and protein expression. Real-time PCR validation results were consistent with the omics data. Among the upregulated DEPs in miR-21KO mice, 21 genes were predicted as miR-21 targets. The miR-21 regulatory network was constructed by target genes and their highly co-expressed proteins, which identified the miR-21 target Itih4 as a hub gene. CONCLUSION MiR-21-gene regulatory network was constructed in mouse lung tissue. MiR-21KO resulted in extensive upregulation of tumor suppressor genes and downregulation of oncogenes.
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Affiliation(s)
- Ge Luan
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China
| | - Ming Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China
| | - Jing Yuan
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China
| | - Xiangting Bu
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China
| | - Jing Song
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China
| | - Chengshuo Wang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China.
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China.
| | - Luo Zhang
- Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, 100730, China.
- Beijing Laboratory of Allergic Diseases and Beijing Key Laboratory of Nasal Diseases, Beijing Institute of Otolaryngology, Beijing, 100005, China.
- Department of Allergy, Beijing TongRen Hospital, Capital Medical University, No. 1, DongJiaoMinXiang, DongCheng District, Beijing, 100730, China.
- Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese Academy of Medical Sciences, Beijing, China.
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Li T, Li X, Mao R, Pan L, Que Y, Zhu C, Jin L, Li S. NLRP2 inhibits cell proliferation and migration by regulating EMT in lung adenocarcinoma cells. Cell Biol Int 2021; 46:588-598. [PMID: 34957627 DOI: 10.1002/cbin.11755] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022]
Abstract
Nucleotide-binding oligomerization domain-like receptors (NLRs) are crucial types of innate immune sensors and well known for their critical roles in the immune system. However, how NLRP2 functions in the progression of cancer is largely unknown. Here, we identified NLRP2 as an antioncogene in lung adenocarcinoma (LUAD) cells. Gain- and loss-of-function studies revealed that NLRP2 silencing promoted cell proliferation and migration by stimulating NF-kB signaling in the microenvironment, which induced epithelial-to-mesenchymal transition (EMT) phenotype and cytoskeleton reorganization in LUAD cells. The addition of the NF-kB inhibitor rescued the function of NLRP2 on EMT. Moreover, NLRP2 increased the level of cofilin phosphorylation and repressed subsequent F-actin reorganization. Consistently, the in vivo study showed that NLRP2 played an inhibitory role in forming metastasis foci. Taken together, NLRP2 inhibited cell proliferation and migration by regulating EMT in LUAD cells, demonstrating the essential function of NLRP2 in the development of LUAD.
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Affiliation(s)
- Tiantian Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xu Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rongchen Mao
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lihua Pan
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuhui Que
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chao Zhu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lai Jin
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shengnan Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
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7
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Wu XY, Chen HC, Li WW, Yan JD, Lv RY. DNMT1 promotes cell proliferation via methylating hMLH1 and hMSH2 promoters in EGFR-mutated non-small cell lung cancer. J Biochem 2021; 168:151-157. [PMID: 32211850 DOI: 10.1093/jb/mvaa034] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/28/2020] [Indexed: 12/12/2022] Open
Abstract
Aberrant DNA methylation is a common form of epigenetic alterations and it has been proved to be closely related to many cancers, while its role in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is not clear. This study focuses on the role of DNA methyltransferase 1 (DNMT1) in EGFR-mutated NSCLC pathogenesis. First, the expression of DNMT1 was up-regulated, while the expressions of human mutL homolog 1(hMLH1) and human mutS homolog 2 (hMSH2) were down-regulated in EGFR-mutated NSCLC patients and cell line HCC827. The results of the correlation analysis showed that DNMT1 expression was inversely correlated with the expressions of hMLH1 and hMSH2. Then, we found that DNMT1 enhanced the promoter methylation levels of hMLH1 and hMSH2, thus suppressing their expressions. DNMT1 knockdown inhibited the proliferation of HCC827 cells, while both hMLH1 knockdown and hMSH2 knockdown could eliminate its inhibitory effect on cell proliferation. In xenograft mouse models, lentiviral vector-sh-DNMT1 could significantly reduce tumor volumes, confirmed that DNMT1 inhibited tumor cell proliferation in vivo. In conclusion, DNMT1 suppressed the expressions of hMLH1 and hMSH2 via elevating their promoter methylation, thus promoting cell proliferation in EGFR-mutated NSCLC.
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Affiliation(s)
- Xiao-Yu Wu
- Department of Respiration, Jinhua Guangfu Cancer Hospital, No. 1296, North Huancheng Rd, Wucheng District, Jinhua, Zhejiang 321000, China
| | - Hua-Chun Chen
- Department of Respiration, Jinhua Guangfu Cancer Hospital, No. 1296, North Huancheng Rd, Wucheng District, Jinhua, Zhejiang 321000, China
| | - Wen-Wen Li
- Department of Respiration, Jinhua Guangfu Cancer Hospital, No. 1296, North Huancheng Rd, Wucheng District, Jinhua, Zhejiang 321000, China
| | - Jia-Dong Yan
- Department of Respiration, Jinhua Guangfu Cancer Hospital, No. 1296, North Huancheng Rd, Wucheng District, Jinhua, Zhejiang 321000, China
| | - Ruo-Ya Lv
- Department of Respiration, Jinhua Guangfu Cancer Hospital, No. 1296, North Huancheng Rd, Wucheng District, Jinhua, Zhejiang 321000, China
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8
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Ahadi A. A systematic review of microRNAs as potential biomarkers for diagnosis and prognosis of gastric cancer. Immunogenetics 2021; 73:155-161. [PMID: 33399935 DOI: 10.1007/s00251-020-01201-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023]
Abstract
Gastric cancer (GC) is the third leading cause of global cancer morbidity and mortality. One of the significant challenges in GC treatment is that most GC patients are diagnosed with advanced-stage disease due to the lack of suitable biomarkers. Recent studies have shown that microRNAs (miRNAs) can acts as a potential biomarker in GC diagnosis and prognosis. I performed a systematic review of published miRNA studies in GC, which includes the miRNA expression profiles between GC tissues and normal tissues and also miRNA studies to evaluate their potential value in the diagnosis and prognosis of GC. Among the studies, upregulation of miR-21, miR-106b, miR-25, miR-214, miR-18a, miR-191, and miR-93 and downregulation of miR-375, miR-148a, miR-92, miR-155, and miR-564 were observed in GC tissues. In evaluating of diagnosis value of miRNAs, the study was performed on a combined miRNA include miR-21, miR-93, miR-106a, and miR-106b indicated the panel of these miRNAs have the highest AUC 0.887 to discriminate GC patients from healthy. Also, miR-940 with a sensitivity of 81.25% and specificity of 98.57% may be used for diagnostic biomarkers for GC. Finally, the pooled prognostic result of miR-21 for hazard ratios (HR) was 1.260 (95% CI 0.370-4.330, P < 0.001), showing that miR-21 could predict poor survival in GC patients. This systematic review can confirm that we need to find a miRNA or a panel of miRNAs with high sensitivity and specificity for further exploration to investigate a better diagnostic or therapeutic tool for personalized management of GC patients.
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Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Doukas SG, Vageli DP, Lazopoulos G, Spandidos DA, Sasaki CT, Tsatsakis A. The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells. Cells 2020; 9:E1031. [PMID: 32326378 PMCID: PMC7226174 DOI: 10.3390/cells9041031] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/04/2020] [Accepted: 04/19/2020] [Indexed: 02/07/2023] Open
Abstract
Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 μM) or high (2 μM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.
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Affiliation(s)
- Sotirios G. Doukas
- Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.G.D.); (A.T.)
- Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USA;
| | - Dimitra P. Vageli
- Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USA;
| | - George Lazopoulos
- Department of Cardiothoracic Surgery, Medical School, University of Crete, 71110 Heraklion, Greece;
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71110 Heraklion, Greece;
| | - Clarence T. Sasaki
- Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USA;
| | - Aristidis Tsatsakis
- Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece; (S.G.D.); (A.T.)
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10
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Zeybek A, Öz N, Kalemci S, Edgünlü T, Kızıltuğ MT, Tosun K, Tunç M, Tekin L, Erdal ME. Diagnostic Value of MiR-125b as a Potential Biomarker for Stage I Lung Adenocarcinoma. Curr Mol Med 2019; 19:216-227. [DOI: 10.2174/1566524019666190314113800] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 03/07/2019] [Accepted: 03/08/2019] [Indexed: 12/31/2022]
Abstract
Background:We aimed at exploring biological functions of differentially expressed miRNAs during carcinogenesis, to identify miRNAs dysegulations involved in DNA repair mechanisms, and to evaluate potential of miRNAs as prognostic and diagnostic biomarkers for early lung adenocarcinomas (LAC).Methods:We obtained 21 LAC and paired adjacent normal formalin-fixed, paraffinembedded lung tissues from patients who underwent curative resection for stage I LAC. We compared expression levels of eight miRNAs involved in the DNA repair mechanism between LAC and adjacent tissues.Results:Expressions of Hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-125a-3p, hsa-miR- 125b-5p, hsa-miR-155-5p, and hsa-let-7a-5p were significantly up-regulated in stage I LAC tissues compared with those in the adjacent tissues. In addition, expressions of hsa-mir-9-5p, hsa-mir-24-3p, hsa-mir-125a-3p, hsa-mir-125b-5p, and hsa-mir-155-5p were significantly up-regulated in stage Ia LAC tissues, whereas expressions of hsa-mir- 125a-3p and hsa-mir-125b-5p were significantly up-regulated in stage Ib LAC tissues. Receiver operating characteristic (ROC) analysis revealed that AUROC of hsa-mir-125b- 5p was 0.875 (P < 0.001).Conclusion:Expression of hsa-mir-125b-5p could be used to distinguish LAC from adjacent tissues. Our result suggests that hsa-mir125b-5p can be a prognostic and diagnostic biomarker for LAC.
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Affiliation(s)
- Arife Zeybek
- Department of Thoracic Surgery, School of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
| | - Necdet Öz
- Department of Thoracic Surgery, Private Medstar Antalya Hospital, Antalya, Turkey
| | | | - Tuba Edgünlü
- Department of Medical Biology, School of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
| | | | - Kürşad Tosun
- Science School, Siena College, Newyork, NY, United States
| | - Mustafa Tunç
- Department of Medical Pathology, Private Antalya Pathology Center, Antalya, Turkey
| | - Leyla Tekin
- Department of Medical Pathology, School of Medicine, Mugla Sitki Kocman University, Mugla, Turkey
| | - Mehmet Emin Erdal
- Department of Medical Biology, School of Medicine, Mersin University, Mersin, Turkey
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Zennami K, Choi SM, Liao R, Li Y, Dinalankara W, Marchionni L, Rafiqi FH, Kurozumi A, Hatano K, Lupold SE. PDCD4 Is an Androgen-Repressed Tumor Suppressor that Regulates Prostate Cancer Growth and Castration Resistance. Mol Cancer Res 2019; 17:618-627. [PMID: 30518628 PMCID: PMC6359980 DOI: 10.1158/1541-7786.mcr-18-0837] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 10/09/2018] [Accepted: 11/21/2018] [Indexed: 12/11/2022]
Abstract
Androgen receptor (AR) transcriptional activity contributes to prostate cancer development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here, we found PDCD4 to be a new target of AR signaling and a potent regulator of prostate cancer cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from prostate cancer tissue samples in The Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21 and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen-dependent cell proliferation and cell-cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 overexpression inhibited miR-21-mediated growth and androgen independence. The stable knockdown of PDCD4 in androgen-dependent prostate cancer cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration-resistant tumor growth. IMPLICATIONS: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating prostate cancer cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4-regulated pathways as potential new targets for castration-resistant prostate cancer.
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Affiliation(s)
- Kenji Zennami
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Su Mi Choi
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ross Liao
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ying Li
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Wikum Dinalankara
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Luigi Marchionni
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Fatema H Rafiqi
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Akira Kurozumi
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Koji Hatano
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Shawn E Lupold
- Department of Urology, The James Buchanan Brady Urologic Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland
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12
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Rahmani M, Mohammadnia-Afrouzi M, Nouri HR, Fattahi S, Akhavan-Niaki H, Mostafazadeh A. Human PBMCs fight or flight response to starvation stress: Increased T-reg, FOXP3, and TGF-β1 with decreased miR-21 and Constant miR-181c levels. Biomed Pharmacother 2018; 108:1404-1411. [PMID: 30453448 DOI: 10.1016/j.biopha.2018.09.163] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 09/27/2018] [Accepted: 09/28/2018] [Indexed: 12/11/2022] Open
Abstract
Regulatory T-lymphocytes play a prominent role in autoimmunity, allergy, and cancer. In some conditions such as inflammation and tumor, immune cells are encountered with metabolic stress. Emerging evidence indicates the contribution of microRNAs in both metabolism and immune regulation. Herewith, we have examined the in vitro effects of serum starvation for 16, 48, 72 and 96 h on the expression of T-reg differentiation markers (CD4, CD25, CD127, and FOXP3) as well as on the Transforming Growth Factor-β1 (TGF-β1) and some microRNAs (miR-21,-29a,-31,146a,-155,-181a and -181c) levels in human Peripheral Blood Mononuclear Cells (PBMCs). The percentage of CD4+CD25+CD127low/-FOXP3+ T-regs, as well as FOXP3 expression, was increased in starved lymphocytes (p < 0.01). 96 h-starved PBMCs had the lowest T-eff/T-reg ratio (p < 0.05). All the studied miRNAs except miR-181c were significantly down-regulated in those cells (p < 0.05), in particular, miR-29a and miR-155 were sharply declined in 48h-starved PBMCs (p < 0.01). There was a negative correlation between time of starvation and microRNAs expression, except for miR-181c (r-value = -0. 61 to -0.9 and p-value = 0.037 to 0). The percentage of T-reg was inversely correlated with all miRNAs levels except for miR-31 and miR-181c (r-value = -0.68 to -0.78 and p-value = 0.015 to 0.003). FOXP3 expression exhibited a same degree of negative correlation with miR-31 and miR-155 expression levels (r = -0.57 and p = 0.05, for both). Increasing starvation duration led to a rise inTGF-β1 protein levels (p<0.01), especially its active form (P<0.001). This study introduced the serum starvation as a tool for immunoregulation which acts probably through increasing TGF-β1 production and inducing some alterations in microRNAs expression.
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Affiliation(s)
- Mahsa Rahmani
- Students Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afrouzi
- Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Hamid Reza Nouri
- Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Sadegh Fattahi
- Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Amrollah Mostafazadeh
- Cellular and Molecular Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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13
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Bica-Pop C, Cojocneanu-Petric R, Magdo L, Raduly L, Gulei D, Berindan-Neagoe I. Overview upon miR-21 in lung cancer: focus on NSCLC. Cell Mol Life Sci 2018; 75:3539-3551. [PMID: 30030592 PMCID: PMC11105782 DOI: 10.1007/s00018-018-2877-x] [Citation(s) in RCA: 171] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 06/25/2018] [Accepted: 07/16/2018] [Indexed: 12/17/2022]
Abstract
Considering the high mortality rate encountered in lung cancer, there is a strong need to explore new biomarkers for early diagnosis and also improved therapeutic targets to overcome this issue. The implementation of microRNAs as important regulators in cancer and other pathologies expanded the possibilities of lung cancer management and not only. MiR-21 represents an intensively studied microRNA in many types of cancer, including non-small cell lung cancer (NSCLC). Its role as an oncogene is underlined in multiple studies reporting the upregulated expression of this sequence in patients diagnosed with this malignancy; moreover, several studies associated this increased expression of miR-21 with a worse outcome within NSCLC patients. The same pattern is supported by the data existent in the Cancer Genome Atlas (TCGA). The carcinogenic advantage generated by miR-21 in NSCLC resides in the target genes involved in multiple pathways such as cell growth and proliferation, angiogenesis, invasion and metastasis, but also chemo- and radioresistance. Therapeutic modulation of miR-21 by use of antisense sequences entrapped in different delivery systems has shown promising results in impairment of NSCLC. Hereby, we review the mechanisms of action of miR-21 in cancer and the associated changes upon tumor cells together a focused perspective on NSCLC signaling, prognosis and therapy.
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Affiliation(s)
- Cecilia Bica-Pop
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", Marinescu 23 Street, 400337, Cluj-Napoca, Romania
| | - Roxana Cojocneanu-Petric
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", Marinescu 23 Street, 400337, Cluj-Napoca, Romania
| | - Lorand Magdo
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", Marinescu 23 Street, 400337, Cluj-Napoca, Romania
| | - Lajos Raduly
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", Marinescu 23 Street, 400337, Cluj-Napoca, Romania
- Department of Pathophysiology, University of Agricultural Sciences and Veterinary Medicine, Calea Mănăștur 3-5 Street, 400372, Cluj-Napoca, Romania
| | - Diana Gulei
- MedFuture Research Center for Advanced Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", 400349, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", Marinescu 23 Street, 400337, Cluj-Napoca, Romania.
- MedFuture Research Center for Advanced Medicine, University of Medicine and Pharmacy "Iuliu-Hatieganu", 400349, Cluj-Napoca, Romania.
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuţă", 400015, Cluj-Napoca, Romania.
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Sonea L, Buse M, Gulei D, Onaciu A, Simon I, Braicu C, Berindan-Neagoe I. Decoding the Emerging Patterns Exhibited in Non-coding RNAs Characteristic of Lung Cancer with Regard to their Clinical Significance. Curr Genomics 2018; 19:258-278. [PMID: 29755289 PMCID: PMC5930448 DOI: 10.2174/1389202918666171005100124] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 07/14/2017] [Accepted: 09/21/2017] [Indexed: 12/17/2022] Open
Abstract
Lung cancer continues to be the leading topic concerning global mortality rate caused by can-cer; it needs to be further investigated to reduce these dramatic unfavorable statistic data. Non-coding RNAs (ncRNAs) have been shown to be important cellular regulatory factors and the alteration of their expression levels has become correlated to extensive number of pathologies. Specifically, their expres-sion profiles are correlated with development and progression of lung cancer, generating great interest for further investigation. This review focuses on the complex role of non-coding RNAs, namely miR-NAs, piwi-interacting RNAs, small nucleolar RNAs, long non-coding RNAs and circular RNAs in the process of developing novel biomarkers for diagnostic and prognostic factors that can then be utilized for personalized therapies toward this devastating disease. To support the concept of personalized medi-cine, we will focus on the roles of miRNAs in lung cancer tumorigenesis, their use as diagnostic and prognostic biomarkers and their application for patient therapy.
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Affiliation(s)
- Laura Sonea
- MEDFUTURE - Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mihail Buse
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diana Gulei
- MEDFUTURE - Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Anca Onaciu
- MEDFUTURE - Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioan Simon
- Surgery Department IV, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Surgery Department, Romanian Railway (CF) University Hospital, Cluj-Napoca, Romania
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- MEDFUTURE - Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Functional Genomics and Experimental Pathology, "Prof. Dr. Ion Chiricuta" The Oncology Institute, Republicii Street, No. 34-36, 401015, Cluj-Napoca, Romania
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15
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Prathyusha AMVN, Raghu G, Bramhachari PV. HIF-1α: Its Role in Metastasis of Oesophageal Malignancy. ROLE OF TRANSCRIPTION FACTORS IN GASTROINTESTINAL MALIGNANCIES 2017:73-89. [DOI: 10.1007/978-981-10-6728-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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16
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Tahamtan A, Inchley CS, Marzban M, Tavakoli‐Yaraki M, Teymoori‐Rad M, Nakstad B, Salimi V. The role of microRNAs in respiratory viral infection: friend or foe? Rev Med Virol 2016; 26:389-407. [PMID: 27373545 PMCID: PMC7169129 DOI: 10.1002/rmv.1894] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 06/06/2016] [Accepted: 06/08/2016] [Indexed: 12/20/2022]
Abstract
MicroRNAs (miRNAs) have emerged as a class of regulatory RNAs in host-pathogen interactions. Aberrant miRNA expression seems to play a central role in the pathology of several respiratory viruses, promoting development and progression of infection. miRNAs may thus serve as therapeutic and prognostic factors for respiratory viral infectious disease caused by a variety of agents. We present a comprehensive review of recent findings related to the role of miRNAs in different respiratory viral infections and discuss possible therapeutic opportunities aiming to attenuate the burden of viral infections. Our review supports the emerging concept that cellular and viral-encoded miRNAs might be broadly implicated in human respiratory viral infections, with either positive or negative effects on virus life cycle. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Alireza Tahamtan
- Department of Virology, School of Public HealthTehran University of Medical SciencesTehranIran
| | - Christopher S. Inchley
- Department of Pediatric and Adolescent MedicineAkershus University HospitalLørenskogNorway
| | - Mona Marzban
- Department of Virology, School of Public HealthTehran University of Medical SciencesTehranIran
| | | | - Majid Teymoori‐Rad
- Department of Virology, School of Public HealthTehran University of Medical SciencesTehranIran
| | - Britt Nakstad
- Department of Pediatric and Adolescent MedicineAkershus University HospitalLørenskogNorway
- Institute of Clinical MedicineUniversity of OsloOsloNorway
| | - Vahid Salimi
- Department of Virology, School of Public HealthTehran University of Medical SciencesTehranIran
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17
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Wang W, Cheng M, Qiao S, Wang Y, Li H, Wang N. Gga-miR-21 inhibits chicken pre-adipocyte proliferation in part by down-regulating Kruppel-like factor 5. Poult Sci 2016; 96:200-210. [PMID: 27587730 DOI: 10.3382/ps/pew281] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/29/2016] [Accepted: 06/30/2016] [Indexed: 12/25/2022] Open
Abstract
Gga-miR-21 is abundantly expressed in chicken pre-adipocytes, but its role is unclear. The present study investigated the role of gga-miR-21 in chicken pre-adipocyte proliferation. Cell proliferation assay and gene expression analysis of proliferating cell nuclear antigen (PCNA) showed that the gga-miR-21 mimic inhibited pre-adipocyte proliferation. In contrast, the gga-miR-21 inhibitor enhanced pre-adipocyte proliferation. The subsequent investigation identified Kruppel-like factor 5 (KLF5) mRNA as a target of gga-miR-21. The gga-miR-21 mimic inhibited KLF5 3'UTR reporter activity and decreased endogenous KLF5 expression in primary pre-adipocytes. KLF5 knockdown using RNAi had a similar effect to that of the gga-miR-21 mimic on cell proliferation. The promoting effect of the gga-miR-21 inhibitor on pre-adipocyte proliferation was partially attenuated by KLF5 knockdown. Taken together, our results demonstrated that miR-21 inhibits chicken pre-adipocyte proliferation, at least in part, by targeting KLF5.
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Affiliation(s)
- Weishi Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Min Cheng
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Shupei Qiao
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Yuxiang Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Hui Li
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
| | - Ning Wang
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture, Harbin, China; Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin, China; College of Animal Science and Technology, Northeast Agricultural University, Harbin, China
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18
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Xu LM, Li LQ, Li J, Li HW, Shen QB, Ping JL, Ma ZH, Zhong J, Dai LC. Upregulation of miR-1280 expression in non-small cell lung cancer tissues. Chin Med J (Engl) 2015; 128:670-3. [PMID: 25698202 PMCID: PMC4834781 DOI: 10.4103/0366-6999.151672] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Background: Non-small cell lung cancer (NSCLC) is a prolific and high-mortality disease with few effective treatments. Although the detection and surgical techniques for NSCLC continue to advance, the survival rate for the patients with NSCLC remains poor. Enhanced predictive biomarkers such as microRNAs (miRNAs) are needed at the time of diagnosis to better tailor therapies for patients. This study focused on the expression of miR-1280 in NSCLC tissues and distal normal tissues in order to explore the association between miR-1280 expression and NSCLC. Methods: A total of 72 newly diagnosed primary NSCLC patients were enrolled in this study. Quantitative real-time polymerase chain reaction (PCR) was performed to identify the expression level of miR-1280 in the NSCLC tissues and distal normal tissues of these patients. Results: The miR-1280 expression was significantly higher in the NSCLC tissues (0.084 ± 0.099) than distal normal tissues (0.014 ± 0.015, P = 0.009). In 54 patients (75%), the miR-1280 expression in the NSCLC tissues was upregulated (2−ΔΔct > 2), and no case showed a downregulation of miR-1280 expression. Conclusions: The expression level of miR-1280 could be regarded as a biomarker for NSCLC.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Li-Cheng Dai
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, Zhejiang 313000, China
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19
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Yang L, Yang J, Li J, Shen X, Le Y, Zhou C, Wang S, Zhang S, Xu D, Gong Z. MircoRNA-33a inhibits epithelial-to-mesenchymal transition and metastasis and could be a prognostic marker in non-small cell lung cancer. Sci Rep 2015; 5:13677. [PMID: 26330060 PMCID: PMC4556976 DOI: 10.1038/srep13677] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 08/03/2015] [Indexed: 01/09/2023] Open
Abstract
Understanding the molecular mechanism by which epithelial mesenchymal transition (EMT)-mediated cancer metastasis and how microRNA (miRNA) regulates lung cancer progression via Twist1-activated EMT may provide potential therapeutic targets for cancer therapy. Here we found that miR-33a, an intronic miRNA located within the sterol regulatory element-binding protein 2 (SREBP-2) gene, is expressed at low levels in metastatic non-small cell lung cancer (NSCLC) cells and is inversely correlated with Twist1 expression. Conversely, miR-33a knockdown induces EMT and miR-33a overexpression blocks EMT by regulating of Twist1 expression in NSCLC cells. Bioinformatical prediction and luciferase reporter assay confirm that Twist1 is a direct target of miR-33a. Additionally, Twist1 knockdown blocks EMT-related metastasis and forced expression of miR-33a inhibits lung cancer metastasis in a xenograft animal model. Clinically, miR-33a is found to be at low levels in NSCLC patients and down-regulation of miR-33a predicts a poor prognosis. These findings suggest that miR-33a targets Twist1 and inhibits invasion and metastasis in NSCLC. Thus, miR-33a might be a potential prognostic marker and of therapeutic relevance for NSCLC metastasis intervention.
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Affiliation(s)
- Lihua Yang
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
| | - Jie Yang
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
| | - Jingqiu Li
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
| | - Xingkai Shen
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
| | - Yanping Le
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
| | | | - Shaomin Wang
- Department of Oncology, The Affiliated Hospital of Ningbo University School of Medicine, Ningbo, ZJ 315020, China
| | - Shun Zhang
- Clinical Laboratory, Ningbo No. 2 Hospital, Ningbo, ZJ 315010, China
| | - Dazhi Xu
- State Key Laboratory of Oncology in South China
- Sun Yat-sen University Cancer Center, Guangzhou, GD 510060, China
| | - Zhaohui Gong
- Institute of Biochemistry and Molecular Biology
- Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, ZJ 315211, China
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Ishii S, Hashimoto-Torii K. Impact of prenatal environmental stress on cortical development. Front Cell Neurosci 2015; 9:207. [PMID: 26074774 PMCID: PMC4444817 DOI: 10.3389/fncel.2015.00207] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 05/13/2015] [Indexed: 12/31/2022] Open
Abstract
Prenatal exposure of the developing brain to various types of environmental stress increases susceptibility to neuropsychiatric disorders such as autism, attention deficit hyperactivity disorder and schizophrenia. Given that even subtle perturbations by prenatal environmental stress in the cerebral cortex impair the cognitive and memory functions, this review focuses on underlying molecular mechanisms of pathological cortical development. We especially highlight recent works that utilized animal exposure models, human specimens or/and induced Pluripotent Stem (iPS) cells to demonstrate: (1) molecular mechanisms shared by various types of environmental stressors, (2) the mechanisms by which the affected extracortical tissues indirectly impact the cortical development and function, and (3) interaction between prenatal environmental stress and the genetic predisposition of neuropsychiatric disorders. Finally, we discuss current challenges for achieving a comprehensive understanding of the role of environmentally disturbed molecular expressions in cortical maldevelopment, knowledge of which may eventually facilitate discovery of interventions for prenatal environment-linked neuropsychiatric disorders.
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Affiliation(s)
- Seiji Ishii
- Center for Neuroscience Research, Children's National Medical Center, Children's Research Institute Washington, DC, USA
| | - Kazue Hashimoto-Torii
- Center for Neuroscience Research, Children's National Medical Center, Children's Research Institute Washington, DC, USA ; Department of Pediatrics, Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University Washington, DC, USA ; Department of Neurobiology, School of Medicine, Kavli Institute for Neuroscience, Yale University New Haven, CT, USA
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21
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Wang SC, Zhang YF, Xie Q. miR-21: a non-invasive biomarker and potential therapeutic target for lung cancer? Cell Biochem Biophys 2015; 70:701-2. [PMID: 24691929 DOI: 10.1007/s12013-014-9927-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Shi-Cun Wang
- PET/CT Center, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, 230001, Anhui, People's Republic of China,
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Russo MV, Faversani A, Gatti S, Ricca D, Del Gobbo A, Ferrero S, Palleschi A, Vaira V, Bosari S. A new mouse avatar model of non-small cell lung cancer. Front Oncol 2015; 5:52. [PMID: 25785245 PMCID: PMC4347595 DOI: 10.3389/fonc.2015.00052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 02/13/2015] [Indexed: 01/08/2023] Open
Abstract
Introduction: Lung cancer remains the leading cause of tumor-related deaths, despite advances in the understanding of the disease pathogenesis and in its clinical treatment. It is crucial to develop novel technologies to discover disease biomarkers and predict individual therapy response. Materials and methods: We established 48 patients-derived tumor xenografts (PDTXs) implanted in the subrenal capsule of immunodeficient mice using thin, precision-cut tumor tissue slices, derived from five patients affected by non-small cell lung cancer. Twenty-six tissue slices were immediately processed and implanted at sample recovery [patients-derived tumor xenografts derived from fresh tissue (dPDTX)], whereas the remaining sections were cultured on specific organotypic supports at 37°C and 5% CO2 for 24 h before grafting [patients-derived tumor xenografts derived from cultured tissue (cPDTX)]. At sacrifice, xenografts tissue morphology, proliferation (Ki67), and histotype markers were analyzed. Oncogenic miRNAs profiles were assessed in PDTXs, human tumors, and serum from one patient. Results: Xenografts retained the original cancer features and there were no differences between dPDTXs and cPDTXs. Squamous cell carcinoma (SCC) xenografts showed a higher engraftment rate than adenocarcinoma (AC)-derived tumors. At basal time, Ki67 levels were higher in SCCs than in ACs, and the expression levels of genes associated to a stem cell-like phenotype were also more expressed in SCC samples. The analysis of oncogenic miRNAs showed that circulating miR-19b, -21, and -210 levels were correlated with higher Ki67 expression in xenografts. Conclusion: Our study implemented the PDTX model with thin, precision-cut tumor slices from small tumors, which could be useful for clinical applications and predictive purposes. The different engraftment success is likely determined by tumor histotype, high proliferation index, and the expression of genes essential for cancer stem cells maintenance. Our PDTXs model could be a valid tool to expand primary tumors for the discovery of new biomarkers and explore therapeutic options.
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Affiliation(s)
- Maria Veronica Russo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy ; Department of Pathophysiology and Transplantation, Doctorate School in Molecular and Translational Medicine, University of Milan , Milan , Italy
| | - Alice Faversani
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Stefano Gatti
- Center for Preclinical Surgical Research, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy ; Department of Medical Biotechnology and Translational Medicine, University of Milan , Milan , Italy
| | - Dario Ricca
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy ; Department of Biomedical, Surgical and Dental Sciences, University of Milan , Milan , Italy
| | - Alessandro Palleschi
- Division of Thoracic Surgery and Lung Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Valentina Vaira
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy ; Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi" (INGM) , Milan , Italy
| | - Silvano Bosari
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy ; Department of Pathophysiology and Transplantation, Doctorate School in Molecular and Translational Medicine, University of Milan , Milan , Italy
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Introduction to microRNAs: Biogenesis, Action, Relevance of Tissue microRNAs in Disease Pathogenesis, Diagnosis and Therapy-The Concept of Circulating microRNAs. EXPERIENTIA SUPPLEMENTUM (2012) 2015; 106:3-30. [PMID: 26608197 DOI: 10.1007/978-3-0348-0955-9_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
MicroRNAs as the endogenous mediators of RNA interference have principal roles in gene expression regulation. Since their discovery in the early 1990s, their number has steadily grown to approximately 2500 known microRNAs at present in humans. MicroRNAs encoded by distinct genes regulate the expression of about 30-60 % of human protein coding genes by targeting their messenger RNAs (mRNAs) and induce mostly posttranscriptional inhibition, or in some cases enhancement. MicroRNAs, as fine regulators of the gene expression, have important roles in development, the physiological functioning of the organism, e.g. organogenesis, immune functioning, vascular system, etc. The deregulation of microRNA expression has been observed in many disorders, such as in carcinogenesis. Given their tissue specificity and stability, and specific disease-related alterations, tissue microRNAs can be exploited as excellent biomarkers in the diagnosis. Moreover, microRNAs might also be envisaged as novel therapeutic targets. Beside tissue microRNAs, novel data show that microRNAs are also present in body fluids that could further extend their diagnostic utility as minimally invasive biomarkers of various diseases, but also raises intriguing questions regarding their biological relevance. In this introductory chapter, we summarise the most relevant features of microRNAs including their biogenesis, action, the biological, pathological, diagnostic and potential therapeutical relevance of tissue microRNAs.
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Meng F, Li Z, Yan J, Manjanatha M, Shelton S, Yarborough S, Chen T. Tissue-specific microRNA responses in rats treated with mutagenic and carcinogenic doses of aristolochic acid. Mutagenesis 2014; 29:357-65. [PMID: 25106556 DOI: 10.1093/mutage/geu027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Aristolochic acid (AA) is an active component in herbal drugs derived from the Aristolochia species. Although these drugs have been used since antiquity, AA is both genotoxic and carcinogenic in animals and humans, resulting in kidney tumours in rats and upper urinary tract tumours in humans. In the present study, we conducted microarray analysis of microRNA (miRNA) expression in tissues from transgenic Big Blue rats that were treated for 12 weeks with 0.1-10mg/kg AA, using a protocol that previous studies indicate eventually results in kidney tumours and mutations in kidney and liver. Global analysis of miRNA expression of rats treated with 10 mg/kg AA indicated that 19 miRNAs were significantly dysregulated in the kidney, with most of the miRNAs related to carcinogenesis. Only one miRNA, miR-34a (a tumour suppressor), was differentially expressed in the liver. The expression of the two most responsive kidney miRNAs (miR-21, an oncomiR and miR-34a) was further examined in the kidney, liver and testis of rats exposed to 0, 0.1, 1.0 and 10mg/kg AA. Expression of miR-21 was up-regulated in the kidney only, while miR-34a was dose-dependently up-regulated in both the kidney and liver; the expression of miR-21 and miR-34a was unaltered by the AA treatment in the testis. Analysis of cII mutations in the testis of treated rats also was negative. Our results indicate that AA treatment of rats produced dysregulation of a large number of miRNAs in the tumour target tissue and that the up-regulation of miR-21 correlated with the carcinogenicity of AA while the up-regulation of miR-34a correlated with its mutagenicity.
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Affiliation(s)
- Fanxue Meng
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Zhiguang Li
- Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and
| | - Jian Yan
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Mugimane Manjanatha
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Sharon Shelton
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Stephanie Yarborough
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA, Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, 9 Lvshun Road South, Dalian, Liaoning 116044, China and Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
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Micro-RNAs in regenerating lungs: an integrative systems biology analysis of murine influenza pneumonia. BMC Genomics 2014; 15:587. [PMID: 25015185 PMCID: PMC4108790 DOI: 10.1186/1471-2164-15-587] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 06/27/2014] [Indexed: 12/20/2022] Open
Abstract
Background Tissue regeneration in the lungs is gaining increasing interest as a potential influenza management strategy. In this study, we explored the role of microRNAs, short non-coding RNAs involved in post-transcriptional regulation, during pulmonary regeneration after influenza infection. Results We profiled miRNA and mRNA expression levels following lung injury and tissue regeneration using a murine influenza pneumonia model. BALB/c mice were infected with a sub-lethal dose of influenza A/PR/8(H1N1) virus, and their lungs were harvested at 7 and 15 days post-infection to evaluate the expression of ~300 miRNAs along with ~36,000 genes using microarrays. A global network was constructed between differentially expressed miRNAs and their potential target genes with particular focus on the pulmonary repair and regeneration processes to elucidate the regulatory role of miRNAs in the lung repair pathways. The miRNA arrays revealed a global down-regulation of miRNAs. TargetScan analyses also revealed specific miRNAs highly involved in targeting relevant gene functions in repair such as miR-290 and miR-505 at 7 dpi; and let-7, miR-21 and miR-30 at 15 dpi. Conclusion The significantly differentially regulated miRNAs are implicated in the activation or suppression of cellular proliferation and stem cell maintenance, which are required during the repair of the damaged lungs. These findings provide opportunities in the development of novel repair strategies in influenza-induced pulmonary injury. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-587) contains supplementary material, which is available to authorized users.
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Joshi P, Middleton J, Jeon YJ, Garofalo M. MicroRNAs in lung cancer. World J Methodol 2014; 4:59-72. [PMID: 25332906 PMCID: PMC4202482 DOI: 10.5662/wjm.v4.i2.59] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/23/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.
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Shrestha S, Hsu SD, Huang WY, Huang HY, Chen W, Weng SL, Huang HD. A systematic review of microRNA expression profiling studies in human gastric cancer. Cancer Med 2014; 3:878-88. [PMID: 24902858 PMCID: PMC4303155 DOI: 10.1002/cam4.246] [Citation(s) in RCA: 117] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 02/14/2014] [Accepted: 03/13/2014] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of global cancer mortality. Most GC patients are diagnosed with advanced-stage disease and show extremely poor prognosis. All of the GC research has a common interest to search for the specific and sensitive biomarkers for early diagnosis of GC. Number of microRNAs play important role in GC. We carried out a systematic review of published miRNA profiling studies that compared the miRNA expression profiles between GC tissues and paired noncancerous gastric tissue. A vote-counting strategy was followed with the collection of information like total number of studies reporting differential expression of miRNA, total number of tissue samples used in the studies, direction of differential expression and fold change. A total of 352 differentially expressed microRNAs were reported in the 14 microRNA expression profiling studies that compared GC tissues with normal tissues with 120 microRNAs reported at least in two studies. In the group of consistently reported microRNAs, miR-21 was reported upregulated in 10 studies followed by miR-25, miR-92, and miR-223 upregulated in eight studies. MiR-375 and miR-148a were found downregulated in six and five studies, respectively, followed by miR-638 in four studies. MiR-107 and miR-103 were reported in nine and eight studies, respectively, but their expression were inconsistent. From this study, the most consistently reported upregulated microRNA was found to be miR-21. This systematic review study of human GC microRNA expression profiling studies would provide information on microRNAs with potential role as the biomarkers in gastric cancer.
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Affiliation(s)
- Sirjana Shrestha
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, 300, Taiwan
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Pando R, Shtaif B, Phillip M, Gat-Yablonski G. A serum component mediates food restriction-induced growth attenuation. Endocrinology 2014; 155:932-40. [PMID: 24456162 DOI: 10.1210/en.2013-1610] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Proper nutrition in terms of calories and essential food components is required to maximize longitudinal growth in children. Our previous study showed that prepubertal male rats subjected to 10 days of 40% food restriction (RES) exhibited a dramatic reduction in weight and epiphyseal growth plate height, as well as changes in gene expression and microRNAs (miRNAs) in the epiphyseal growth plate. These findings reversed rapidly after renewal of the regular food supply (catch-up [CU]). To further elucidate the mechanisms underlying the nutrition-growth association, serum collected from the RES and CU rats and control rats fed ad libitum (AL) was added to the culture medium of the chondrocyte cell line ATDC5 (instead of fetal calf serum). Serum from the RES group induced a reduction in cell viability (25%, P < .05) concomitant with an increase in cell differentiation compared with that for the AL group serum. The most interesting observation, in our opinion, was the significant reduction in the expression of specific miRNAs, including the chondro-specific miR-140. These effects were not observed for serum from refed (CU) rats. Serum levels of IGF-I, leptin, and fibroblast growth factor 21 were reduced by food restriction. The addition of IGF-I and leptin to the culture increased cell viability, whereas fibroblast growth factor 21 reduced it, suggesting the involvement of IGF-I, leptin, and possibly other still unidentified serum factors in chondrocyte cell growth. In conclusion, specific miRNAs respond to nutritional cues, and these effects are mediated by serum-borne factors. These results may promote the development of superior interventions for children with malnutrition and growth abnormalities.
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Affiliation(s)
- Rakefet Pando
- Sackler School of Medicine (R.P., B.S., M.P., G.G.-Y.), Tel Aviv University, Tel Aviv 6997801, Israel; Felsentein Medical Research Center (B.S., M.P., G.G.-Y.), Petach Tikva 4945102, Israel; and The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes (M.P., G.G.-Y.), National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel
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Ribeiro J, Sousa H. MicroRNAs as biomarkers of cervical cancer development: a literature review on miR-125b and miR-34a. Mol Biol Rep 2014; 41:1525-31. [PMID: 24402874 DOI: 10.1007/s11033-013-2998-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 12/28/2013] [Indexed: 12/21/2022]
Abstract
MicroRNAs are non-coding RNAs with important functions in several biological processes, such as, regulation of cell cycle, immune response, inflammation, and apoptosis. In fact, deregulation and abnormal expression of these molecules is associated with human pathologies including cancer and several have already emerged as potential prognostic biomarkers in different neoplasias. miR-34a is directly regulated by p53 and acts as tumor suppressor while miR-125b plays a significant role in immune response and apoptosis. In cervical carcinogenesis, HPV proteins seem to interact with both miR-34a and miR-125b changing its expression and promoting persistent infection and cervical cancer development. In this review we describe the potential role of miR-125b and miR-34a in cervical carcinogenesis, including interaction with HPV and mechanism of deregulation. Additionally, their clinical applications in cervical cancer as prognostic/predictive biomarkers are also briefly discussed.
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Affiliation(s)
- Joana Ribeiro
- Faculty of Medicine, University of Porto, 4200-072, Porto, Portugal
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Zhang W, Bai W, Zhang W. MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin Transl Oncol 2013; 16:708-13. [PMID: 24293118 DOI: 10.1007/s12094-013-1135-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Accepted: 11/11/2013] [Indexed: 12/19/2022]
Abstract
PURPOSE Curcumin, a natural phytochemical, exhibits potent anticancer activities. Here, we sought to determine the molecular mechanisms underlying the cytotoxic effects of curcumin against human non-small cell lung cancer (NSCLC) cells. METHODS MTT assay and annexin-V/PI staining were used to analyze the effects of curcumin on the proliferation and apoptosis of A549 cells. The expression of microRNA-21 in curcumin-treated A549 cells was measured by quantitative real-time polymerase chain reaction assay. The protein level of phosphatase and tensin homolog (PTEN), a putative target of microRNA-21, was determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA was performed to modulate the expression of microRNA-21 and PTEN under the treatment of curcumin. RESULTS Curcumin at 20-40 μM inhibited cell proliferation and induced apoptosis in A549 cells. Curcumin treatment produced a dose-dependent and significant (P < 0.05) suppression of microRNA-21 expression, compared to untreated A549 cells. Moreover, the protein level of PTEN, a putative target of microRNA-21, was significantly elevated in curcumin-treated A549 cells, as determined by Western blot analysis. Transfection of A549 cells with microRNA-21 mimic or PTEN small interfering RNA significantly (P < 0.05) reversed the growth suppression and apoptosis induction by curcumin, compared to corresponding controls. CONCLUSIONS Our data suggest a novel molecular mechanism in which inhibition of microRNA-21 and upregulation of PTEN mediate the anticancer activities of curcumin in NSCLC cells. Suppression of microRNA-21 may thus have therapeutic benefits against this malignancy.
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Affiliation(s)
- W Zhang
- Department of Respiratory Diseases, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China
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How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation. PLoS Comput Biol 2013; 9:e1003210. [PMID: 24009496 PMCID: PMC3757060 DOI: 10.1371/journal.pcbi.1003210] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 07/19/2013] [Indexed: 12/25/2022] Open
Abstract
Osteosarcomas (OS) are complex bone tumors with various genomic alterations. These alterations affect the expression and function of several genes due to drastic changes in the underlying gene regulatory network. However, we know little about critical gene regulators and their functional consequences on the pathogenesis of OS. Therefore, we aimed to determine microRNA and transcription factor (TF) co-regulatory networks in OS cell proliferation. Cell proliferation is an essential part in the pathogenesis of OS and deeper understanding of its regulation might help to identify potential therapeutic targets. Based on expression data of OS cell lines divided according to their proliferative activity, we obtained 12 proliferation-related microRNAs and corresponding target genes. Therewith, microRNA and TF co-regulatory networks were generated and analyzed regarding their structure and functional influence. We identified key co-regulators comprising the microRNAs miR-9-5p, miR-138, and miR-214 and the TFs SP1 and MYC in the derived networks. These regulators are implicated in NFKB- and RB1-signaling and focal adhesion processes based on their common or interacting target genes (e.g., CDK6, CTNNB1, E2F4, HES1, ITGA6, NFKB1, NOTCH1, and SIN3A). Thus, we proposed a model of OS cell proliferation which is primarily co-regulated through the interactions of the mentioned microRNA and TF combinations. This study illustrates the benefit of systems biological approaches in the analysis of complex diseases. We integrated experimental data with publicly available information to unravel the coordinated (post)-transcriptional control of microRNAs and TFs to identify potential therapeutic targets in OS. The resulting microRNA and TF co-regulatory networks are publicly available for further exploration to generate or evaluate own hypotheses of the pathogenesis of OS (http://www.complex-systems.uni-muenster.de/co_networks.html).
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Qian NS, Liu WH, Lv WP, Xiang X, Su M, Raut V, Chen YL, Dong JH. Upregulated microRNA-92b regulates the differentiation and proliferation of EpCAM-positive fetal liver cells by targeting C/EBPß. PLoS One 2013; 8:e68004. [PMID: 23936298 PMCID: PMC3732262 DOI: 10.1371/journal.pone.0068004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 05/29/2013] [Indexed: 12/15/2022] Open
Abstract
microRNAs (miRNAs) are short noncoding RNAs that negatively regulate gene expression. Although recent evidences have been indicated that their aberrant expression may play an important role in cancer stem cells, the mechanism of their deregulation in neoplastic transformation of liver cancer stem cells (LCSCs) has not been explored. In our study, the HCC model was established in F344 rats by DEN induction. The EpCAM(+) cells were sorted out from unfractionated fetal liver cells and liver cancer cells using the FACS analysis and miRNA expression profiles of two groups were screened through microarray platform. Gain-of-function studies were performed in vitro and in vivo to determine the role of miR-92b on proliferation and differentiation of the hepatic progenitors. In addition, luciferase reporter system and gene function analysis were used to predict miR-92b target. we found that miR-92b was highly downregulated in EpCAM(+) fetal liver cells in expression profiling studies. RT-PCR analysis demonstrated reverse correlation between miR-92b expression and differentiation degree in human HCC samples. Overexpression of miR-92b in EpCAM(+) fetal liver cells significantly increased proliferation and inhibited differentiation as well as in vitro and in vivo studies. Moreover, we verified that C/EBPß is a direct target of miR-92b and contributes to its effects on proliferation and differentiation. We conclude that aberrant expression of miR-92b can result in proliferation increase and differentiation arrest of hepatic progenitors by targeting C/EBPß.
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Affiliation(s)
- Nian-Song Qian
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, Hainan Branch of PLA General Hospital, Sanya, China
| | - Wei-Hui Liu
- Department of Hepatobiliary Surgery, General Hospital of Chengdu Military Region, Chengdu, China
| | - Wen-Ping Lv
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, Hainan Branch of PLA General Hospital, Sanya, China
| | - Xin Xiang
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, Hainan Branch of PLA General Hospital, Sanya, China
| | - Ming Su
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, Hainan Branch of PLA General Hospital, Sanya, China
| | - Vikram Raut
- Department of Hepatobiliary Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yong-Liang Chen
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
- Department of Hepatobiliary Surgery, Hainan Branch of PLA General Hospital, Sanya, China
| | - Jia-Hong Dong
- Department of Hepatobiliary Surgery, PLA General Hospital, Beijing, China
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MiR-21 mediates the radiation resistance of glioblastoma cells by regulating PDCD4 and hMSH2. ACTA ACUST UNITED AC 2013; 33:525-529. [PMID: 23904372 DOI: 10.1007/s11596-013-1153-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Revised: 06/19/2013] [Indexed: 12/14/2022]
Abstract
The purpose of this study was to investigate the molecular mechanism by which miR-21 and its target genes mediate radiation resistance of glioblastoma cells. Real-time PCR was employed to detect miR-21 expression in normal brain tissues, glioblastoma tissues and glioblastoma cell lines (A172, T98G and U87MG). T98G cells were transfected with anti-miR-21 oligonucleotides, or plasmids containing PDCD4 or hMSH2 (PDCD4-pcDNA3 and hMSH2-pcDNA3). The survival curve was obtained to investigate the sensitivity of T98G cells to radiation. Cell apoptosis was measured by using the Caspase-3/7 kit and cell cycle by flow cytometry. Western blotting was performed to detect the expression of hMSH2 and PDCD4 in miR-21-inhibiting T98G cells. The results showed that miR-21 expression in glioblastoma cells and tissues was conversely associated with the radiation sensitivity. Over-expression of miR-21 resulted in radiation resistance, while knockdown of miR-21 led to higher sensitivity of glioblastma cells to radiation. After miR-21 knockdown, the apoptosis of T98G cells was significantly increased and the G(2) phase arrest was more significant. In addition, miR-21 knockdown increased the expression of endogenous PDCD4 and hMSH2, which contributed to the apoptosis and G(2) arrest of T98G cells. The findings suggested that miR-21 may mediate the resistance of glioblastoma cells against radiation via its target genes PDCD4 and hMSH2. MiR-21 and its target genes may be used as potential molecular targets for clinical radiotherapy sensitization in the future.
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Wang N, Zhang CQ, He JH, Duan XF, Wang YY, Ji X, Zang WQ, Li M, Ma YY, Wang T, Zhao GQ. MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci 2013; 58:1863-70. [PMID: 23504349 DOI: 10.1007/s10620-013-2612-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 02/18/2013] [Indexed: 12/18/2022]
Abstract
BACKGROUND miR-21 is overexpressed in esophageal squamous cell carcinoma (ESCC) and is thought to be correlated with the development of the cancer. The target gene of miR-21 including FASL, TIMP3 and RECK is revealed by researchers. miR-21 may be involved in the tumorgenesis of ESCC by targeting FASL, TIMP3 and RECK. AIMS The purpose of this study was to explore the mechanism of miR-21 in the development of ESCC. METHODS miR-21 expression in ESCC and the matched non-malignant adjacent tissues (NMATs) was examined by qRT-PCR. Cell growth, cell apoptosis and cell invasion ability of EC9706 and EC-1 cells was examined after the cells were transfected with miR-21 inhibitor. The potential target genes of miR-21 including FASL, TIMP3 and RECK were examined by western blot and Luciferase reporter assay. RESULTS miR-21 expression was increased significantly in ESCC tissues compared with NMAT. miR-21 down-regulation inhibits cell growth, cell invasion and induces cells to apoptosis. FASL, TIMP3 and RECK are direct targets of miR-21. CONCLUSIONS miR-21 down-regulation inhibits cell growth, invasion and induces cells to apoptosis by targeting FASL, TIMP3 and RECK genes.
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Affiliation(s)
- Na Wang
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China.
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MicroRNA-31-5p modulates cell cycle by targeting human mutL homolog 1 in human cancer cells. Tumour Biol 2013; 34:1959-65. [PMID: 23539435 DOI: 10.1007/s13277-013-0741-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 03/05/2013] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) and DNA mismatch repair (MMR) have been linked to human cancer progression. Human mutL homolog 1 (hMLH1), one of the core MMR genes, defects in lung cancer development. However, the interaction between miRNAs and MMR genes and their regulatory effect on cell cycle remain poorly understood. In this study, we investigated the role of miR-31-5p in hMLH1 gene expression and the effect of miR-31-5p on cell cycle in non-small cell lung cancer (NSCLC). We found that miR-31-5p was inversely correlated with hMLH1 expression in NSCLC cell lines and hMLH1 was a direct target of miR-31-5p. Knockdown of miR-31-5p induced a cell cycle arrest at G2/M phase and increased hMLH1 protein expression in NSCLC cells. Conversely, overexpression of miR-31-5p significantly induced cell cycle arrest at S phase and decreased hMLH1 protein expression. Furthermore, knockdown of hMLH1 upregulated miR-31-5p expression and caused cell cycle arrest at S phase. Data from this study revealed that miR-31-5p modulates cell cycle by targeting hMLH1 protein at the posttranscriptional level in NSCLC, which may represent a novel therapy strategy for lung cancer by targeting miR-31-5p.
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