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Li C, Xing X, Huang S, Zhu T, Yan B. Circular RNA LDLRAD3 promotes gastric cancer progression by upregulating COL4A5 through sponging miR-h37. J Chin Med Assoc 2024; 87:1018-1028. [PMID: 39161132 DOI: 10.1097/jcma.0000000000001153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Circular RNAs play an important role in the development of gastric cancer (GC). circ-low-density lipoprotein receptor class A domain containing 3 (LDLRAD3) has been confirmed to be related to GC progression. miR-137 is also a suppressor in GC. However, the impact of the interaction between circ-LDLRAD3 and miR-137 on the progression of GC remains unclear at present. METHODS The study identified expression level differences of circ-LDLRAD3, miR-137, and COL4A5 in GC pathological specimens compared to normal tissue samples. Furthermore, through in vitro experiments, including flow cytometry, cell counting kit-8 (CCK-8) assays, wound healing, Western blotting, and colony formation assays, we further explored the molecular regulatory mechanisms by which these factors promote the progression of GC. RESULTS In this study, circ-LDLRAD3 was confirmed to have higher expression, and miR-137 had lower expression in GC tissues and cell lines. circ-LDLRAD3 knockdown and miR-137 overexpression promoted apoptosis and inhibited proliferation, migration, and invasion in GC cell lines. Further experiments validated that COL4A5 had a positive relationship with GC and that circ-LDLRAD3 promoted the expression of COL4A5. circ-LDLRAD3 could be sponged and inhibited by miR-137 in GC cells. As a result, the promotional effect of circ-LDLRAD3 on COL4A5 was counteracted by miR-137. CONCLUSION Our study showed that the knockdown of circ-LDLRAD3 suppressed the development of GC by regulating the miR-137/COL4A5 axis.
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Affiliation(s)
- Chenghui Li
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xiao Xing
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Sinian Huang
- Department of Pathology Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Ting Zhu
- Department of Pathology Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Bin Yan
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
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Norollahi SE, Vahidi S, Shams S, Keymoradzdeh A, Soleymanpour A, Solymanmanesh N, Mirzajani E, Jamkhaneh VB, Samadani AA. Analytical and therapeutic profiles of DNA methylation alterations in cancer; an overview of changes in chromatin arrangement and alterations in histone surfaces. Horm Mol Biol Clin Investig 2023; 44:337-356. [PMID: 36799246 DOI: 10.1515/hmbci-2022-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 01/24/2023] [Indexed: 02/18/2023]
Abstract
DNA methylation is the most important epigenetic element that activates the inhibition of gene transcription and is included in the pathogenesis of all types of malignancies. Remarkably, the effectors of DNA methylation are DNMTs (DNA methyltransferases) that catalyze de novo or keep methylation of hemimethylated DNA after the DNA replication process. DNA methylation structures in cancer are altered, with three procedures by which DNA methylation helps cancer development which are including direct mutagenesis, hypomethylation of the cancer genome, and also focal hypermethylation of the promoters of TSGs (tumor suppressor genes). Conspicuously, DNA methylation, nucleosome remodeling, RNA-mediated targeting, and histone modification balance modulate many biological activities that are essential and indispensable to the genesis of cancer and also can impact many epigenetic changes including DNA methylation and histone modifications as well as adjusting of non-coding miRNAs expression in prevention and treatment of many cancers. Epigenetics points to heritable modifications in gene expression that do not comprise alterations in the DNA sequence. The nucleosome is the basic unit of chromatin, consisting of 147 base pairs (bp) of DNA bound around a histone octamer comprised of one H3/H4 tetramer and two H2A/H2B dimers. DNA methylation is preferentially distributed over nucleosome regions and is less increased over flanking nucleosome-depleted DNA, implying a connection between nucleosome positioning and DNA methylation. In carcinogenesis, aberrations in the epigenome may also include in the progression of drug resistance. In this report, we report the rudimentary notes behind these epigenetic signaling pathways and emphasize the proofs recommending that their misregulation can conclude in cancer. These findings in conjunction with the promising preclinical and clinical consequences observed with epigenetic drugs against chromatin regulators, confirm the important role of epigenetics in cancer therapy.
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Affiliation(s)
- Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shima Shams
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arman Keymoradzdeh
- Department of Neurosurgery, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Soleymanpour
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nazanin Solymanmanesh
- Student Research Committee, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ebrahim Mirzajani
- Department of Biochemistry and Biophysics, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Vida Baloui Jamkhaneh
- Department of Veterinary Medicine, Islamic Azad University of Babol Branch, Babol, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Uppala SN, Tryphena KP, Naren P, Srivastava S, Singh SB, Khatri DK. Involvement of miRNA on Epigenetics landscape of Parkinson's disease: From pathogenesis to therapeutics. Mech Ageing Dev 2023:111826. [PMID: 37268278 DOI: 10.1016/j.mad.2023.111826] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 05/21/2023] [Accepted: 05/29/2023] [Indexed: 06/04/2023]
Abstract
The development of novel therapeutics for the effective management of Parkinson's disease (PD) is undertaken seriously by the scientific community as the burden of PD continues to increase. Several molecular pathways are being explored to identify novel therapeutic targets. Epigenetics is strongly implicated in several neurodegenerative diseases (NDDs) including PD. Several epigenetic mechanisms were found to dysregulated in various studies. These mechanisms are regulated by several miRNAs which are associated with a variety of pathogenic mechanisms in PD. This concept is extensively investigated in several cancers but not well documented in PD. Identifying the miRNAs with dual role i.e., regulation of epigenetic mechanisms as well as modulation of proteins implicated in the pathogenesis of PD could pave way for the development of novel therapeutics to target them. These miRNAs could also serve as potential biomarkers and can be useful in the early diagnosis or assessment of disease severity. In this article we would like to discuss about various epigenetic changes operating in PD and how miRNAs are involved in the regulation of these mechanisms and their potential to be novel therapeutic targets in PD.
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Affiliation(s)
- Sai Nikhil Uppala
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Kamatham Pushpa Tryphena
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Padmashri Naren
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037
| | - Shashi Bala Singh
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037.
| | - Dharmendra Kumar Khatri
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Telangana-500037.
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Nejati-Koshki K, Roberts CT, Babaei G, Rastegar M. The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology. Cancers (Basel) 2023; 15:2683. [PMID: 37345019 PMCID: PMC10216337 DOI: 10.3390/cancers15102683] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 06/23/2023] Open
Abstract
Epigenetic mechanisms are gene regulatory processes that control gene expression and cellular identity. Epigenetic factors include the "writers", "readers", and "erasers" of epigenetic modifications such as DNA methylation. Accordingly, the nuclear protein Methyl-CpG-Binding Protein 2 (MeCP2) is a reader of DNA methylation with key roles in cellular identity and function. Research studies have linked altered DNA methylation, deregulation of MeCP2 levels, or MECP2 gene mutations to different types of human disease. Due to the high expression level of MeCP2 in the brain, many studies have focused on its role in neurological and neurodevelopmental disorders. However, it is becoming increasingly apparent that MeCP2 also participates in the tumorigenesis of different types of human cancer, with potential oncogenic properties. It is well documented that aberrant epigenetic regulation such as altered DNA methylation may lead to cancer and the process of tumorigenesis. However, direct involvement of MeCP2 with that of human cancer was not fully investigated until lately. In recent years, a multitude of research studies from independent groups have explored the molecular mechanisms involving MeCP2 in a vast array of human cancers that focus on the oncogenic characteristics of MeCP2. Here, we provide an overview of the proposed role of MeCP2 as an emerging oncogene in different types of human cancer.
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Affiliation(s)
- Kazem Nejati-Koshki
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil 85991-56189, Iran;
| | - Chris-Tiann Roberts
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
| | - Ghader Babaei
- Department of Clinical Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia 57157-89400, Iran;
| | - Mojgan Rastegar
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
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Zhao Y, Qin F, Han S, Li S, Zhao Y, Wang H, Tian J, Cen X. MicroRNAs in drug addiction: Current status and future perspectives. Pharmacol Ther 2022; 236:108215. [DOI: 10.1016/j.pharmthera.2022.108215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/11/2022] [Accepted: 05/16/2022] [Indexed: 12/21/2022]
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Diagnostic Value of Prostate-Specific Antigen Combined with Plasma miRNA-149 Expression in Patients with Prostate Cancer Based on Experimental Data and Bioinformatics. CONTRAST MEDIA & MOLECULAR IMAGING 2022; 2022:6094409. [PMID: 35935308 PMCID: PMC9337946 DOI: 10.1155/2022/6094409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/12/2022] [Accepted: 06/23/2022] [Indexed: 11/17/2022]
Abstract
Purpose The aim of this study is to explore the diagnostic value of prostate-specific antigen (PSA) combined with serum miRNA-149 expression in prostate cancer (PCa) by conducting experiments and bioinformatics analysis. Patients and Methods. 50 PCa patients were enrolled on the experimental group from January 2020 to December 2021. 56 patients with benign prostatic hyperplasia (BPH) were selected as the control group at the same time. Real-time fluorescent quantitative PCR was applied to investigate the miRNA-149 expression. PSA was detected by using a chemiluminescence meter using Abbott i4000. Applying bioinformatics analysis, we explored the expression of hsa-miR-149 in PCa in The Cancer Genome Atlas (TCGA) database. Kaplan–Meier analyses were used to evaluate the prognostic value, and the ROC curve was applied. Results The expression level of miRNA-149 in the PCa group was significantly higher than that in the BPH group (P < 0.05). The PSA level in the PCa group was also significantly higher than that in the BPH group (P < 0.05). TCGA data analysis revealed that PCa tissues had significantly increased hsa-miR-149 expression. The results of survival analysis showed that patients with high expression of hsa-miR-149 had better prognosis. Additionally, the pathological N stage of PCa correlates with the hsa-miR-149 expression level (P = 0.002). According to ROC curve analysis, the region under the curve was 0.653, 95% CI: 0.576–0.730. Conclusion High expression of serum miRNA-149 is associated with PCa patients. Although combined PSA did not improve the diagnostic efficacy, miRNA-149 has high specificity in the diagnosis of PCa. miRNA-149 might be a novel marker for early diagnosis and prognosis assessment for PCa.
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Tian W, Pang X, Luan F. Diagnosis value of miR-181, miR-652, and CA72-4 for gastric cancer. J Clin Lab Anal 2022; 36:e24411. [PMID: 35446997 PMCID: PMC9169223 DOI: 10.1002/jcla.24411] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/01/2022] Open
Abstract
PURPOSE To find a useful disease marker for early diagnosis of gastric cancer, we tried to explore the expression of serum miR-181, miR-652, and carbohydrate antigen 72-4 (CA72-4). PATIENTS AND METHODS According to clinical pathologic stages, 112 patients with gastric cancer were divided into early gastric cancer group (n = 60) and advanced gastric cancer group (n = 52), stage I-II (n = 65), and stage III-IV (n = 47). Another 50 cases of gastric benign lesions and 40 healthy controls were also selected. Real-time quantitative PCR together with chemiluminescence were applied to detect expression levels. ROC curve was applied to judge their diagnostic efficiency. Pearson's correlation analysis was put into use to investigate the relevance of three indicators. RESULTS Compared with benign lesions group and control group, significantly higher expression levels were found in patients of gastric cancer (all p < 0.001). Similarly, compared with early gastric cancer group, significantly higher expression levels were found in advanced gastric cancer group (all p < 0.001). The same result was also found in stage III-IV (all p < 0.001). The best cutoff values were 0.93, 2.38, and 16.94 U/ml, respectively. The area under the curve (0.917, 95%CI: 0.856-0.975) of the three combined diagnosis of early gastric cancer was the largest, and its sensitivity and specificity were 92.5% and 86.8%. And miR-181 and miR-652 were positively correlated with CA72-4 (r = 0.772, p < 0.001, r = 0.853, p < 0.001). CONCLUSION Serum miR-181, miR-652, and CA72-4 are closely linked to the occurrence and development of gastric cancer. Combination of three indicators has diagnostic value for early gastric cancer.
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Affiliation(s)
- Wenyan Tian
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Xueqin Pang
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Fujuan Luan
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
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Wu F, Yang Q, Mi Y, Wang F, Cai K, Zhang Y, Wang Y, Wang X, Gui Y, Li Q. miR-29b-3p Inhibitor Alleviates Hypomethylation-Related Aberrations Through a Feedback Loop Between miR-29b-3p and DNA Methylation in Cardiomyocytes. Front Cell Dev Biol 2022; 10:788799. [PMID: 35478963 PMCID: PMC9035530 DOI: 10.3389/fcell.2022.788799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 03/18/2022] [Indexed: 11/17/2022] Open
Abstract
As a member of the miR-29 family, miR-29b regulates global DNA methylation through target DNA methyltransferases (DNMTs) and acts as both a target and a key effector in DNA methylation. In this study, we found that miR-29b-3p expression was inversely correlated with DNMT expression in the heart tissues of patients with congenital heart disease (CHD), but whether it interacts with DNMTs in cardiomyocytes remains unknown. Further results revealed a feedback loop between miR-29b-3p and DNMTs in cardiomyocytes. Moreover, miR-29b-3p inhibitor relieved the deformity of hypomethylated zebrafish and restored the DNA methylation patterns in cardiomyocytes, resulting in increased proliferation and renormalization of gene expression. These results suggest mutual regulation between miR-29b-3p and DNMTs in cardiomyocytes and support the epigenetic normalization of miRNA-based therapy in cardiomyocytes.
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Affiliation(s)
- Fang Wu
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Department of Neonatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qian Yang
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Yaping Mi
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Feng Wang
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Ke Cai
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Yawen Zhang
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
| | - Youhua Wang
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xu Wang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yonghao Gui
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- Cardiovascular Center, NHC Key Laboratory of Neonatal Diseases, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- *Correspondence: Qiang Li, ; Yonghao Gui,
| | - Qiang Li
- Translational Medical Center for Development and Disease, Shanghai Key Laboratory of Birth Defect Prevention and Control, NHC Key Laboratory of Neonatal Diseases, Institute of Pediatrics, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, China
- *Correspondence: Qiang Li, ; Yonghao Gui,
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Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer. Pharmacol Res 2021; 176:106041. [PMID: 34952200 DOI: 10.1016/j.phrs.2021.106041] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Drug resistance is one of the most critical challenges facing researchers in treating breast cancer. Despite numerous treatments for breast cancer, including conventional chemical drugs, monoclonal antibodies, and immunotherapeutic drugs known as immune checkpoint inhibitors (ICI), many patients resist various approaches. In recent years, the relationship between gene expression profiles and drug resistance phenotypes has attracted much attention. Non-coding RNAs (ncRNAs) are regulatory molecules that have been shown to regulate gene expression and cell transcriptome. Two categories, microRNAs and long non-coding RNAs have been more considered and studied among these ncRNAs. Studying the role of different ncRNAs in chemical drug resistance and ICI resistance together can be beneficial in selecting more effective treatments for breast cancer. Changing the expression and action mechanism of these regulatory molecules on drug resistance phenotypes is the main topic of this review article.
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Choi JM, Kim SG. Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.
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Xie Y, Hang X, Xu W, Gu J, Zhang Y, Wang J, Zhang X, Cao X, Zhan J, Wang J, Gan J. CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway. Cancer Cell Int 2021; 21:410. [PMID: 34348712 PMCID: PMC8335894 DOI: 10.1186/s12935-021-02120-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/28/2021] [Indexed: 12/29/2022] Open
Abstract
Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02120-6.
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Affiliation(s)
- Ying Xie
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, 188 Shizi street, Suzhou, 215000, China.,Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Xiaofeng Hang
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Wensheng Xu
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Jing Gu
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, 188 Shizi street, Suzhou, 215000, China
| | - Yuanjing Zhang
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Jianrong Wang
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Xiucui Zhang
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Xinghao Cao
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Junjie Zhan
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China
| | - Junxue Wang
- Department of Infectious Disease, Changzheng Hospital, Naval Medical University, 415 Fengyang street, Shanghai, 200003, China.
| | - Jianhe Gan
- Department of Infectious Disease, The First Affiliated Hospital of Soochow University, 188 Shizi street, Suzhou, 215000, China.
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Bure IV, Nemtsova MV. Methylation and Noncoding RNAs in Gastric Cancer: Everything Is Connected. Int J Mol Sci 2021; 22:ijms22115683. [PMID: 34073603 PMCID: PMC8199097 DOI: 10.3390/ijms22115683] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 12/18/2022] Open
Abstract
Despite recent progress, gastric cancer remains one of the most common cancers and has a high mortality rate worldwide. Aberrant DNA methylation pattern and deregulation of noncoding RNA expression appear in the early stages of gastric cancer. Numerous investigations have confirmed their significant role in gastric cancer tumorigenesis and their high potential as diagnostic and prognostic biomarkers. Currently, it is clear that these epigenetic regulators do not work alone but interact with each other, generating a complex network. The aim of our review was to summarize the current knowledge of this interaction in gastric cancer and estimate its clinical potential for the diagnosis, prognosis, and treatment of the disease.
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Affiliation(s)
- Irina V. Bure
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Correspondence: ; Tel.: +49-915-069-2721
| | - Marina V. Nemtsova
- Laboratory of Medical Genetics, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119991 Moscow, Russia;
- Laboratory of Epigenetics, Research Centre for Medical Genetics, 115522 Moscow, Russia
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Li Z, Li Y, Wang X, Liang Y, Luo D, Han D, Li C, Chen T, Zhang H, Liu Y, Wang Z, Chen B, Wang L, Zhao W, Yang Q. LINC01977 Promotes Breast Cancer Progression and Chemoresistance to Doxorubicin by Targeting miR-212-3p/GOLM1 Axis. Front Oncol 2021; 11:657094. [PMID: 33869063 PMCID: PMC8046671 DOI: 10.3389/fonc.2021.657094] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 03/15/2021] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNAs(lncRNAs) play an important role in cancer initiation and progression. However, hub lncRNAs involved in breast cancer still remain underexplored. In this study, integrated bioinformatics analysis was used to define LINC01977 as a key oncogenic driver in breast cancer. Subsequently, in vitro assays showed that LINC01977 could significantly promote breast cancer progression and chemoresistance to doxorubicin. To further investigate its biological mechanism, we performed dual-luciferase reporter assay, real-time PCR, RNA immunoprecipitation (RIP), and rescue assay. Our results indicated that LINC01977 may function as ceRNA to prevent GOLM1 gene from miRNA-mediated repression by sponging miR-212-3p. Overall, LINC01977 can serve as a novel prognostic indicator, and help develop more effective therapeutic approaches for breast cancer patients.
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Affiliation(s)
- Zheng Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yaming Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaolong Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yiran Liang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dan Luo
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dianwen Han
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Chen Li
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Tong Chen
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hanwen Zhang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Ying Liu
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Zekun Wang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Bing Chen
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, China
| | - Lijuan Wang
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, China
| | - Wenjing Zhao
- Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, China
| | - Qifeng Yang
- Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, China.,Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, China.,Research Institute of Breast Cancer, Shandong University, Jinan, China
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14
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Heydarzadeh S, Ranjbar M, Karimi F, Seif F, Alivand MR. Overview of host miRNA properties and their association with epigenetics, long non-coding RNAs, and Xeno-infectious factors. Cell Biosci 2021; 11:43. [PMID: 33632341 PMCID: PMC7905430 DOI: 10.1186/s13578-021-00552-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 02/06/2021] [Indexed: 12/19/2022] Open
Abstract
MicroRNA-derived structures play impressive roles in various biological processes. So dysregulation of miRNAs can lead to different human diseases. Recent studies have extended our comprehension of the control of miRNA function and features. Here, we overview some remarkable miRNA properties that have potential implications for the miRNA functions, including different variants of a miRNA called isomiRs, miRNA arm selection/arm switching, and the effect of these factors on miRNA target selection. Besides, we review some aspects of miRNA interactions such as the interaction between epigenetics and miRNA (different miRNAs and their related processing enzymes are epigenetically regulated by multiple DNA methylation enzymes. moreover, DNA methylation could be controlled by diverse mechanisms related to miRNAs), direct and indirect crosstalk between miRNA and lnc (Long Non-Coding) RNAs as a further approach to conduct intercellular regulation called "competing endogenous RNA" (ceRNA) that is involved in the pathogenesis of different diseases, and the interaction of miRNA activities and some Xeno-infectious (virus/bacteria/parasite) factors, which result in modulation of the pathogenesis of infections. This review provides some related studies to a better understanding of miRNA involvement mechanisms and overcoming the complexity of related diseases that may be applicable and useful to prognostic, diagnostic, therapeutic purposes and personalized medicine in the future.
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Affiliation(s)
- Samaneh Heydarzadeh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Ranjbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farokh Karimi
- Department of Biotechnology, Faculty of Science, University of Maragheh, Maragheh, Iran
| | - Farhad Seif
- Department of Immunology and Allergy, Academic Center for Education, Culture, and Research (ACECR), Tehran, Iran
- Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Fang D, Lu G. Expression and role of nuclear receptor-interacting protein 1 (NRIP1) in stomach adenocarcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1293. [PMID: 33209873 PMCID: PMC7661897 DOI: 10.21037/atm-20-6197] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Background Nuclear receptor-interacting protein 1 (NRIP1), also named NR140, has been observed differentially express in multiple cancers, but the expression levels and the prognostic role of NRIP1 in stomach adenocarcinoma (STAD) remain unclear. Methods We used the Gene Expression Profiling Interactive Analysis (GEPIA) to analyze the NRIP1 expression levels in STAD, subgroups analysis of expression of NRIP1 via the UALCAN dataset. Further, cBioPortal was used to investigate the aberration type, co-mutations status, and located mutation of NRIP1. Correlated genes, and kinases, microRNA (miRNA), and transcription factor (TF) targets were identified using LinkedOmics. The Kaplan-Meier (K-M) plotter was used to analyze the prognosis of NRIP1 and the significantly correlated genes in STAD. Then, the tumor immune estimation resource (Timer) was used to explore the relation between NRIP1 and the immune cell infiltration, and the role of immune cells in STAD. The Human Protein Atlas (HPA) was used to confirm the NRIP1 protein express in STAD stomach tissue and normal stomach tissue. Results NRIP1 significantly overexpress in STAD, and the NRIP1 expression levels were impacted by clinical features. Overexpression of NRIP1 indicated the poor prognosis of STAD. Functional enrichment analysis showed the NRIP1 mainly enriched in immune response-regulating signaling pathway, cell-substrate adhesion, mRNA processing, and pathway in cancer. Overexpression USP25, SNYJ1 indicated the poor outcome of STAD, but the overexpression of BACH1 indicated protective biomarker. MIR-331 and MIR-132 have important role in STAD. Further, NRIP1 had a significant relation with immune infiltrates and other defined genes that significantly impact immune infiltrates. Immunohistochemical showed NRIP1 protein was higher in STAD than normal sample. Conclusions In this study, we revealed that overexpression of NRIP1 in the STAD sample compared to normal samples, NRIP1 significantly associated with macrophage. The high expression levels of NRIP1 and more macrophage infiltration led to poor prognosis of STAD.
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Affiliation(s)
- Dalang Fang
- Department of Glandular Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Guanming Lu
- Department of Glandular Surgery, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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16
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Karimzadeh MR, Pourdavoud P, Ehtesham N, Qadbeigi M, Asl MM, Alani B, Mosallaei M, Pakzad B. Regulation of DNA methylation machinery by epi-miRNAs in human cancer: emerging new targets in cancer therapy. Cancer Gene Ther 2020; 28:157-174. [PMID: 32773776 DOI: 10.1038/s41417-020-00210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 07/24/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
Disruption in DNA methylation processes can lead to alteration in gene expression and function that would ultimately result in malignant transformation. In this way, studies have shown that, in cancers, methylation-associated silencing inactivates tumor suppressor genes, as effectively as mutations. DNA methylation machinery is composed of several genes, including those with DNA methyltransferases activity, proteins that bind to methylated cytosine in the promoter region, and enzymes with demethylase activity. Based on a prominent body of evidence, DNA methylation machinery could be regulated by microRNAs (miRNAs) called epi-miRNAs. Numerous studies demonstrated that dysregulation in DNA methylation regulators like upstream epi-miRNAs is indispensable for carcinogenesis; consequently, the malignant capacity of these cells could be reversed by restoring of this regulatory system in cancer. Conceivably, recognition of these epi-miRNAs in cancer cells could not only reveal novel molecular entities in carcinogenesis, but also render promising targets for cancer therapy. In this review, at first, we have an overview of the methylation alteration in cancers, and the effect of this phenomenon in miRNAs expression and after that, we conduct an in-depth discussion about the regulation of DNA methylation regulators by epi-miRNAs in cancer cells.
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Affiliation(s)
- Mohammad Reza Karimzadeh
- Department of medical Genetics, School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | | | - Naeim Ehtesham
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Masood Movahedi Asl
- Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Behrang Alani
- Department of Applied Cell Sciences, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Mosallaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Bahram Pakzad
- Department of Internal Medicine, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran.
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17
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Mohammad Hoseini Azar MR, Shanehbandi D, Mansouri M, Pashaei Sarand S, Asadi M, Akbari M, Sadeghzadeh M, Abolghasemi M, Poursaei E, Gasembaglou S. Altered expression levels of miR-212, miR-133b and miR-27a in tongue squamous cell carcinoma (TSCC) with clinicopathological considerations. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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18
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Tang Y, Ji H, Liu H, Liu J, Gu W, Peng T, Li X. Pro-inflammatory cytokine-induced microRNA-212-3p expression promotes myocyte contraction via methyl-CpG-binding protein 2: a novel mechanism for infection-related preterm parturition. Mol Hum Reprod 2020; 25:274-282. [PMID: 30892651 DOI: 10.1093/molehr/gaz005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/31/2018] [Accepted: 03/18/2019] [Indexed: 12/12/2022] Open
Abstract
Preterm labour is a common pregnancy complication contributing to major maternal and fetal morbidity and mortality. We have found microRNA (miR)-212-3p, a potential infection-associated molecule, was significantly over-expressed during human preterm labour. However, the mechanism remains unknown. In this study, we have adopted a lipopolysaccharide (LPS)-induced Institute of Cancer Research murine preterm model to examine the role of miR-212-3p in the infection-induced preterm labour. Myometrial miR-212-3p expression was increased by nearly 4-fold in the term labour group (P = 0.10) and 12-fold (P = 0.03) in the LPS-induced preterm labour group compared with the non-labour group. In vitro cellular experiments confirmed that a series of pro-inflammatory cytokines, including interleukin (IL)1B (P = 0.02) and IL-6 (P = 0.01), rather than LPS (P = 0.08) itself could significantly upregulate miR-212-3p expression in human myometrial smooth muscle cells. Methyl-CpG-binding protein 2 (MeCP2), as a target gene of miR-212-3p confirmed by our dual luciferase assay, influenced myocyte contractility and connexin 43 expression which is an important contraction-associated protein. Therefore, we conclude that miR-212-3p may be involved in infection-induced preterm labour through MeCP2 and it is a promoting molecule and novel target for the diagnosis and treatment of preterm labour in the future.
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Affiliation(s)
- Yao Tang
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China
| | - Hongjing Ji
- Department of Obstetrics, The First Affiliated Hospital of Dalian Medical University, Liaoning Province, Dalian 116011, People's Republic of China
| | - Haiyan Liu
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China
| | - Jing Liu
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China
| | - Weirong Gu
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China
| | - Ting Peng
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China
| | - Xiaotian Li
- Department of Obstetrics, Shanghai Obstetrics and Gynecology Hospital of Fudan University, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Huang Pu District, Shanghai 200011, People's Republic of China.,Shanghai Key Laboratory of Birth Defects and the Key Specialty Project of the Ministry of Health, Shanghai 200032, People's Republic of China
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19
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Ahadi A. Dysregulation of miRNAs as a signature for diagnosis and prognosis of gastric cancer and their involvement in the mechanism underlying gastric carcinogenesis and progression. IUBMB Life 2020; 72:884-898. [DOI: 10.1002/iub.2259] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 02/08/2020] [Indexed: 02/06/2023]
Affiliation(s)
- Alireza Ahadi
- Department of Medical Genetics, School of MedicineShahid Beheshti University of Medical Sciences Tehran Iran
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20
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MUC13 promotes intrahepatic cholangiocarcinoma progression via EGFR/PI3K/AKT pathways. J Hepatol 2020; 72:761-773. [PMID: 31837357 DOI: 10.1016/j.jhep.2019.11.021] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 10/31/2019] [Accepted: 11/15/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Mucin 13 (MUC13) is reportedly overexpressed in human malignancies. However, the clinicopathological and biological significance of MUC13 in human intrahepatic cholangiocarcinoma (iCCA) remain unclear. The aim of this study was to define the role of MUC13 in the progression of iCCA. METHODS Expression levels of MUC13 in human iCCA samples were evaluated by immunohistochemistry, western blot, and real-time PCR. In vitro and in vivo experiments were used to assess the effect of MUC13 on iCCA cell growth and metastasis. Crosstalk between MUC13 and EGFR/PI3K/AKT signaling was analyzed by molecular methods. The upstream regulatory effects of MUC13 were evaluated by Luciferase and DNA methylation assays. RESULTS MUC13 was overexpressed in human iCCA specimens and iCCA cells. MUC13 overexpression positively correlated with clinicopathological characteristics of iCCA, such as vascular invasion and lymph node metastasis, and was independently associated with poor survival. Results from loss-of-function and gain-of-function experiments suggested that knockdown of MUC13 attenuated, while overexpression of MUC13 enhanced, the proliferation, motility, and invasiveness of iCCA cells in vitro and in vivo. Mechanistically, we found that the phosphatidylinositol 3-kinase-AKT signal pathway and its downstream effectors, such as tissue inhibitor of metalloproteinases 1 and matrix metallopeptidase 9, were required for MUC13-mediated tumor metastasis of iCCA. MUC13 interacted with epidermal growth factor receptor (EGFR) and subsequently activated the EGFR/PI3K/AKT signaling pathway by promoting EGFR dimerization and preventing EGFR internalization. We also found that MUC13 was directly regulated by miR-212-3p, whose downregulation was related to aberrant CpG hypermethylation in the promoter area. CONCLUSIONS These findings suggest that aberrant hypermethylation-induced downregulation of miR-212-3p results in overexpression of MUC13 in iCCA, leading to metastasis via activation of the EGFR/PI3K/AKT signaling pathway. LAY SUMMARY Mucin 13 overexpression has been implicated in the development of malignancies, although its role in intrahepatic cholangiocarcinoma has not been studied. Herein, we show that mucin 13 plays a critical role in intrahepatic cholangiocarcinoma. Mucin 13 could have therapeutic value both as a prognostic marker and as a treatment target.
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21
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Interference of miR-212 and miR-384 promotes osteogenic differentiation via targeting RUNX2 in osteoporosis. Exp Mol Pathol 2020; 113:104366. [DOI: 10.1016/j.yexmp.2019.104366] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 12/04/2019] [Accepted: 12/28/2019] [Indexed: 12/11/2022]
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22
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Zhao JT, Chi BJ, Sun Y, Chi NN, Zhang XM, Sun JB, Chen Y, Xia Y. LINC00174 is an oncogenic lncRNA of hepatocellular carcinoma and regulates miR-320/S100A10 axis. Cell Biochem Funct 2020; 38:859-869. [PMID: 32128852 DOI: 10.1002/cbf.3498] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 11/24/2019] [Accepted: 12/17/2019] [Indexed: 01/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Multiple long non-coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumour suppressors. In this study, we explored the effects of LINC00174 on the progression of HCC. Expression levels of LINC00174 and microRNA-320 (miR-320) in HCC tissue samples were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The association between pathological indices and LINC00174 was also analysed. Human HCC cell lines Hep3B and Huh7 were used as cell models. CCK-8 and bromodeoxyuridine (BrdU) assays were used to assess the effect of LINC00174 on HCC cell line proliferation. Flow cytometry was used to study the effect of LINC00174 on HCC apoptosis. Transwell assay was conducted to detect the effect of LINC00174 on migration and invasion. Furthermore, luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the binding relationship between miR-320 and LINC00174. Additionally, western blot was used to detect the regulatory function of LINC00174 on oncogene S100 calcium binding protein A10 (S100A10). We demonstrated that LINC00174 expression in HCC clinical samples was significantly increased and this was correlated with higher T stage. Its overexpression remarkably accelerated proliferation and metastasis of HCC cells while reduced apoptosis. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of LINC00174 significantly reduced the expression of miR-320 by sponging it, in turn enhanced the expression of S100A10. In conclusion, LINC00174 is a sponge of tumour suppressor miR-320, enhances the expression of S100A10 indirectly and functions as an oncogenic lncRNA in HCC. SIGNIFICANCE OF THE STUDY: LINC00174 is a novel lncRNA, whose function is rarely investigated. It is reported that it is oncogenic in colorectal cancer, while its role in HCC remains unclear. Herein, we report that LINC00174 is significantly up-regulated in HCC tissues and promotes the malignant phenotypes. We demonstrate that LINC00174 functions as a sponge for miR-320, increases the expression level of oncogene S100A10 in HCC. This study helps clarify the mechanism of HCC tumorigenesis and progression, and uncover the role of LINC00174 in human disease.
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Affiliation(s)
- Jin-Tao Zhao
- Department of Second Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Bao-Jin Chi
- Department of Urology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Yao Sun
- Department of Vascular Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Nan-Nan Chi
- Department of Second Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Xue-Mei Zhang
- Department of Second Gastroenterology, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Jia-Bin Sun
- Intensive Care Unit, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Ying Chen
- Intensive Care Unit, The First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Yong Xia
- Department of Blood Transfusion, Affiliated Hospital of Xiangnan University, Chenzhou, China
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23
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Dang Y, Liu T, Yan J, Reinhardt JD, Yin C, Ye F, Zhang G. Gastric cancer proliferation and invasion is reduced by macrocalyxin C via activation of the miR-212-3p/Sox6 Pathway. Cell Signal 2020; 66:109430. [PMID: 31726103 DOI: 10.1016/j.cellsig.2019.109430] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/03/2019] [Accepted: 09/26/2019] [Indexed: 01/09/2023]
Abstract
Gastric cancer is a malignancy of very poor prognosis and survival rates. Macrocalyxin C is a Chinese herb-derived diterpenoid compound that has been postulated to possess anti-cancer characteristics. Gastic cell viability and stage of cell cycle were assessed using CCK8 assay and flow cytometry, respectively. Cell migration and invation were assessed using the wound healing and Transwell assays. Rate of apoptosis was determined via AV/PI-staining. Athymic nude mice xenograft models were used to evaluate the in vivo efficacy of macrocalyxin C. Western blot, luciferase experiments, cell transfection and real-time PCR allowed further study into the activation of the miR-212-3p/Sox6 pathway during macrocalyxin C treatment. We conclude that macrocalyxin C may halt the proliferation of gastric malignancies through alteration of cell invasion, apoptosis, progression through the cell cycle and cell growth. The macrocalyxin C→miR-212-3p┤Sox6 signal pathway was identified to be involved in Sox6 attenuation through augmentation of miR-212-3p values.
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Affiliation(s)
- Yini Dang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - TingYu Liu
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Affiliated Zhongshan Hospital of fudan university, Shanghai, China
| | - Jin Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Jan D Reinhardt
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, Sichuan Province, China; Epidemiology of Functioning, Swiss Paraplegic Research, Nottwil, Switzerland
| | - Chengqiang Yin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China; Department of Gastroenterology, Sir Run Run Hospital Affiliated with Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Feng Ye
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China
| | - Guoxin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; First Clinical Medical College of Nanjing Medical University, Nanjin, Jiangsu Province, China.
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24
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Chen W, Song J, Bian H, Yang X, Xie X, Zhu Q, Qin C, Qi J. The functions and targets of miR-212 as a potential biomarker of cancer diagnosis and therapy. J Cell Mol Med 2020; 24:2392-2401. [PMID: 31930653 PMCID: PMC7028855 DOI: 10.1111/jcmm.14966] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 12/17/2019] [Accepted: 12/22/2019] [Indexed: 12/14/2022] Open
Abstract
Cancer is a major health problem worldwide. An increasing number of researchers are studying the diagnosis, therapy and mechanisms underlying the development and progression of cancer. The study of noncoding RNA has attracted a lot of attention in recent years. It was found that frequent alterations of miRNA expression not only have various functions in cancer but also that miRNAs can act as clinical markers of diagnosis, stage and progression of cancer. MiR-212 is an important example of miRNAs involved in cancer. According to recent studies, miR-212 may serve as an oncogene or tumour suppressor by influencing different targets or pathways during the oncogenesis and the development and metastasis of cancer. Its deregulation may serve as a marker for the diagnosis or prognosis of cancer. In addition, it was recently reported that miR-212 was related to the sensitivity or resistance of cancer cells to chemotherapy or radiotherapy. Here, we summarize the current understanding of miR-212 functions in cancer by describing the relevant signalling pathways and targets. The role of miR-212 as a biomarker and its therapeutic potential in cancer is also described. The aim of this review was to identify new methods for the diagnosis and treatment of human cancers.
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Affiliation(s)
- Wenjun Chen
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Jing Song
- Departments of Gastroenterology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Qingdao, China
| | - Hongjun Bian
- Departments of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xia Yang
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Xiaoyu Xie
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Qiang Zhu
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Chengyong Qin
- Departments of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Jianni Qi
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
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Wu S, Ai H, Zhang K, Yun H, Xie F. Long Non-Coding RNA EGOT Promotes the Malignant Phenotypes of Hepatocellular Carcinoma Cells and Increases the Expression of HMGA2 via Down-Regulating miR-33a-5p. Onco Targets Ther 2019; 12:11623-11635. [PMID: 32021242 PMCID: PMC6942514 DOI: 10.2147/ott.s218308] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 10/25/2019] [Indexed: 12/28/2022] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). EGOT is a long non-coding RNA (lncRNA) induced after HCV infection that increases viral replication by antagonizing the antiviral response. Interestingly, EGOT also acts as a crucial regulator in multiple cancers. However, its role in HCC remains unclear. Methods Real-time PCR (RT-PCR) was used to detect the expression of EGOT in HCC samples and cell lines. CCK-8 assay and colony formation assay were performed to evaluate the effect of EGOT on proliferation. Scratch healing assay and transwell assay were used to detect the changes of migration and invasion. Flow cytometry was used to detect the effect of EGOT on apoptosis. Interaction between EGOT and miR-33a-5p was determined by bioinformatics analysis, RT-PCR, and dual-luciferase reporter assay. Western blot was used to confirm that high mobility group protein A2 (HMGA2) could be modulated by EGOT. Results Compared with normal liver tissues, the expression level of EGOT in HCC tissues was significantly up-regulated. EGOT markedly regulated viability, migration and invasion of HCC cells. The expression level of EGOT was negatively correlated the expression level of miR-33a-5p. It is also confirmed that EGOT could specifically bind to miR-33a-5p and could reduce its expression, in turn, up-regulate the expression of HMGA2. Conclusion Our data imply that EGOT may be a novel therapeutic target for HCC, and highlights the key role of EGOT/miR-33a-5p/HMGA2 in the progression of this deadly disease.
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Affiliation(s)
- Shimin Wu
- Center for Clinical Laboratory, General Hospital of the Yangtze River Shipping, Wuhan Brain Hospital, Wuhan 430030, People's Republic of China
| | - Hongwu Ai
- Center for Clinical Laboratory, Wuhan Kangjian Maternal and Infant Hospital, Wuhan 430050, People's Republic of China
| | - Kehui Zhang
- Wuhan Center for Clinical Laboratory, Wuhan Fourth Hospital, Wuhan 430030, People's Republic of China.,Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, People's Republic of China
| | - Hao Yun
- Wuhan Center for Clinical Laboratory, Wuhan Fourth Hospital, Wuhan 430030, People's Republic of China.,Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, People's Republic of China
| | - Fei Xie
- Wuhan Center for Clinical Laboratory, Wuhan Fourth Hospital, Wuhan 430030, People's Republic of China.,Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, People's Republic of China
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26
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Zare A, Ganji M, Omrani MD, Alipoor B, Ghaedi H. Gastric Cancer MicroRNAs Meta-signature. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2019; 8:94-102. [PMID: 32215261 DOI: 10.22088/ijmcm.bums.8.2.94] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 08/14/2019] [Indexed: 12/19/2022]
Abstract
Gastric cancer (GC) is one of the most common types of cancer and the second leading cause of cancer-associated mortality. Identification of novel biomarkers is critical to prolonging patient survival. MicroRNAs (miRNAs) proved to play diverse roles in the physiological and pathological state in cancers including GC. Herein we aimed at performing a meta-analysis on miRNA profiling studies that used microarray platforms. Relevant studies were retrieved from PubMed and GEO databases. We used the robust rank aggregation to perform the meta-analysis. Moreover, for meta-signature miRNAs target genes, we performed pathway enrichment and GO molecular function enrichment analysis. A total of 19 upregulated miRNAs and seven downregulated miRNAs in GC samples were identified. However, only three upregulated and one downregulated miRNA reached statistical significance after multiple test correction. Here we showed that hsa-miR-21-5p, hsa-miR-93-5p, hsa-miR-25-3p, and hsa-miR-375 are differentially expressed in GC samples.
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Affiliation(s)
- Ali Zare
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maziar Ganji
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mir Davood Omrani
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behnam Alipoor
- Department of Laboratory Sciences, Faculty of Para medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hamid Ghaedi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wu X, Chen H, Zhang G, Wu J, Zhu W, Gu Y, He Y. MiR-212-3p inhibits cell proliferation and promotes apoptosis by targeting nuclear factor IA in bladder cancer. J Biosci 2019. [DOI: 10.1007/s12038-019-9903-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Jia P, Wei G, Zhou C, Gao Q, Wu Y, Sun X, Li X. Upregulation of MiR-212 Inhibits Migration and Tumorigenicity and Inactivates Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma. Technol Cancer Res Treat 2019; 17:1533034618765221. [PMID: 29618288 PMCID: PMC5894900 DOI: 10.1177/1533034618765221] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma-related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated. MATERIALS AND METHODS Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212. RESULTS In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/β-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear β-catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth. CONCLUSION Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment.
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Affiliation(s)
- Pengbo Jia
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,2 Department of General Surgery, The First People's Hospital of Xianyang City, Xianyang, China
| | - Guangbing Wei
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Cancan Zhou
- 3 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qi Gao
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yunhua Wu
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuejun Sun
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuqi Li
- 1 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Wang S, Ran L, Zhang W, Leng X, Wang K, Liu G, Song J, Wang Y, Zhang X, Wang Y, Zhang L, Ma Y, Liu K, Li H, Zhang W, Qin G, Song F. FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer. Sci Rep 2019; 9:5281. [PMID: 30918291 PMCID: PMC6437149 DOI: 10.1038/s41598-019-41717-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 03/14/2019] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer (GC) is the fourth most common malignant neoplasm and the second leading cause of cancer death. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression facilitates early GC diagnosis and the development of targeted therapies for advanced GC patients. Emerging evidence has revealed a close correlation between forkhead box (FOX) proteins and cancer development. However, the prognostic significance of forkhead box S1 (FOXS1) in patients with GC and the function of FOXS1 in GC progression remain undefined. In this study, we found that upregulation of FOXS1 was frequently detected in GC tissues and strongly correlated with an aggressive phenotype and poor prognosis. Functional assays confirmed that FOXS1 knockdown suppressed cell proliferation and colony numbers, with induction of cell arrest in the G0/G1 phase of the cell cycle, whereas forced expression of FOXS1 had the opposite effect. Additionally, forced expression of FOXS1 accelerated tumor growth in vivo and increased cell migration and invasion through promoting epithelial–mesenchymal transition (EMT) both in vitro and in vivo. Mechanistically, the core promoter region of FOXS1 was identified at nucleotides −660~ +1, and NFKB1 indirectly bind the motif on FOXS1 promoters and inhibit FOXS1 expression. Gene set enrichment analysis revealed that the FOXS1 gene was most abundantly enriched in the hedgehog signaling pathway and that GLI1 expression was significantly correlated with FOXS1 expression in GC. GLI1 directly bound to the promoter motif of FOXS1 and significantly decreased FOXS1 expression. Finally, we found that miR-125a-5p repressed FOXS1 expression at the translational level by binding to the 3′ untranslated region (UTR) of FOXS1. Together, these results suggest that FOXS1 can promote GC development and could be exploited as a diagnostic and prognostic biomarker for GC.
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Affiliation(s)
- Sen Wang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Longke Ran
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China.,Department of Bioinformatics, Chongqing Medical University, Chongqing, 400016, China
| | - Wanfeng Zhang
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China.,Department of Bioinformatics, Chongqing Medical University, Chongqing, 400016, China
| | - Xue Leng
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Kexin Wang
- Department of Radiology, Affiliated Hospital of Southwest Medical University, Sichuan Province, 646000, China
| | - Geli Liu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Jing Song
- Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China.,Department of Bioinformatics, Chongqing Medical University, Chongqing, 400016, China
| | - Yujing Wang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Xianqin Zhang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Yitao Wang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Lian Zhang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Yan Ma
- Information Technology Office of Chongqing Medical University, Chongqing, 400016, China
| | - Kun Liu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China
| | - Haiyu Li
- Chongqing Public Health Medical Center, Chongqing Medical University, Chongqing, 400016, China
| | - Wei Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guijun Qin
- Department of Endocrinology of the Frist Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Fangzhou Song
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China. .,Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, 400016, China.
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Chen W, Zhou Y, Zhi X, Ma T, Liu H, Chen BW, Zheng X, Xie S, Zhao B, Feng X, Dang X, Liang T. Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin. Biomaterials 2019; 192:590-600. [PMID: 30553134 DOI: 10.1016/j.biomaterials.2018.11.035] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 11/15/2018] [Accepted: 11/29/2018] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a destructive cancer with poor prognosis. Both novel therapeutic targets and approaches are needed to improve the overall survival of PDAC patients. MicroRNA-212 (miR-212) has been reported as a tumor suppressor in multiple cancers, but its definitive role and exact mechanism in the progression of pancreatic cancer is unclear. In this study, we developed a new chimeric peptide (PL-1) composed of plectin-1-targeted PDAC-specific and arginine-rich RNA-binding motifs which could condense miRNA to self-assemble supramolecular nanoparticles. These nanoparticles could deliver miR-212 into PDAC cells specifically and efficiently which also showed good stability in RNase and serum. Moreover, we demonstrated that PL-1/miR-212 nanoparticles could dramatically enhance the chemotherapeutic effect of doxorubicin for PDAC both in vitro and in vivo. In terms of mechanism, combined miR-212 intervention by PL-1/miR-212 nanoparticles resulted in obvious decrease of USP9X expression (ubiquitin specific peptidase 9, X-linked, USP9X) and eventually enhanced the doxorubicin induced apoptosis and autophagy of PDAC cells. These findings provide a new promising anti-cancer strategy via PL-1/miR-212 nanoparticles and identify miR-212/USP9X as a new potential target for future systemic therapy against human PDAC.
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Affiliation(s)
- Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Zhi
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Ma
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hao Liu
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Brayant Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoxiao Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shangzhi Xie
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Bin Zhao
- Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China
| | - Xinhua Feng
- Life Sciences Institute, Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China
| | - Xiaowei Dang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
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Xu XC, Zhang WB, Li CX, Gao H, Pei Q, Cao BW, He TH. Up-Regulation of MiR-1915 Inhibits Proliferation, Invasion, and Migration of Helicobacter pylori-Infected Gastric Cancer Cells via Targeting RAGE. Yonsei Med J 2019; 60:38-47. [PMID: 30554489 PMCID: PMC6298885 DOI: 10.3349/ymj.2019.60.1.38] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/05/2018] [Accepted: 11/20/2018] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Helicobacter pylori (HP)-infected gastric cancer (GC) is known to be a fatal malignant tumor, but the molecular mechanisms underlying its proliferation, invasion, and migration remain far from being completely understood. Our aim in this study was to explore miR-1915 expression and its molecular mechanisms in regulating proliferation, invasion, and migration of HP-infected GC cells. MATERIALS AND METHODS Quantitative real-time PCR and western blot analysis were performed to determine miR-1915 and receptor for advanced glycation end product (RAGE) expression in HP-infected GC tissues and gastritis tissues, as well as human gastric mucosal cell line GES-1 and human GC cell lines SGC-7901 and MKN45. CCK8 assay and transwell assay were performed to detect the proliferation, invasion, and migration capabilities. MiR-1915 mimics and miR-1915 inhibitor were transfected into GC cells to determine the target relationship between miR-1915 and RAGE. RESULTS MiR-1915 was under-expressed, while RAGE was over-expressed in HP-infected GC tissues and GC cells. Over-expressed miR-1915 could attenuate cellular proliferation, invasion, and migration capacities. RAGE was confirmed to be the target gene of miR-1915 by bioinformatics analysis and luciferase reporter assay. Moreover, HP-infected GC cellular proliferation, invasion, and migration were inhibited after treatment with pcDNA-RAGE. CONCLUSION MiR-1915 exerted tumor-suppressive effects on cellular proliferation, invasion, and migration of HP-infected GC cells via targeting RAGE, which provided an innovative target candidate for treatment of HP-infected GC.
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Affiliation(s)
- Xin Cai Xu
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wen Bin Zhang
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
| | - Chun Xing Li
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hua Gao
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Qi Pei
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Bo Wei Cao
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Tie Han He
- Department of Gastrointestinal Tumor, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
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32
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Li H, Tian G, Tian F, Shao L. Long non-coding RNA TUG1 promotes osteosarcoma cell proliferation and invasion through inhibition of microRNA-212-3p expression. Exp Ther Med 2018; 16:779-787. [PMID: 30116332 PMCID: PMC6090373 DOI: 10.3892/etm.2018.6216] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Accepted: 04/20/2018] [Indexed: 12/14/2022] Open
Abstract
Taurine upregulated gene 1 (TUG1), a long non-coding RNA (lncRNA), has recently been suggested to be associated with the development of osteosarcoma (OS), but the underlying molecular mechanism still remains largely unclear. In the present study, it was revealed that TUG1 was significantly upregulated whereas miR-212-3p was significantly downregulated in OS tissues and cell lines, when compared with adjacent non-tumor tissues and normal osteoblasts cell lines, respectively. An inverse association between the TUG1 and miR-212-3p expression was also observed in OS tissues. Furthermore, TUG1 directly interacted with miR-212-3p and negatively regulated the expression of miR-212-3p in OS cells. In vitro experiments further indicated that inhibition of TUG1 suppressed the proliferation and invasion of OS cells. Furthermore, knockdown of miR-212-3p eliminated the suppressive effects of TUG1 inhibition on the proliferation and invasion of OS cells. Taken together, these findings demonstrate that TUG1 promotes OS cell proliferation and invasion by inhibition of miR-212-3p expression, thus suggesting that TUG1 may become a potential therapeutic target for OS.
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Affiliation(s)
- Heng Li
- Department of Orthopedics, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Guofeng Tian
- Department of Orthopedics, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Feipeng Tian
- Department of Orthopedics, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
| | - Lin Shao
- Department of Orthopedics, Daqing Longnan Hospital, Daqing, Heilongjiang 163453, P.R. China
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Splicing factors as regulators of miRNA biogenesis – links to human disease. Semin Cell Dev Biol 2018; 79:113-122. [DOI: 10.1016/j.semcdb.2017.10.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 10/09/2017] [Accepted: 10/09/2017] [Indexed: 12/16/2022]
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35
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Park JK, Doseff AI, Schmittgen TD. MicroRNAs Targeting Caspase-3 and -7 in PANC-1 Cells. Int J Mol Sci 2018; 19:E1206. [PMID: 29659498 PMCID: PMC5979519 DOI: 10.3390/ijms19041206] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs), a critical part of the RNA silencing machinery, are known to play important regulatory roles in cancer. However, the consequence of miRNA deregulation in cancer is unknown for many miRNAs. Here, we define that miRNAs, miR-17-5p, miR-132-3p/-212-3p, and miR-337-3p are significantly up-regulated in the pancreatic ductal adenocarcinomas (PDAC) compared to the normal and benign tissues. Furthermore, by using PANC-1 cells, we demonstrate that overexpressed miR-337-3p and miR-17-5p/miR-132-3p/-212-3p can regulate executioner caspases-3 and -7, respectively. In addition, over-expression of miRNAs, especially miR-337-3p, attenuates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity in PANC-1 cells. Our findings unveil an important biological function for miRNAs up-regulated in PDAC in coordinately regulating caspases, potentially contributing to the malignant progression of PDAC.
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Affiliation(s)
- Jong Kook Park
- Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 24252, Korea.
| | - Andrea I Doseff
- Department of Physiology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
| | - Thomas D Schmittgen
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
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36
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Xia L, Li D, Lin C, Ou S, Li X, Pan S. Comparative study of joint bioinformatics analysis of underlying potential of 'neurimmiR', miR-212-3P/miR-132-3P, being involved in epilepsy and its emerging role in human cancer. Oncotarget 2018; 8:40668-40682. [PMID: 28380454 PMCID: PMC5522300 DOI: 10.18632/oncotarget.16541] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/20/2017] [Indexed: 12/27/2022] Open
Abstract
Considering the critical roles of miR-132/212 participated in central nervous system, many researches started to explored the contributions of miR-132/212 to epilepsy and achieve something worthwhile. Further illuminates all the genes targeted by miR-132/212 may be a valuable means for us to completely understand the working mechanism playing in epilepsy, by which it can influence diverse biological process. This study attempts to establish macrocontrol regulation system and knowledge that miR-212-3p/132-3p effected the epilepsy, for this literature search, miRbase, Vienna RNAfold webserver, Human miRNA tissue atlas, DIANA-TarBase, miRtarbase, STRING, TargetScanhuman, Cytoscape plugin ClueGO + Cluepedia+STRING, DAVID Bioinformatics Resources, Starbase, GeneCards suite and GEO database are comprehensive employed, miR-132-3p/212-3p and its target gene were found have highly expressed in brain and lots of molecular function and metabolic pathways associated with epilepsy may be intervened by it. Meanwhile, the emerging role of miR-132-3p/212-3p being involved in human cancer also been analyzed by several webtools for TCGA data integrative analysis, most remarkably and well worth exploring in our research conclusion that showed miR-132-3p/212-3p may be the core molecular underlying tumor-induced epileptogenesis.
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Affiliation(s)
- Lu Xia
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Provinces, China
| | - Daojiang Li
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Changwei Lin
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China.,Center for Experimental Medicine, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Shuchun Ou
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Provinces, China
| | - Xiaorong Li
- Department of General Surgery, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China.,Center for Experimental Medicine, The Third XiangYa Hospital of Central South University, Changsha, Hunan 410013, China
| | - Songqing Pan
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Provinces, China
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Zhu F, Wu Q, Ni Z, Lei C, Li T, Shi Y. miR-19a/b and MeCP2 repress reciprocally to regulate multidrug resistance in gastric cancer cells. Int J Mol Med 2018; 42:228-236. [PMID: 29568890 PMCID: PMC5979884 DOI: 10.3892/ijmm.2018.3581] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 02/20/2018] [Indexed: 12/18/2022] Open
Abstract
Despite the improvement in gastric cancer (GC) treatment, multidrug resistance (MDR) is still a significant reason for chemotherapy failure. Our previous studies have demonstrated that miR-19a/b upregulation directly promoted MDR in GC cells. However, the exact regulation and the potential molecule mechanisms have not been fully clarified. In this study, we found that miR-19a/b was directly involved in 5-aza-2'-deoxycytidine (5-Aza-dC) induced MDR of GC cells. Mechanically, demethylation of miR-19a/b repressed methyl CpG binding protein 2 (MeCP2) expression via direct binding at the 3'-untranslated regions, which then alleviated the inhibitory effects of MeCP2 on miR-19a/b expression. Thus, the mutual regulatory network sustains preservation of the expression levels of miR-19a/b. We further demonstrated that miR-19a/b expression was inversely correlated to MeCP2 expression in GC tissues. These data showed an intimate interplay among miR-19a/b methylation, MeCP2 activity, and MDR, revealing a potential therapeutic target for GC.
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Affiliation(s)
- Fei Zhu
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Qiong Wu
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Zhen Ni
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Chao Lei
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Ting Li
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Yongquan Shi
- State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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Hu B, Jin X, Wang J. MicroRNA-212 Targets Mitogen-Activated Protein Kinase 1 to Inhibit Proliferation and Invasion of Prostate Cancer Cells. Oncol Res 2018; 26:1093-1102. [PMID: 29321092 PMCID: PMC7844748 DOI: 10.3727/096504018x15154112497142] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Prostate cancer (PCa) is the second most commonly diagnosed malignancy and the fifth leading cause of cancer-related deaths in males worldwide. MicroRNAs (miRNAs) may serve as important regulators in PCa occurrence and development. Therefore, understanding the expression and functions of PCa-related miRNAs may be beneficial for the identification of novel therapeutic methods for patients with PCa. In this study, miRNA-212 (miR-212) was evidently downregulated in PCa tissues and several PCa cell lines. Functional assays showed that the resumption of miR-212 expression attenuated cell proliferation and invasion and increased the apoptosis of PCa. In addition, mitogen-activated protein kinase 1 (MAPK1), a well-known oncogene, was identified as a novel target of miR-212 in PCa, as confirmed by bioinformatics, luciferase reporter assay, qRT-PCR, and Western blot analysis. Furthermore, MAPK1 expression was upregulated in PCa tissues and inversely correlated with miR-212 expression. Rescue experiments also demonstrated that restored MAPK1 expression reversed the tumor-suppressing effects of miR-212 on PCa cell proliferation, invasion, and apoptosis. In conclusion, miR-212 may exert tumor-suppressing roles in PCa by regulating MAPK1 and could be a novel therapeutic target for treatment of patients with this malignancy.
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Affiliation(s)
- Bo Hu
- Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Xunbo Jin
- Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China
| | - Jianbo Wang
- Department of Oncology, Qilu Hospital of Shandong University, Shandong, P.R. China
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MECP2 promotes the growth of gastric cancer cells by suppressing miR-338-mediated antiproliferative effect. Oncotarget 2017; 7:34845-59. [PMID: 27166996 PMCID: PMC5085194 DOI: 10.18632/oncotarget.9197] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 03/31/2016] [Indexed: 12/30/2022] Open
Abstract
The methyl-CpG-binding protein 2 (MECP2), a transcriptional suppressor, is involved in gene regulation by binding to methylated promoters. We found that MECP2 is overexpressed in gastric cancer (GC), and that Mecp2 knockdown affects the growth of GC cells both in vitro and in vivo. MECP2 can directly bind to the methylated-CpG island of miR-338 promoter and suppress the expression of two mature microRNAs, namely, miR-338-3p and miR-338-5p. Furthermore, miR-338-5p can suppress GC cell growth by targeting BMI1 (B lymphoma Mo-MLV insertion region 1 homolog). We additionally found that decreased miR-338-5p expression in GC tissues, relative to normal tissues, was significantly negatively correlated with increased BMI1 expression. Silencing MECP2 can indirectly lead to reduced expression of P-REX2, which has been identified as the miR-338-3p target, as well as BMI1 and increasing expression of P16 or P21 both in vitro and in vivo. Altogether, our results indicate that MECP2 promote the proliferation of GC cells via miR-338 (miR-338-3p and miR-338-5p)-mediated antitumor and gene regulatory effect.
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Gu C, Wang Z, Jin Z, Li G, Kou Y, Jia Z, Yang J, Tian F. MicroRNA-212 inhibits the proliferation, migration and invasion of renal cell carcinoma by targeting X-linked inhibitor of apoptosis protein (XIAP). Oncotarget 2017; 8:92119-92133. [PMID: 29190902 PMCID: PMC5696168 DOI: 10.18632/oncotarget.20786] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/28/2017] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs have been found to be critical regulator of cancer cell biology. MicroRNA-212 (miR-212) was identified to be a critical cancer-associated microRNA playing either oncogenic functions or tumor suppressive roles in different types of human cancers. In this study, we found that the level of miR-212 in renal cell carcinoma (RCC) tissues was significantly lower than that in adjacent non-tumor tissues. Decreased level of miR-212 was associated with advanced T stage and TNM stage of RCC. The expression of miR-212 was decreased in RCC cell lines as compared with the HK-2 cell line. Overexpression of miR-212 inhibited cell viability, proliferation, migration and invasion of CAKI-2 cells. Knockdown of miR-212 increased cell viability and proliferation, migration and invasion of ACHN cells. In vivo experiments showed that miR-212 inhibited the proliferation and promoted the apoptosis of ACHN cells in nude mice and thus inhibited the in vivo tumor growth of CAKI-2 cells. Furthermore, we confirmed that X-linked inhibitor of apoptosis protein (XIAP) was the downstream target of miR-212. The expression level of miR-212 was negatively correlated with XIAP expression in RCC tissues. Moreover, XIAP mediated the tumor suppressive roles of miR-212 in RCC. Finally, we demonstrated that the aberrant expression of miR-212 and XIAP was evidently correlated with poor prognosis of RCC patients. In all, miR-212 can act as a prognostic biomarker for RCC patients and inhibits the growth and metastasis of RCC cells by inhibiting XIAP.
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Affiliation(s)
- Chaohui Gu
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhiyu Wang
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhibo Jin
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Guanru Li
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yiping Kou
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhankui Jia
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jinjian Yang
- Department of Urology and Henan Institute of Urology, Zhengzhou Key Laboratory for Molecular Biology of Urological Tumor Research, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Fengyan Tian
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Tang T, Huan L, Zhang S, Zhou H, Gu L, Chen X, Zhang L. MicroRNA-212 functions as a tumor-suppressor in human non-small cell lung cancer by targeting SOX4. Oncol Rep 2017; 38:2243-2250. [DOI: 10.3892/or.2017.5885] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 07/21/2017] [Indexed: 11/05/2022] Open
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Wu WS, Tu BW, Chen TT, Hou SW, Tseng JT. CSmiRTar: Condition-Specific microRNA targets database. PLoS One 2017; 12:e0181231. [PMID: 28704505 PMCID: PMC5509330 DOI: 10.1371/journal.pone.0181231] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 06/28/2017] [Indexed: 01/11/2023] Open
Abstract
MicroRNAs (miRNAs) are functional RNA molecules which play important roles in the post-transcriptional regulation. miRNAs regulate their target genes by repressing translation or inducing degradation of the target genes’ mRNAs. Many databases have been constructed to provide computationally predicted miRNA targets. However, they cannot provide the miRNA targets expressed in a specific tissue and related to a specific disease at the same time. Moreover, they cannot provide the common targets of multiple miRNAs and the common miRNAs of multiple genes at the same time. To solve these two problems, we construct a database called CSmiRTar (Condition-Specific miRNA Targets). CSmiRTar collects computationally predicted targets of 2588 human miRNAs and 1945 mouse miRNAs from four most widely used miRNA target prediction databases (miRDB, TargetScan, microRNA.org and DIANA-microT) and implements functional filters which allows users to search (i) a miRNA’s targets expressed in a specific tissue or/and related to a specific disease, (ii) multiple miRNAs’ common targets expressed in a specific tissue or/and related to a specific disease, (iii) a gene’s miRNAs related to a specific disease, and (iv) multiple genes’ common miRNAs related to a specific disease. We believe that CSmiRTar will be a useful database for biologists to study the molecular mechanisms of post-transcriptional regulation in human or mouse. CSmiRTar is available at http://cosbi.ee.ncku.edu.tw/CSmiRTar/ or http://cosbi4.ee.ncku.edu.tw/CSmiRTar/.
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Affiliation(s)
- Wei-Sheng Wu
- Department of Electrical Engineering, National Cheng Kung University, Tainan, Taiwan
- * E-mail: (WSW); (JTT)
| | - Bor-Wen Tu
- Department of Electrical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Tsung-Te Chen
- Department of Electrical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Wei Hou
- Department of Electrical Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Joseph T. Tseng
- Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan
- * E-mail: (WSW); (JTT)
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Zhou Y, Ji Z, Yan W, Zhou Z, Li H. The biological functions and mechanism of miR‑212 in prostate cancer proliferation, migration and invasion via targeting Engrailed-2. Oncol Rep 2017; 38:1411-1419. [PMID: 28713997 PMCID: PMC5549026 DOI: 10.3892/or.2017.5805] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 07/06/2017] [Indexed: 11/06/2022] Open
Abstract
Accumulating evidence indicates that Engrailed-2 (EN-2), which is a homeobox-containing transcription factor, act as a candidate oncogene in prostate cancer (PCa). Even though there are some treatments targeting EN-2, however, it is limited because the mechanism of EN-2 upregulation in PCa cells is still unknown. In this study, we investigate the role of miR‑212 on EN-2 expression and explored the mechanism of prostate cancer survival and metastasis. The relative expression levels of miR‑212 and EN-2 in PCa samples and adjacent normal tissues as well as in PCa cell lines were detected by using quantitative real-time PCR. CCK-8, TUNEL and Transwell assays were used to analyze cell proliferation, apoptosis and invasion, respectively. EN-2 was identified as a direct target of miR‑212 via luciferase reporter and western blot assays. Results showed that the expression level of miR‑212 was downregulated in both PCa samples and PCa cell lines when compared with prostate epithelial cells and the adjacent no tumor tissues. Moreover, we found that overexpression of miR‑212 suppressed PCa cell proliferation and invasion, promoted PCa cell apoptosis. EN-2 was identified as a direct target gene of miR‑212 by using luciferase reporter and western blot assays. Also, the expression of EN-2 and miR‑212 in the PCa cells had an opposite correlation. The critical role of miR‑212 in inhibiting prostate tumor growth was verified in xenograft models of prostate cancer. These findings highlighted the role of miR‑212 in PCa progression. More importantly, we speculate that EN-2 is a direct target gene of miR‑212.
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Affiliation(s)
- Yi Zhou
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Weigang Yan
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Zhien Zhou
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
| | - Hanzhong Li
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100000, P.R. China
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Friedman A, Hao W. The Role of Exosomes in Pancreatic Cancer Microenvironment. Bull Math Biol 2017; 80:1111-1133. [PMID: 28382422 DOI: 10.1007/s11538-017-0254-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 02/03/2017] [Indexed: 12/11/2022]
Abstract
Exosomes are nanovesicles shed by cells as a means of communication with other cells. Exosomes contain mRNAs, microRNAs (miRs) and functional proteins. In the present paper, we develop a mathematical model of tumor-immune interaction by means of exosomes shed by pancreatic cancer cells and dendritic cells. Cancer cells' exosomes contain miRs that promote their proliferation and that inhibit immune response by dendritic cells, and by CD4+ and CD8+ T cells. Dendritic cells release exosomes with proteins that induce apoptosis of cancer cells and that block regulatory T cells. Simulations of the model show how the size of the pancreatic cancer can be determined by measurement of specific miRs (miR-21 and miR-203 in the case of pancreatic cancer), suggesting these miRs as biomarkers for cancer.
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Affiliation(s)
- Avner Friedman
- Department of Mathematics, Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, USA
| | - Wenrui Hao
- Department of Mathematics, Pennsylvania State University, University Park, PA, 16802, USA.
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Abstract
microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper- and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.
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Affiliation(s)
- Sumei Wang
- a Department of Oncology , Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, Guangdong , P. R. China.,b Department of Systems Biology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Wanyin Wu
- a Department of Oncology , Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, Guangdong , P. R. China
| | - Francois X Claret
- b Department of Systems Biology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.,c Experimental Therapeutics Academic Program and Cancer Biology Program , The University of Texas Graduate School of Biomedical Sciences at Houston , Houston , TX , USA
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Azarnezhad A, Mehdipour P. Cancer Genetics at a Glance: The Comprehensive Insights. CANCER GENETICS AND PSYCHOTHERAPY 2017:79-389. [DOI: 10.1007/978-3-319-64550-6_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Fu W, Tao T, Qi M, Wang L, Hu J, Li X, Xing N, Du R, Han B. MicroRNA-132/212 Upregulation Inhibits TGF-β-Mediated Epithelial-Mesenchymal Transition of Prostate Cancer Cells by Targeting SOX4. Prostate 2016; 76:1560-1570. [PMID: 27527117 DOI: 10.1002/pros.23241] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Accepted: 07/21/2016] [Indexed: 01/02/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) are noncoding RNAs that are important for embryonic stem cell development and epithelial to mesenchymal transition (EMT). Accumulating evidence indicates that miRNAs play critical roles in prostate cancer (PCa) metastasis and have potential use as therapeutic targets. Although dysregulated miR-132/212 have been suggested to be directly involved in the proliferation and invasion of multiple malignancies, the exact role of miR-132/212 in PCa has not yet been fully understood. METHODS Real-time quantitative PCR (RT-qPCR) and bioinformatics analysis were used to validate the expression levels of miR-132/212 in PCa cell lines as well as in prostatic tissues. The biological function of miR-132/212 was evaluated by MTS, transwell, and wound healing assays, respectively. RT-qPCR and Western blot were used to study the transcript and protein expression levels. Bioinformatics tools and luciferase reporter assay were utilized to identify the molecular target of miR-132/212. Immunohistochemistry (IHC) was used to detect the expression of SOX4. RESULTS miR-132 and miR-212 from the same gene cluster are downregulated in human PCa tissues when compared with benign prostatic hyperplasia tissues (both P < 0.05). Functionally, upregulation of miR-132/212 inhibits the migration and invasive capacity of Vcap and Lncap cells by wound-healing and transwell assays, respectively. Notably, overexpression of miR-132/212 could inhibit TGF-β (transforming growth factor-β)-induced EMT in Vcap and Lncap cells at both the mRNA and protein expression levels. SOX4 gene, an important EMT regulator of PCa, was identified as the target of miR-132/212 by bioinformatics tools and luciferase reporter assay. Clinically, miR-132/212 expression levels were adversely correlated with Gleason score (P < 0.001) and SOX4 expression by IHC and RT-qPCR in PCa tissues. CONCLUSION Our data suggested that miR-132/212 may act as tumor suppressors in PCa progression through disrupting EMT process by directly targeting SOX4. Prostate 76:1560-1570, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Weiwei Fu
- Department of Pathology, Shandong University Medical School, Jinan, China
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tao Tao
- Department of Urology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Mei Qi
- Department of Pathology, Shandong University Medical School, Jinan, China
| | - Lin Wang
- Research Center for Medicinal Biotechnology, Shandong Academy of Medicinal Sciences, Jinan, China
| | - Jing Hu
- Department of Pathology, Shandong University Medical School, Jinan, China
| | - Xinjun Li
- Department of Pathology, Binzhou People's Hospital, Binzhou, China
| | - Naidong Xing
- Department of Urology, Qilu Hospital of Shandong University, Jinan, China
| | - Ran Du
- Department of Human Biology, University of Toronto, Toronto, Canada
| | - Bo Han
- Department of Pathology, Shandong University Medical School, Jinan, China.
- Department of Pathology, Qilu Hospital of Shandong University, Jinan, China.
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Liu J, Chen B, Yue B, Yang J. MicroRNA-212 suppresses the proliferation and migration of osteosarcoma cells by targeting forkhead box protein A1. Exp Ther Med 2016; 12:4135-4141. [PMID: 28101191 DOI: 10.3892/etm.2016.3880] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/06/2016] [Indexed: 12/16/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that function as critical gene regulators by targeting the 3' untranslated region (UTR) of mRNA, causing translational repression or mRNA degradation. Deregulation of specific miRNAs, including miR-212, has been identified in patients with osteosarcoma. However, the underlying mechanism is yet to be fully elucidated. The present study aimed to reveal the regulatory mechanism of miR-212 in osteosarcoma cell viability and migration. Quantitative polymerase chain reaction data revealed that miR-212 was significantly downregulated in osteosarcoma tissues compared with normal bone tissues. miR-212 was also downregulated in osteosarcoma cell lines compared with normal osteoblast cell lines. Overexpression of miR-212 significantly suppressed the viability and migration of human osteosarcoma MG-63 and Saos-2 cell lines. In addition, forkhead box protein A1 (FOXA1), an oncogene in osteosarcoma, was predicted to be a putative target of miR-212 by bioinformatical analysis. Furthermore, luciferase reporter assay data confirmed that miR-212 could directly bind to the seed sequences within the 3'UTR of FOXA1 mRNA, and miR-212 negatively mediated the protein levels of FOXA1 in osteosarcoma MG-63 and Saos-2 cells. Moreover, knockdown of FOXA1 also led to a significant decrease in the viability and migration of osteosarcoma MG-63 and Saos-2 cells and the expression levels of FOXA1 were significantly upregulated in osteosarcoma tissues and cell lines. These data suggest that miR-212 inhibits the viability and migration of osteosarcoma cells by targeting FOXA1. Accordingly, miR-212 may become a potential candidate for osteosarcoma therapy.
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Affiliation(s)
- Jian Liu
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Bohua Chen
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Bin Yue
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
| | - Junde Yang
- Department of Orthopedics, Eighth People's Hospital of Qingdao, Medical School of Qingdao University, Qingdao, Shandong 266100, P.R. China
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Zhu L, Huang F, Deng G, Nie W, Huang W, Xu H, Zheng S, Yi Z, Wan T. MicroRNA-212 targets FOXA1 and suppresses the proliferation and invasion of intrahepatic cholangiocarcinoma cells. Exp Ther Med 2016; 12:3790-3796. [PMID: 28105112 DOI: 10.3892/etm.2016.3824] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 06/20/2016] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs), which are a class of small RNAs, have been shown to negatively regulate the expression of their target genes by directly binding to the 3'-untranslated region (3'-UTR) of mRNA. miRNA dysregulation has been associated with the pathogenesis of numerous types of human cancer. However, the role of miRNAs in intrahepatic cholangiocarcinoma (ICC) has yet to be fully elucidated. The present study aimed to investigate the role of miR-212 in the growth and metastasis of ICC in vitro, as well as the underlying mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to examine mRNA and protein expression. An MTT assay and transwell assay were conducted to determine cell proliferation and invasion rates. The results of the RT-qPCR demonstrated that miR-212 was downregulated in the majority of investigated ICC tissues, as compared with their matched adjacent non-tumor tissues. In addition, miR-212 expression was shown to be markedly downregulated in three ICC cell lines, as compared with human intrahepatic biliary epithelial cells. Furthermore, restoration of miR-212 expression significantly suppressed the proliferation and invasion of ICC QBC939 cells. Forkhead box protein A1 (FOXA1) was predicted to be a putative target of miR-212 by bioinformatics analysis with TargetScan. Therefore, a luciferase reporter assay was conducted to confirm that miR-212 was able to directly bind to the 3'-UTR of FOXA1 mRNA. In addition, using western blot analysis, the protein expression of FOXA1 was shown to be negatively regulated by miR-212 in ICC QBC939 cells. In conclusion, it was demonstrated that FOXA1 was frequently upregulated in various ICC tissues and cell lines. The results of the present study suggested that miR-212 inhibits the proliferation and invasion of ICC cells by directly targeting FOXA1, and thus may be considered a potential candidate for the treatment of ICC.
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Affiliation(s)
- Lei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Feizhou Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Gang Deng
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Wanpin Nie
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Wei Huang
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Hongbo Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Shaopeng Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Zhongjie Yi
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Tao Wan
- Department of Hepatobiliary and Pancreatic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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